WO2018136961A1 - METHODS OF TREATING PATIENTS WITH A RETINOIC ACID RECEPTOR-α AGONIST AND AN ANTI-CD38 ANTIBODY - Google Patents
METHODS OF TREATING PATIENTS WITH A RETINOIC ACID RECEPTOR-α AGONIST AND AN ANTI-CD38 ANTIBODY Download PDFInfo
- Publication number
- WO2018136961A1 WO2018136961A1 PCT/US2018/014904 US2018014904W WO2018136961A1 WO 2018136961 A1 WO2018136961 A1 WO 2018136961A1 US 2018014904 W US2018014904 W US 2018014904W WO 2018136961 A1 WO2018136961 A1 WO 2018136961A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tamibarotene
- subject
- antibody
- cell
- treatment
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 45
- 239000000556 agonist Substances 0.000 title abstract description 71
- 102000006802 Retinoic Acid Receptor alpha Human genes 0.000 title 1
- 108091008726 retinoic acid receptors α Proteins 0.000 title 1
- 238000011282 treatment Methods 0.000 claims abstract description 93
- MUTNCGKQJGXKEM-UHFFFAOYSA-N tamibarotene Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1NC(=O)C1=CC=C(C(O)=O)C=C1 MUTNCGKQJGXKEM-UHFFFAOYSA-N 0.000 claims description 153
- 229950010130 tamibarotene Drugs 0.000 claims description 140
- 206010028980 Neoplasm Diseases 0.000 claims description 87
- 229960002204 daratumumab Drugs 0.000 claims description 69
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 52
- 201000011510 cancer Diseases 0.000 claims description 42
- 230000002489 hematologic effect Effects 0.000 claims description 28
- 208000034578 Multiple myelomas Diseases 0.000 claims description 26
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 claims description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 14
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 9
- 238000009097 single-agent therapy Methods 0.000 claims description 5
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 4
- 229940126634 CD38 inhibitor Drugs 0.000 claims description 3
- VJQALSOBHVEJQM-UHFFFAOYSA-N COCCOC1CCC(CC1)Nc1cc(=O)n(C)c2ccc(cc12)-c1cncs1 Chemical compound COCCOC1CCC(CC1)Nc1cc(=O)n(C)c2ccc(cc12)-c1cncs1 VJQALSOBHVEJQM-UHFFFAOYSA-N 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 abstract description 44
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 15
- 230000008901 benefit Effects 0.000 abstract description 7
- 238000002648 combination therapy Methods 0.000 abstract description 4
- 230000001413 cellular effect Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 107
- 101001112293 Homo sapiens Retinoic acid receptor alpha Proteins 0.000 description 89
- 102100023606 Retinoic acid receptor alpha Human genes 0.000 description 89
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 57
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 53
- 150000004492 retinoid derivatives Chemical class 0.000 description 46
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 39
- 229930002330 retinoic acid Natural products 0.000 description 38
- 230000000694 effects Effects 0.000 description 34
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 29
- 108020004999 messenger RNA Proteins 0.000 description 28
- 210000004881 tumor cell Anatomy 0.000 description 28
- 201000000050 myeloid neoplasm Diseases 0.000 description 26
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 22
- 239000003795 chemical substances by application Substances 0.000 description 19
- 150000001875 compounds Chemical class 0.000 description 19
- 230000014509 gene expression Effects 0.000 description 19
- 230000006698 induction Effects 0.000 description 19
- 239000000203 mixture Substances 0.000 description 17
- 230000001225 therapeutic effect Effects 0.000 description 17
- 239000000090 biomarker Substances 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 239000013610 patient sample Substances 0.000 description 15
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 description 14
- 208000025324 B-cell acute lymphoblastic leukemia Diseases 0.000 description 14
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 14
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 14
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 description 14
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 description 14
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 14
- 210000000822 natural killer cell Anatomy 0.000 description 14
- 241000699666 Mus <mouse, genus> Species 0.000 description 12
- 208000024891 symptom Diseases 0.000 description 12
- 102100038069 Interferon regulatory factor 8 Human genes 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 10
- 238000003501 co-culture Methods 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- 101001032345 Homo sapiens Interferon regulatory factor 8 Proteins 0.000 description 9
- 238000011284 combination treatment Methods 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 206010025323 Lymphomas Diseases 0.000 description 8
- 239000012472 biological sample Substances 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- 238000011081 inoculation Methods 0.000 description 8
- 108090000064 retinoic acid receptors Proteins 0.000 description 8
- 230000008685 targeting Effects 0.000 description 8
- 208000011691 Burkitt lymphomas Diseases 0.000 description 7
- 208000017604 Hodgkin disease Diseases 0.000 description 7
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 7
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 230000001684 chronic effect Effects 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 102000003702 retinoic acid receptors Human genes 0.000 description 7
- 238000010186 staining Methods 0.000 description 7
- 230000030833 cell death Effects 0.000 description 6
- 230000002055 immunohistochemical effect Effects 0.000 description 6
- 230000001939 inductive effect Effects 0.000 description 6
- 230000028327 secretion Effects 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 239000013543 active substance Substances 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 230000001419 dependent effect Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000003623 enhancer Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 230000006051 NK cell activation Effects 0.000 description 4
- 102000034527 Retinoid X Receptors Human genes 0.000 description 4
- 108010038912 Retinoid X Receptors Proteins 0.000 description 4
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000011198 co-culture assay Methods 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 238000011532 immunohistochemical staining Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 108010082117 matrigel Proteins 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000011269 treatment regimen Methods 0.000 description 4
- 230000005748 tumor development Effects 0.000 description 4
- 230000035899 viability Effects 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 3
- VVTNSTLJOVCBDL-UHFFFAOYSA-N 4-[[3,5-bis(trimethylsilyl)benzoyl]amino]benzoic acid Chemical compound C[Si](C)(C)C1=CC([Si](C)(C)C)=CC(C(=O)NC=2C=CC(=CC=2)C(O)=O)=C1 VVTNSTLJOVCBDL-UHFFFAOYSA-N 0.000 description 3
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 3
- 108090000672 Annexin A5 Proteins 0.000 description 3
- 102000004121 Annexin A5 Human genes 0.000 description 3
- 102000008070 Interferon-gamma Human genes 0.000 description 3
- 108010074328 Interferon-gamma Proteins 0.000 description 3
- 206010028811 Natural killer-cell leukaemia Diseases 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 208000015230 aggressive NK-cell leukemia Diseases 0.000 description 3
- 229960001445 alitretinoin Drugs 0.000 description 3
- 238000011393 cytotoxic chemotherapy Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 229960003130 interferon gamma Drugs 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 208000025113 myeloid leukemia Diseases 0.000 description 3
- 230000031942 natural killer cell mediated cytotoxicity Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000004797 therapeutic response Effects 0.000 description 3
- 230000009261 transgenic effect Effects 0.000 description 3
- 229960001727 tretinoin Drugs 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- 241000272517 Anseriformes Species 0.000 description 2
- 241000271566 Aves Species 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- 238000011579 SCID mouse model Methods 0.000 description 2
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 2
- 238000011292 agonist therapy Methods 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000001640 apoptogenic effect Effects 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000002458 cell surface marker Substances 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 230000002380 cytological effect Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- -1 elixirs Substances 0.000 description 2
- 230000009786 epithelial differentiation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 102000052645 human CD38 Human genes 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 238000013188 needle biopsy Methods 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 230000004983 pleiotropic effect Effects 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 210000003296 saliva Anatomy 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 238000011301 standard therapy Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000004114 suspension culture Methods 0.000 description 2
- 210000001138 tear Anatomy 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000011285 therapeutic regimen Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 235000019155 vitamin A Nutrition 0.000 description 2
- 239000011719 vitamin A Substances 0.000 description 2
- 229940045997 vitamin a Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- AKJHMTWEGVYYSE-AIRMAKDCSA-N 4-HPR Chemical compound C=1C=C(O)C=CC=1NC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-AIRMAKDCSA-N 0.000 description 1
- UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 1
- 102000000074 ADP-ribosyl Cyclase Human genes 0.000 description 1
- 108010080394 ADP-ribosyl Cyclase Proteins 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 241000282567 Macaca fascicularis Species 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 108700026244 Open Reading Frames Proteins 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 101150066717 Rara gene Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- SYESMXTWOAQFET-YCNIQYBTSA-N all-trans-3,4-didehydroretinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)C=CCC1(C)C SYESMXTWOAQFET-YCNIQYBTSA-N 0.000 description 1
- GGCUJPCCTQNTJF-FRCNGJHJSA-N all-trans-4-oxoretinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)C(=O)CCC1(C)C GGCUJPCCTQNTJF-FRCNGJHJSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 229950008343 amsilarotene Drugs 0.000 description 1
- 230000019552 anatomical structure morphogenesis Effects 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 210000002459 blastocyst Anatomy 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 239000002771 cell marker Substances 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000012829 chemotherapy agent Substances 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000008556 epithelial cell proliferation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 229950003662 fenretinide Drugs 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 201000006122 hypervitaminosis A Diseases 0.000 description 1
- 229940075628 hypomethylating agent Drugs 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 108010051621 interferon regulatory factor-8 Proteins 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229950007752 isatuximab Drugs 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 238000001531 micro-dissection Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 210000002445 nipple Anatomy 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000000771 oncological effect Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 210000000287 oocyte Anatomy 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 238000011499 palliative surgery Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 238000002135 phase contrast microscopy Methods 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 210000004915 pus Anatomy 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 231100000916 relative toxicity Toxicity 0.000 description 1
- 102000027483 retinoid hormone receptors Human genes 0.000 description 1
- 108091008679 retinoid hormone receptors Proteins 0.000 description 1
- 229960003471 retinol Drugs 0.000 description 1
- 235000020944 retinol Nutrition 0.000 description 1
- 239000011607 retinol Substances 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 102000005969 steroid hormone receptors Human genes 0.000 description 1
- 108020003113 steroid hormone receptors Proteins 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 210000003537 structural cell Anatomy 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 102000004217 thyroid hormone receptors Human genes 0.000 description 1
- 108090000721 thyroid hormone receptors Proteins 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
Definitions
- Retinoids are a class of compounds structurally related to vitamin A, comprising natural and synthetic compounds.
- retinoids Several series of retinoids have been found clinically useful in the treatment of dermatological and oncological diseases.
- Retinoic acid and its other naturally occurring retinoid analogs (9-cis retinoic acid, all-trans 3,4-didehydro retinoic acid, 4-oxo retinoic acid and retinol) are pleiotropic regulatory compounds that modulate the structure and function of a wide variety of inflammatory, immune and structural cells. They are important regulators of epithelial cell proliferation, differentiation and morphogenesis in lungs.
- Retinoids exert their biological effects through a series of hormone nuclear receptors that are ligand inducible transcription factors belonging to the
- the retinoid receptors are classified into two families, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), each consisting of three distinct subtypes ( ⁇ , ⁇ , and ⁇ ). Each subtype of the RAR gene family encodes a variable number of isoforms arising from differential splicing of two primary RNA transcripts. All-trans retinoic acid is the physiological hormone for the retinoic acid receptors and binds with
- Retinoids have anti-inflammatory effects, alter the progression of epithelial cell differentiation, and inhibit stromal cell matrix production. These properties have led to the development of topical and systemic retinoid therapeutics for dermatological disorders such as psoriasis, acne, and hypertrophic cutaneous scars. Other applications include the control of acute promyelocytic leukemia, adeno- and squamous cell carcinoma, and hepatic fibrosis.
- retinoids A limitation in the therapeutic use of retinoids has stemmed from the relative toxicity observed with the naturally occurring retinoids, all-trans retinoic acid and 9-cis retinoic acid. These natural ligands are non-selective in terms of RAR subtype and therefore have pleiotropic effects throughout the body, which are often toxic.
- RARA specific agonists have held high promise for the treatment of cancers and many have entered human clinical trials.
- RARA specific agonist only one RARA specific agonist, tamibarotene, has ever been approved for the treatment of cancer.
- tamibarotene is only approved in Japan and only for the treatment of acute promyelocytic leukemia, despite trials in the US and Europe.
- the disconnect between the theoretical efficacy of RARA agonists in cancer and the dearth of regulatory approvals for such agents raises the question of why such agonists are not effective and safe in humans. Therefore, there is a need to better understand why RARA agonists have not met their therapeutic potential.
- Cluster of differentiation 38 is a protein expressed on the surface, primarily on white blood cells, and considered a cell surface marker indicative of differentiation initiation. It functions as a cyclic ADP-ribose hydrolase which plays a role in cell signaling (Mehta, K. & Cheema, S., Leuk. Lymphoma, 32, 441-449 (1999)). It is generally found to be highly expressed in cells of the B-cell and plasma cell lineage. In multiple myeloma a subset of patients have high CD38 expression, which has led to the development of anti-CD38 therapeutic antibodies, such as daratumumab (Lokhorst, H. M. et al., N. Engl. J.
- cancer cells which express CD38 can be selectively targeted for elimination by the immune system using these therapeutic antibodies.
- CD38 hl high CD38-expressing tumor cells
- lower levels of CD38 expression cause the therapeutic antibody to have less to no effect (Nijhof, I. S. et al., Blood, 128, 959-970 (2016)). This is why normal white blood cells or multiple myeloma cells that are initially low in CD38 expression (or becomes low as a mechanism of resistance) do not get efficiently cleared by anti-CD38 treatment.
- CD38 expression in AML is considered to be generally low (CD38 lD ), but moderate in expression in a subset of patients (CD38 dim ).
- Naturally-occurring CD38 hi AML cells are not typical and the percent positivity in AML is generally low.
- AML is believed unlikely to respond to anti-CD38 treatment, a finding that has been demonstrated with daratumumab monotherapy (Dos Santos, C. et al., Blood, 124, 2312-2312 (2014).
- the present disclosure provides methods for treating a subject suffering from a hematological cancer (e.g., multiple myeloma (MM), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma
- MM multiple myeloma
- AML acute myeloid leukemia
- MDS myelodysplastic syndrome
- ALCL anaplastic large cell lymphoma
- BALL B-cell acute lymphoblastic leukemia
- BNHL B-cell non-Hodgkin lymphoma
- CML chronic myelogenous lymphoma
- DLBCL Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), or T-cell acute lymphoblastic leukemia (TALL)
- a retinoid e.g., a retinoic acid receptor alpha- specific agonist, e.g., tamibarotene
- an anti-CD38 antibody e.g., daratumumab
- the method is employed when the hematological cancer is: a) unresponsive to a CD38 inhibitor as a monotherapy; and/or b) characterized as CD38 " , CD38 lD , or CD38 dim .
- the invention provides a method for treating a subject having a hematological cancer that is unresponsive to a treatment with an anti-CD38 antibody in the absence of a retinoid, wherein the method comprises co-administering to the subject a retinoid and an anti-CD38 antibody.
- the subject is only selected for treatment if their hematological cancer has been unresponsive to a prior treatment with an anti-CD38 antibody as a monotherapy (i.e., in the absence of coadministration of a retinoid).
- the subject is suffering from a hematological cancer selected from multiple myeloma (MM), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), or T-cell acute lymphoblastic leukemia (TALL).
- MM multiple myeloma
- AML acute myeloid leukemia
- MDS myelodysplastic syndrome
- ALCL anaplastic large cell lymphoma
- BALL B-cell acute lymphoblastic leukemia
- BALL B-cell non-Hodgkin lymphoma
- CML chronic myelogen
- the subject is suffering from a hematological cancer selected from anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, or T-cell acute lymphoblastic leukemia (TALL).
- ACL anaplastic large cell lymphoma
- BALL B-cell acute lymphoblastic leukemia
- BNHL B-cell non-Hodgkin lymphoma
- CML chronic myelogenous lymphoma
- DLBCL diffuse large B-cell lymphoma
- Hodgkin lymphoma or T-cell acute lymphoblastic leukemia (TALL).
- the subject is suffering from a hematological cancer selected from multiple myeloma (MM), non-acute promyelocytic myeloid leukemia (non-APL AML), myelodysplastic syndrome (MDS), or chronic lymphocytic leukemia (CLL).
- MM multiple myeloma
- non-APL AML non-acute promyelocytic myeloid leukemia
- MDS myelodysplastic syndrome
- CLL chronic lymphocytic leukemia
- the retinoid is a RARA-specific agonist. In more specific aspects of the first embodiment, the retinoid is tamibarotene. In other aspects of the first embodiment, the anti-CD38 antibody is daratumumab.
- the subject is administered a retinoid (e.g., a RARA agonist, e.g., tamibarotene) for a period of time prior to administration of an anti-CD38 antibody (e.g., daratumumab); and is co-administered the anti-CD38 antibody only when the CD38 level in the subject (e.g., in the subject's hematological cancer cells) is determined to be CD38 hl following initial administration of the retinoid (e.g., tamibarotene).
- a retinoid e.g., a RARA agonist, e.g., tamibarotene
- the CD38 level in the subject is determined at one or more different times following the initial administration of the retinoid (e.g., tamibarotene). In some aspects of the first embodiment, the CD38 level in the subject is determined at one or more times between 6 hours and two weeks following the initial administration of the retinoid (e.g., tamibarotene). In some aspects of the first embodiment, the CD38 level in the subject is determined between 6 and 120 hours following the initial administration of the retinoid (e.g., tamibarotene).
- the CD38 level in the subject is determined at one or more of the following time period following initial administration of the retinoid (e.g., tamibarotene): 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, and 14 days. In some aspects of the first embodiment, the CD38 level in the subject is determined between 6 and 72 hours following the initial administration of the retinoid (e.g., tamibarotene).
- the retinoid e.g., tamibarotene
- a sample of a subject's diseased cells is tested for CD38 induction prior to any treatment.
- this would involve obtaining a sample of the subject's diseased cells; growing such cells ex vivo; optionally measuring a baseline level of CD38 induction in those cells; treating the ex vivo cells with a retinoid (e.g., tamibarotene); and determining the level of CD38 induction following such treatment.
- a retinoid e.g., tamibarotene
- the subject is determined to be a candidate for the retinoid (e.g., tamibarotene)/anti-CD38 antibody (e.g., daratumumab) combination treatment.
- retinoid e.g., tamibarotene
- anti-CD38 antibody e.g., daratumumab
- the anti-CD38 antibody e.g., daratumumab
- the retinoid e.g., a RARA agonist, e.g., tamibarotene
- the treatment regimen does not require any specific order of administering the retinoid and the anti-CD38 antibody.
- it may be advantageous to administer the anti-CD38 antibody prior to the retinoid so as to limit or eliminate any side effects of the antibody and/or to optimize the pharmacokinetics of each agent.
- the anti-CD38 antibody e.g., daratumumab
- the retinoid e.g., a RARA agonist, e.g., tamibarotene
- the invention provides a method for treating a subject having a hematological cancer that is characterized as CD38 " , CD38 lD or CD38 dim , wherein the method comprises co-administering to the subject a retinoid and an anti-CD38 antibody.
- the subject is only selected for treatment if they have a hematological cancer that is characterized as CD38 " , CD38 lD or CD38 dim .
- the subject is suffering from a hematological cancer selected from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, or T-cell acute lymphoblastic leukemia (TALL).
- AML acute myeloid leukemia
- MDS myelodysplastic syndrome
- ALCL anaplastic large cell lymphoma
- BALL B-cell acute lymphoblastic leukemia
- BALL B-cell non-Hodgkin lymphoma
- CML chronic myelogenous lymphoma
- DLBCL diffuse large B-cell lymphoma
- Hodgkin lymphoma or T-cell
- the subject is suffering from a hematological cancer selected from anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, or T-cell acute lymphoblastic leukemia (TALL).
- ACL anaplastic large cell lymphoma
- BALL B-cell acute lymphoblastic leukemia
- BNHL B-cell non-Hodgkin lymphoma
- CML chronic myelogenous lymphoma
- DLBCL diffuse large B-cell lymphoma
- Hodgkin lymphoma or T-cell acute lymphoblastic leukemia (TALL).
- the subject is suffering from a hematological cancer selected from multiple myeloma (MM), non-acute promyelocytic myeloid leukemia (non-APL AML), myelodysplastic syndrome (MDS), or chronic lymphocytic leukemia (CLL).
- MM multiple myeloma
- non-APL AML non-acute promyelocytic myeloid leukemia
- MDS myelodysplastic syndrome
- CLL chronic lymphocytic leukemia
- the retinoid is a RARA-specific agonist.
- the retinoid is tamibarotene, ATRA, or a derivative thereof (e.g., fenretinide).
- the anti-CD38 antibody is daratumumab.
- the CD38 level in the subject is determined prior to administration of the therapy.
- a sample of a subject's diseased cells is tested for CD38 induction prior to any treatment as described for the fourth embodiment. If the CD38 level in this sample of the subject's diseased cells is determined to be CD38 hl after treatment with the retinoid, then the subject is determined to be a candidate for the retinoid (e.g., tamibarotene)/anti-CD38 antibody (e.g., daratumumab) combination treatment.
- the retinoid e.g., tamibarotene
- anti-CD38 antibody e.g., daratumumab
- the subject is administered a retinoid (e.g., a RARA agonist, e.g., tamibarotene) for a period of time prior to administration of the anti-CD38 antibody (e.g., daratumumab); and is co-administered the anti-CD38 antibody only when the CD38 level in the subject (e.g., in the subject's hematological cancer cells) is determined to be CD38 hl following initial administration of the retinoid (e.g., tamibarotene).
- a retinoid e.g., a RARA agonist, e.g., tamibarotene
- the CD38 level in the subject is determined at one or more different times following the initial administration of the retinoid (e.g., tamibarotene). In some aspects of the first embodiment, the CD38 level in the subject is determined at one or more times between 6 hours and two weeks following the initial administration of the retinoid (e.g., tamibarotene). In some aspects of the first embodiment, the CD38 level in the subject is determined between 6 and 120 hours following the initial administration of the retinoid (e.g., tamibarotene).
- the CD38 level in the subject is determined at one or more of the following time period following initial administration of the retinoid (e.g., tamibarotene): 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, and 14 days. In some aspects of the first embodiment, the CD38 level in the subject is determined between 6 and 72 hours following the initial administration of the retinoid (e.g., tamibarotene).
- the retinoid e.g., tamibarotene
- the anti-CD38 antibody e.g., daratumumab
- the retinoid e.g., a RARA agonist, e.g., tamibarotene
- the treatment regimen does not require any specific order of administering the retinoid and the anti-CD38 antibody.
- it may be advantageous to administer the anti-CD38 antibody prior to the retinoid so as to limit or eliminate any side effects of the antibody and/or to optimize the pharmacokinetics of each agent.
- the anti-CD38 antibody e.g., daratumumab
- the retinoid e.g., a RARA agonist, e.g., tamibarotene
- the determination of whether a subject's hematological cancer is CD38 " , CD38 10 , CD38 dim or CD38 hi is made by analyzing the subject's blood cells (e.g., bone marrow, PBMCs and/or enriched PBMCs) using an anti-human CD38 antibody in conjunction with a fluorescence-activated cell sorter (FACS).
- FACS fluorescence-activated cell sorter
- the invention provides a method for treating a subject having a hematological cancer, wherein the method comprises co-administering to the subject a retinoid and an anti-CD38 antibody.
- the subject is suffering from a hematological cancer selected from multiple myeloma (MM), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, or T-cell acute lymphoblastic leukemia (TALL).
- MM multiple myeloma
- AML acute myeloid leukemia
- MDS myelodysplastic syndrome
- ALCL anaplastic large cell lymphoma
- BALL
- the subject is suffering from a hematological cancer selected from anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma
- ACL anaplastic large cell lymphoma
- BALL B-cell acute lymphoblastic leukemia
- BNHL B-cell non-Hodgkin lymphoma
- CML chronic myelogenous lymphoma
- diffuse large B-cell lymphoma selected from anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma
- the subject is suffering from a hematological cancer selected from multiple myeloma (MM), non-acute promyelocytic myeloid leukemia (non-APL AML), myelodysplastic syndrome (MDS), or chronic lymphocytic leukemia (CLL).
- MM multiple myeloma
- non-APL AML non-acute promyelocytic myeloid leukemia
- MDS myelodysplastic syndrome
- CLL chronic lymphocytic leukemia
- the retinoid is a RARA-specific agonist.
- the retinoid is tamibarotene.
- the anti-CD38 antibody is daratumumab.
- the anti-CD38 antibody e.g., daratumumab
- the retinoid e.g., a RARA agonist, e.g., tamibarotene
- the anti-CD38 antibody e.g., daratumumab
- the retinoid e.g., a RARA agonist, e.g., tamibarotene
- the present invention features a method for treating a subject having a hematological cancer (e.g., non-APL AML, MDS or MM), wherein the composition comprises an agonist of RARA (e.g., tamibarotene) co- administered with an antibody specific for CD38 (e.g., daratumumab).
- RARA e.g., tamibarotene
- tamibarotene is administered orally.
- the subject is administered
- the anti-CD38 antibody is administered no more than once a week at a dose of between 10-20 mg/kg body weight of the subject.
- Figs. 1 A- IF depict the effect of tamibarotene ("SY1425") on CD38 levels in various AML cell lines.
- Figs. 11A-11D demonstrate the effect of tamibarotene on different cell lines as measured by FITC cell sorting.
- Fig. HE is a graphical representation of the CD38 mRNA levels in various cell lines before and after treatment with tamibarotene.
- Fig. 1 IF is a graphical representation of the % of cells that are positive for CD38 as determined by FITC cell sorting.
- Figs. 2A-2D depict the effect of tamibarotene and daratumumab ("Dara"), alone or in combination, on NK cell proliferation and tumor cell death in various NK cell/ AML cell line co-cultures, as observed by phase contrast microscopy.
- Dara daratumumab
- Figs. 3A-3C depict the effect of a control antibody or Dara alone or in combination with tamibarotene on the number of apoptotic cells in NK cell/ AML co-culture for various AML cell lines.
- Fig. 4 depicts the effect of a control antibody or Dara alone or in
- Figs. 5A-5B depict the effect of a control antibody or Dara alone or in combination with tamibarotene on CD38 levels in two different multiple myeloma cell line (MM1S; Fig. 5A) (HUNS1; Fig. 5B) as measured by FITC cell sorting.
- Fig. 6 depicts the effect of a control antibody or Dara alone or in
- Fig. 7 depicts the effect of a control antibody or Dara alone or in combination with tamibarotene on interferon-gamma secretion in a NK cell/multiple myeloma co-culture for the various multiple cell lines depicted in Figs. 5A-5B and 6.
- Fig. 8A depicts the effect of tamibarotene treatment on the expression of
- FIG. 8B depicts the effect of tamibarotene treatment on the expression of CD38 in various AML and MDS patient samples after 24 or 48 hours as measured by FACS, as well as the expression of RARA and IRF8 mRNA as measured by qPCR.
- Figs. 9A-9D compares the effect of tamibarotene treatment on CD38 levels in an AML cell line, an AML patient sample, and a multiple myeloma cell line, as well as the baseline CD38 level in a CD38 hl multiple myeloma patient sample.
- Figs 10A-10D compare the effect of tamibarotene and all-trans retinoic acid
- Fig. 11 compares the effect of tamibarotene and all-trans retinoic acid
- Fig. 12 compares the effect of tamibarotene and all- trans retinoic acid (ATRA) on CD38 levels in a mouse Kasumi-1 xenograft model after one week as measured by FACS.
- ATRA all- trans retinoic acid
- Fig. 13 compares the effect of tamibarotene and all- trans retinoic acid
- ATRA on CD38 levels in mouse THP-1, Kasumi-1 and MV4-11 xenograft models after one week as measured by IHC.
- Fig. 14 depicts the effect of various treatments on the size of a xenograft
- FIG. 15A-15E depict sections of xenograft MV-411 tumors removed from mice following various treatments and stained with anti-human CD38 antibody.
- Fig. 16 depicts the effect of various treatments on the size of a xenograft MM1S tumor over time in a mouse.
- Fig. 17 depicts the effect of various treatments on the size of a xenograft
- administer As used herein, the terms “administer,” “administering,” or
- administration refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing an inventive compound, or a pharmaceutical composition thereof.
- an agonist may be used to refer to an agent, condition, or event whose presence, level, degree, type, or form correlates with increased level or activity of another agent (i.e. , the agonized agent).
- an agonist may be or include an agent of any chemical class including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and/or any other entity that shows the relevant activating activity.
- an agonist may be direct (in which case it exerts its influence directly upon its target); in some embodiments, an agonist may be indirect (in which case it exerts its influence by other than binding to its target; e.g. , by interacting with a regulator of the target, so that level or activity of the target is altered).
- tissue samples such as tissue sections and needle biopsies of a tissue
- cell samples e.g. , cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
- Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsied tissue (e.g.
- Biological samples also include those biological samples that are transgenic, such as transgenic oocyte, sperm cell, blastocyst, embryo, fetus, donor cell, or cell nucleus.
- a biological sample from a subject suffering from a hematological cancer is a bone marrow aspirate.
- a biological sample from a subject suffering from a hematological cancer is a fractionated whole blood sample.
- a biological sample from a subject suffering from a hematological cancer is a PBMC fraction from the subject's whole blood (a "PBMC sample").
- a PBMC sample from a subject suffering from a hematological cancer is further enriched for specific blasts using various enrichment techniques such as antibody-linked bead enrichment protocols, fluorescent label cell sorting, or other techniques known in the art (an "enriched PBMC sample").
- biomarker refers to an entity whose presence, level, or form, correlates with a particular biological event or state of interest, so that it is considered to be a "marker” of that event or state.
- a biomarker may be or comprises a marker for a particular disease state or stage, or for likelihood that a particular disease, disorder or condition may develop.
- a biomarker may be or comprise a marker for a particular disease or therapeutic outcome, or likelihood thereof.
- a biomarker is predictive, in some embodiments, a biomarker is prognostic, in some embodiments, a biomarker is diagnostic, of the relevant biological event or state of interest.
- a biomarker may be an entity of any chemical class.
- a biomarker may be or comprise a nucleic acid, a polypeptide, a lipid, a carbohydrate, a small molecule, an inorganic agent (e.g. , a metal or ion), or a combination thereof.
- a biomarker is a cell surface marker.
- a biomarker is intracellular.
- a biomarker is found outside of cells (e.g.
- a presence or level of a particular marker correlates with activity (or activity level) of a particular signaling pathway, for example that may be characteristic of a particular class of tumors.
- the statistical significance of the presence or absence of a biomarker may vary depending upon the particular biomarker.
- detection of a biomarker is highly specific in that it reflects a high probability that the tumor is of a particular subclass. Such specificity may come at the cost of sensitivity (e.g. , a negative result may occur even if the tumor is a tumor that would be expected to express the biomarker).
- co-administer or “co- administering” as used herein in the context of the administration of therapies (e.g., a RARA agonist and an antibody specific for CD38), indicates that one therapy may be used in combination with another therapy or therapies during the course of the subject's affliction with the disorder.
- therapies e.g., a RARA agonist and an antibody specific for CD38
- the administration of therapies is simultaneous or concurrent, meaning that the delivery of one treatment is still occurring when the delivery of the second begins.
- the delivery of one treatment ends before the delivery of the other treatment begins.
- the treatment is more effective because of combined administration.
- the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment.
- delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other.
- the effect of the two treatments can be partially additive, wholly additive, or greater than additive.
- the delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.
- a RARA agonist and an antibody specific to CD38 can be administered simultaneously, in the same or in separate compositions, or sequentially.
- the RARA agonist can be administered first, and the antibody specific to CD38 can be administered second, or the order of administration can be reversed.
- condition As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably.
- an "effective amount" of a compound described herein, such a RARA agonist and/or an antibody specific for CD38 refers to an amount sufficient to elicit the desired biological response, i.e. , treating the condition.
- the effective amount of a compound described herein, such a RARA agonist and/or an antibody specific for CD38 may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
- an effective amount encompasses therapeutic and prophylactic treatment.
- an effective amount encompasses only therapeutic treatment.
- an effective amount of an inventive compound or composition may reduce the tumor burden or stop the growth or spread of a tumor.
- a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e. , a male or female of any age group, e.g. , a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g. , young adult, middle-aged adult, or senior adult)) and/or other non-human animals, for example, mammals (e.g. , primates (e.g. , cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g.
- humans i.e. , a male or female of any age group, e.g. , a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g. , young adult, middle-aged adult, or senior adult)) and/or other non-human animals, for example, mammals
- the animal is a mammal.
- the animal may be a male or female and at any stage of development.
- a non-human animal may be a transgenic animal.
- the subject is a human.
- a "therapeutically effective amount" of a compound described herein, such a RARA agonist and/or an antibody specific for CD38 is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
- a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition.
- a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
- the term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.
- treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a "pathological condition” (e.g. , a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein.
- pathological condition e.g. , a disease, disorder, or condition, or one or more signs or symptoms thereof
- “treatment,” “treat,” and “treating” require that signs or symptoms of the disease disorder or condition have developed or have been observed.
- treatment may be administered in the absence of signs or symptoms of the disease or condition.
- treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g. , in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
- the present invention features methods of treating a subject having cancer
- RARA e.g., non-APL AML, MDS or MM
- RARA agonist in combination with an antibody specific for CD38, for example, when a biomarker for RARA or IRF8 is identified
- RARA agonist with which to treat a patient identified as having a super enhancer associated with a RARA gene may be made from any RARA agonist known in the art. It is preferable that the RARA agonist utilized in the methods of the invention be specific for RARA and have significantly less (at least 10X less, at least 100X less, at least 1,000X less, at least 10,000X less, at least 100,000X less) agonistic activity against other forms of RaR, e.g., RaR- ⁇ and RaR- ⁇ .
- the RARA agonist is selected from a compound disclosed in or any compound falling within the genera set forth in any one of the following United States patents: US 4,703,110, US 5,081,271, US 5,089,509, US 5,455,265, US 5,759,785, US 5,856,490, US 5,965,606, US 6,063,797, US 6,071,924, US 6,075,032, US 6,187,950, US 6,355,669, US 6,358,995, and US 6,387,950, each of which is incorporated by reference.
- the RARA agonist is selected from any of the following known RARA agonists set forth in Table 1, or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the foregoing: Table 1.
- the RARA agonist is (AGN-195183).
- Antibodies Specific for CD38 is (AGN-195183).
- CD38 is a transmembrane glycoprotein involved in a number of metabolic functions including the catabolism of extracellular nucleotides, receptor-mediated adhesion, regulation of migration, and a variety of signaling events.
- Antibodies targeting CD38 may modulate any one of these functions, thus contributing to the efficacy of a RARA agonist in the treatment of a cancer.
- the antibody specific for CD38 may recognize and/or bind to any portion of fragment of CD38.
- the antibody specific for CD38 may comprise a monoclonal antibody, a humanized antibody, or a human antibody.
- Exemplary antibodies that are specific for CD38 include isatuximab, daratumumab,
- the antibody specific for CD38 is daratumumab.
- the subject to be treated with a RARA agonist (e.g. , tamibarotene) and an antibody specific for CD38 is suffering from relapsed or refractory non- APL AML.
- a subject is classified as having relapsed or refractory non-APL AML if they: a) do not demonstrate a partial response after a first cycle of induction chemotherapy; or b) do not demonstrate a complete response after a second cycle of induction chemotherapy; or c) relapse after conventional chemotherapy; or d) relapse are undergoing a single stem cell transplantation.
- the subject to be treated with a RARA agonist (e.g. , tamibarotene) and an antibody specific for CD38 is suffering from refractory MM.
- the subject to be treated with a RARA agonist is an elderly unfit subject.
- a RARA agonist e.g. , tamibarotene
- the term "elderly unfit" as used herein means the subject is a human at least 60 years of age and who is determined by a physician to not be a candidate for standard induction therapy.
- the subject is co-administered a RARA agonist (e.g., tamibarotene) and an antibody specific to CD38 (e.g., daratumumab).
- a RARA agonist e.g., tamibarotene
- the RARA agonist is administered simultaneously with the antibody specific to CD38 (e.g., daratumumab).
- the RARA agonist e.g., tamibarotene
- the antibody specific to CD38 e.g., daratumumab
- the subject is co-administered a RARA agonist (e.g., tamibarotene) and an antibody specific to CD38 (e.g., daratumumab).
- the RARA agonist e.g., tamibarotene
- an antibody specific to CD38 e.g., daratumumab
- the RARA agonist and an antibody specific to CD38 are administered within about 1 minute, about 2 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 36 hours, or about 48 hours of one another.
- a patient population includes one or more subjects
- a patient population includes one or more subjects (e.g. , comprises or consists of subjects) who have not received previous therapy for treatment of cancer (e.g. , non-APL AML, MDS or MM).
- a patient population comprises or consists of patients who have not received previous therapy for treatment of non-APL AML, MDS or MM.
- a patient who received previous therapy may have received previous therapy selected from the group consisting of chemotherapy,
- a patient has received a transplant.
- a patient has received standard cytotoxic chemotherapy.
- standard cytotoxic chemotherapy includes cytarabine and/or an anthracycline.
- standard cytotoxic chemotherapy may include additional chemotherapy and/or hematopoietic stem cell transplantation (HSTC).
- HSTC hematopoietic stem cell transplantation
- a patient has received hypomethylating agents.
- a patient has received lenalidomide.
- a patient population includes one or more subjects
- a RARA agonist therapy e.g., tamibarotene
- a composition is administered in combination with the other therapy (e.g. chemotherapy agents), in addition to an antibody specific for CD38.
- the other therapy e.g. chemotherapy agents
- such other therapy may comprise or consist of therapy for cancer (e.g., as described herein), pain, nausea, constipation, for treatment of one or more side effects (e.g., pruritus, hair loss, sleeplessness, etc.) associated with cancer therapy, etc., or any combination thereof.
- the present invention provides a method of treating non-APL AML, MDS or MM, which comprises treating a patient identified as having non- APL AML, MDS or MM, with a therapeutically effective amount of RARA agonist therapy (e.g., tamibarotene) or a pharmaceutically acceptable salt thereof and an antibody specific for CD38.
- RARA agonist therapy e.g., tamibarotene
- the invention provides a method for treating a patient for non-APL AML, MDS or MM previously treated with a treatment regimen comprising chemotherapy by administering to such a patient a therapeutically effective amount of a RARA agonist (e.g., tamibarotene) and an antibody specific CD38.
- a RARA agonist e.g., tamibarotene
- the present disclosure provides a method for treating a patient for non-APL AML, MDS or MM where no standard therapies exist.
- the present disclosure provides a method for treating a patient that is not suited for standard therapy.
- a patient or patient population may not be (e.g. , may exclude) a patient who has a previous history of hypersensitivity to an ingredient of tamibarotene.
- a patient or patient population may not be (e.g. , may exclude) a patient who is receiving vitamin A formulations.
- a patient or patient population may not be (e.g. , may exclude) a patient who has hypervitaminosis A.
- a patient or patient population may not be (e.g. , may exclude) an elderly patient.
- a patient or patient population may be or include one or more elderly patients.
- an elderly patient may be monitored more frequently to detect potential adverse events (including for example, low levels of serum albumin and/or elevated concentrations of free drug in plasma, etc.) as compared with one or more younger patients.
- the administration of the RARA agonist and/or the antibody specific CD38 may be reduced, suspended, and/or terminated for an elderly patient determined to display one or more signs of such an adverse event.
- each active agent e.g., a RARA agonist or an antibody specific for CD38
- a RARA agonist for use in accordance with the present invention is formulated, dosed, and administered in a therapeutically effective amount using pharmaceutical compositions and dosing regimens that are consistently with good medical practice and appropriate for the relevant agent(s) and subject.
- therapeutic compositions can be administered by any appropriate method known in the art, including, without limitation, oral, mucosal, by- inhalation, topical, buccal, nasal, rectal, or parenteral (e.g., intravenous, infusion, intratumoral, intranodal, subcutaneous, intraperitoneal, intramuscular, intradermal, transdermal, or other kinds of administration).
- a RARA agonist e.g., tamibarotene
- an antibody specific for CD38 will be administered intravenously.
- a dosing regimen for a particular active agent may involve intermittent or continuous administration, for example to achieve a particular desired pharmacokinetic profile or other pattern of exposure in one or more tissues or fluids of interest in the subject receiving therapy.
- different agents administered in combination may be administered via different routes of delivery and/or according to different schedules.
- one or more doses of a first active agent is administered substantially simultaneously with, and in some embodiments via a common route and/or as part of a single composition with, one or more other active agents.
- Factors to be considered when optimizing routes and/or dosing schedule for a given therapeutic regimen may include, for example, the particular indication being treated, the clinical condition of a subject (e.g., age, overall health, prior therapy received and/or response thereto, etc.) the site of delivery of the agent, the nature of the agent, the mode and/or route of administration of the agent, the presence or absence of combination therapy, and other factors known to medical practitioners.
- relevant features of the indication being treated may include, among other things, one or more of cancer type, stage, location, etc.
- one or more features of a particular pharmaceutical composition and/or of a utilized dosing regimen may be modified over time (e.g., increasing or decreasing amount of active in any individual dose, increasing or decreasing time intervals between doses, etc.), for example in order to optimize a desired therapeutic effect or response.
- type, amount, and frequency of dosing of active agents in accordance with the present invention are governed by safety and efficacy requirements that apply when relevant agent(s) is/are administered to a mammal, preferably a human.
- such features of dosing are selected to provide a particular, and typically detectable, therapeutic response as compared with what is observed absent therapy.
- an exemplary desirable therapeutic response may involve, but is not limited to, inhibition of and/or decreased tumor growth, tumor size, metastasis, one or more of the symptoms and side effects that are associated with a tumor, as well as increased apoptosis of tumor cells, therapeutically relevant decrease or increase of one or more cell marker or circulating markers and the like.
- Such criteria can be readily assessed by any of a variety of immunological, cytological, and other methods that are disclosed in the literature.
- therapeutic dosing regimens may be combined with or adjusted in light of detection methods that assess expression of one or more inducible markers prior to and/or during therapy.
- a RARA agonist (e.g. , tamibarotene) therapy regimen comprises at least one (or includes or consists of exactly one) dose of about 1 mg/m 2 , 2 mg/m 2 , 3 mg/m 2 , 4 mg/m 2 , 5 mg/m 2 , 6 mg/m 2 , 7 mg/m 2 , 8 mg/m 2 , 9 mg/m 2 , 10 mg/m 2 , 11 mg/m 2 , 12 mg/m 2 , 13 mg/m 2 , 14 mg/m 2 , 15 mg/m 2 , 16 mg/m 2 , or a dose between any two of these values of a RARA agonist (e.g.
- a RARA agonist (e.g. , tamibarotene) therapy regimen comprises a dose of between 1 mg/m 2 and 50 mg/m 2 . In some embodiments, a RARA agonist (e.g. , tamibarotene) therapy regimen comprises a dose of between 5 mg/m 2 and 25 mg/m 2 . In some embodiments, a RARA agonist (e.g. , tamibarotene) therapy regimen comprises a dose of between 5 mg/m 2 and 15 mg/m 2 . In some embodiments, a RARA agonist (e.g. , tamibarotene) therapy regimen comprises a dose of 12 mg/m 2 . In some embodiments, a RARA agonist (e.g. , tamibarotene) therapy regimen comprises a dose of 6 mg/m 2 .
- a RARA agonist (e.g., tamibarotene) therapy regimen comprises a plurality of doses of a tamibarotene composition.
- a tamibarotene therapy regimen comprises, for example 2, 5, 10, 20, 30, 60, 90, 180, 365 doses or a number of doses between any two of these values and/or comprises a repeated pattern of doses (e.g. , at least one cycle of two daily doses, which cycle may be repeated, optionally with a period of alternative administration, or optionally no administration, separating different cycles).
- a tamibarotene therapy regimen is administered twice a day.
- a tamibarotene therapy regimen is administered once a day. In some embodiments, a tamibarotene therapy regimen comprises a total dose of 6 mg/m 2 to 12 mg/m 2 , divided as twice daily oral dosing.
- an antibody specific for CD38 (e.g. , daratumumab) therapy regimen comprises at least one (or includes or consists of exactly one) dose of about 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, or a dose between any two of these values of a an antibody specific for CD38 (e.g.
- an antibody specific for CD38 (e.g. , daratumumab) therapy regimen comprises a dose of between 1 mg/kg and 100 mg/kg. In some embodiments, an antibody specific for CD38 (e.g. , daratumumab) therapy regimen comprises a dose of between 5 mg/kg and 50 mg/kg. In some embodiments, an antibody specific for CD38 (e.g. , daratumumab) therapy regimen comprises a dose of between 10 mg/kg and 20 mg/kg.
- an antibody specific for CD38 (e.g. , daratumumab) therapy regimen comprises a plurality of doses of a daratumumab composition.
- a daratumumab therapy regimen comprises, for example 2, 5, 10, 20, 30, 60, 90, 180, 365 doses or a number of doses between any two of these values and/or comprises a repeated pattern of doses (e.g. , at least one cycle of two daily doses, which cycle may be repeated, optionally with a period of alternative administration, or optionally no
- a daratumumab therapy regimen is administered once a week. In some embodiments, a daratumumab therapy regimen is administered no more than once a week. In some embodiments, a daratumumab therapy regimen is administered once every two weeks. In some embodiments, a daratumumab therapy regimen comprises a total dose of 10 mg/kg to 20 mg/kg no more than once a week.
- a pharmaceutical composition refers to a mixture of a compound, such as tamibarotene or an antibody specific for CD38, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
- a compound such as tamibarotene or an antibody specific for CD38
- other chemical components such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
- the pharmaceutical composition facilitates
- compositions containing a compound may be administered in therapeutically effective amounts by any conventional form and route known in the art including, but not limited to: intravenous, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, and topical administration.
- a compound can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers or excipients well known in the art.
- Such carriers permit the compounds described herein to be formulated as tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
- excipients such as fillers, disintegrants, glidants, surfactants, recrystallization inhibitors, lubricants, pigments, binders, flavoring agents, and so forth can be used for customary purposes and in typical amounts without affecting the properties of the compositions.
- the excipient is one or more of lactose hydrate, corn starch, hydroxypropyl cellulose and/or magnesium stearate.
- tamibarotene may be formulated with one or more of lactose hydrate, corn starch, hydroxypropyl cellulose and/or magnesium stearate.
- the packaged pharmaceutical compositions of the present invention comprise a written insert or label comprising instructions to use the RARA agonist and the antibody targeting CD38 in a subject suffering from a cancer.
- the instructions may be adhered or otherwise attached to a vessel comprising the RARA agonist and the antibody targeting CD38.
- the instructions and the vessel comprising the RARA agonist will be separate from one another, but present together in a single package, box or other type of container.
- the instructions in the packaged pharmaceutical composition will typically be mandated or recommended by a governmental agency approving the therapeutic use of the RARA agonist and the antibody targeting CD38.
- the instructions may optionally comprise dosing information, the types of cancer for which treatment with the RARA agonist and/or and the antibody targeting CD38 were approved, physicochemical information about the RARA agonist and/or and the antibody targeting CD38; pharmacokinetic information about the RARA agonist and/or and the antibody targeting CD38; or drug-drug interaction information.
- the instructions direct that the composition be administered to a subject diagnosed as suffering from non-APL AML.
- the instructions direct that the composition be administered to a subject diagnosed as suffering from non-APL MM.
- the pharmaceutical composition comprises tamibarotene. In some aspects, the pharmaceutical composition comprises AGN-195183. In some aspects, the pharmaceutical composition comprises daratumumab. In some embodiments, the pharmaceutical composition comprises both tamibarotene and daratumumab.
- FIG. 1A shows that 72h tamibarotene treatment at a concentration of 50 nmol/L does not induce CD38 expression in a RARA mRNA low cell line, Kasumi (CD38 ).
- Fig. IB demonstrates that following 72h tamibarotene treatment of RARA mRNA high cell line, MV411, the entire cell population expresses high levels of CD38 (CD38 hl ).
- OCI-AML3 RARA mRNA high
- has low CD38 MFI CD38 DIM
- Fig. ID shows 72h tamibarotene treatment does not induce CD38 expression in another RARA mRNA low cell line, OCI-M1 (CD38 ).
- CD38 hl induction by tamibarotene can be predicted by RARA mRNA level.
- Fig. IE shows the level of CD38 mRNA expression detected in each cell line before and after treatment.
- Fig. IF shows the percentage of CD38 hi cells based on FACS are shown before and after tamibarotene treatment.
- the APL cell line, NB4 is also shown.
- Example 2 RARA mRNA predicts NK cell mediated cytotoxicity of AML cell line, MV411, following tamibarotene and daratumumab combination therapy
- FIGS. 2A-2D are representative images of phase contrast images of RARA mRNA high MV411 cell line in co-culture assay with the following treatment conditions: Fig. 2A) 72h DMSO MV411 cell line pretreatment and 38h co-culture control antibody treatment. Fig.
- FIG. 2B 72h SY1425 (50nM) MV411 cell line pretreatment and 38h co-culture control antibody treatment.
- Fig. 2C 72h DMSO MV411 cell line pretreatment and 38h co-culture daratumumab treatment.
- Fig. 2D 72h SY1425 (50nM) MV411 cell line pretreatment and 38h co-culture daratumumab treatment.
- Example 3 RARA mRNA level predicts NK cell mediated cytotoxicity of AML cell lines following tamibarotene and daratumumab combination therapy
- Example 4 NK cell activation in co-culture assay only occurs post tamibarotene and daratumumab combination treatment as determined by NK cell IFN gamma secretion.
- Interferon gamma (IFNy) secretion is an indication of NK cell activation.
- IFNy secretion was quantitated 38h post AML cell line and NK cell co-culture following the indicated treatment conditions (Fig. 4).
- Significantly increased levels of IFNy are observed following combination treatment with tamibarotene and daratumumab only in the RARA mRNA high AML cell lines (MV411 and OCI-AML3) and NK cell co-culture assay in comparison to single agent treatment conditions.
- MV411 and OCI-AML3 the RARA mRNA high AML cell lines
- NK cell co-culture assay in comparison to single agent treatment conditions.
- these are the only cell lines that demonstrate the CD38 hl phenotype following tamibarotene treatment.
- Example 5 Tamibarotene increases the intensity of CD38 expression in multiple myeloma cells.
- MM multiple myeloma cell line
- Fig. 5 A multiple myeloma cell line
- Fig. 5B dim state
- Example 6 Tamibarotene increase in CD38 ffl phenotype further sensitizes MM cell line to daratumumab dependent NK cell-mediated cytotoxicity.
- MM cell lines with tamibarotene will increase sensitivity to CD38 antibody treatment.
- Fig. 6 demonstrates that following tamibarotene and daratumumab combination treatment, MM IS tumor cell death is increased in comparison to single agent anti-CD38 antibody treatment as quantitated by Annexin V staining.
- Fig. 7 The multiple myeloma cell line that achieved high CD38 intensity, MM1S, showed strong cell killing in response to combination treatment.
- Example 7 Tamibarotene induces CD38 ffl phenotype in primary non-APL AML and MPS patient samples.
- the CD38 induction levels observed for AML patient samples correlated well with results obtained from high RARA RNA AML cell lines (e.g., compare tamibarotene-induced CD38 MFI in patient sample AML_1 with AML cell line MV411 in Fig. 9C-9D).
- tamibarotene caused an increase in the CD38 hl phenotype similar to that observed in daratumumab-sensitive multiple myeloma cell lines and multiple myeloma patients (e.g., compare patient sample MM_1 with multiple myeloma cell line MM1S in Fig. 9A-9B).
- the inventors believe that high RARA mRNA AML patients will benefit from a combination treatment of a RARA-specific agonist, such as tamibarotene, and an anti-CD38 antibody, such as daratumumab.
- Example 8 Tamibarotene Causes a Greater Increase in CD38 Induction than ATRA in AML cell line xenografts having high RARA or IRF8 Levels.
- ATRA causes a greater induction in CD38 levels than tamibarotene in HL-60 cells, an AML cell lines typically characterized as APL (A Uruno et al., 2011, J Leuk Biol, 90, pp 235-247).
- APL A Uruno et al., 2011, J Leuk Biol, 90, pp 235-247.
- MV411 has a high level of RARA mRNA and IRF8 mRNA (i.e., above a threshold), while THP-1 has a high level of IRF-8 mRNA. Kasumi-1 cells are considered to have levels of IRF8 and RARA that are below the threshold.
- THP-1 cells RPMI1640 medium supplemented with 10% heat inactivated fetal bovine serum and 0.05mM ⁇ -mercaptoethanol
- MV4-11 cells IMDM medium supplemented with 10% heat inactivated fetal bovine serum
- Kasumi-1 cells
- RPMI1640 medium supplemented with 20% heat inactivated fetal bovine serum
- 37°C in an atmosphere of 5% CO 2 in air.
- the cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
- mice were ⁇ -irradiated (200 rads) 24 h before tumor cell inoculation.
- Each mouse was inoculated subcutaneously at the right flank region with the appropriate tumor cell line (THP-1 cells: lx 10 7 cells in 0.1 ml of PBS (1:1 Matrigel); MV4-11 cells: 5 x 10 6 cells in 0.1 ml of PBS (1:1 Matrigel); Kasumi-1 cells: 1 x 10 7 cells in 0.1 ml of PBS (1:1 Matrigel)) for tumor development.
- THP-1 cells lx 10 7 cells in 0.1 ml of PBS (1:1 Matrigel
- MV4-11 cells 5 x 10 6 cells in 0.1 ml of PBS (1:1 Matrigel
- Kasumi-1 cells 1 x 10 7 cells in 0.1 ml of PBS (1:1 Matrigel)
- Treatment with tamibarotene, ATRA or vehicle was started when the mean tumor size reached approximately 100-200 mm 3 .
- the mice were divided into 3 groups of nine and each was orally administered drug (ATRA 4 mg/kg;
- tamibarotene 3 mg/kg or vehicle alone BID for up to 28 days.
- the date of tumor cell inoculation was denoted as day 0.
- Three mice per group were sacrificed on day 7, 14, and 21 after grouping (4-week study total).
- Half of the tumor was collected for embedding into a FFPE block for immunohistochemistry staining (IHC), and the other half of tumor was collected for CD38 FACS analysis of the tumor cells.
- IHC immunohistochemistry staining
- FFPE blocks were sectioned (3 ⁇ ) on a manual rotary microtome and prepared for IHC staining utilizing a BOND RX autostainer (Leica) following manufacturer's directions and using an anti-CD38 antibody directed against the C-terminus of CD38 (clone SP149; Abeam; Cat. No. abl83326).
- Antibody was diluted 1:100 in pH 9.0 EDTA buffer and then incubated with tumor slices for 20 minutes. Signal was developed using DAB and the manufacturer's (Leica) Bond Polymer Refine Detection kit.
- tamibarotene-treated MV4-11 xenograft mice showed a mean fluorescence intensity (MFI) of over 200 with over 80% of the tumor cells being CD38 hi by FACS analysis.
- MFI mean fluorescence intensity
- ATRA-treated MV4-11 xenograft mice showed a MFI of slightly over 100 with approximately 70% of the tumor cells being CD38 hl .
- FIG. 10B Immunohistochemical staining of tumor sections with an anti-CD38 antibody confirmed the surprising and unexpected superiority of tamibarotene over ATRA in this xenograft model (FIG. 10B). This trend became even more pronounced at 3 weeks.
- FIG. IOC at three weeks, in tamibarotene-treated MV4-11 xenografts, over 60% of the tumor cells remained CD38 hl , with a MFI of around 110, while in ATRA-treated xenografts less than 20% of the tumor cells remained CD38 hi with a MFI of around 50.
- FIG. 10D shows immunohistochemical staining of tumor cells after three weeks, which confirms the superiority of tamibarotene over ATRA.
- Example 9 A combination of Tamibarotene and Daratumumab is superior to a combination of ATRA and Daratumumab in inhibiting the growth of an AML cell line xenograft.
- Subcutaneous MV4-11 xenografts were established in NOD.SCID mice at
- Example 8 Crown Bioscience (Beijing, China), essentially as described in Example 8.
- Each mouse was inoculated subcutaneously at the right flank region with MV4-11 tumor cells (5 x 10 6 ) in 0.1 ml of PBS (1 : 1 matrigel) for tumor development.
- the treatments were started when the mean tumor size reached approximately 50-150 mm 3 .
- the date of tumor cell inoculation was denoted as day 0.
- the animals were checked for any effects of tumor growth and treatments on normal behavior such as mobility, visual estimation of food and water consumption, body weight gain/loss (body weights measured twice per week), eye/hair matting and any other abnormal effect.
- the entire procedures of dosing as well as tumor and body weight measurement was conducted in a Laminar Flow Cabinet.
- Tamibarotene was formulated by using a DMSO stock solution (30 mg/ml), diluted 1/100 into PBS to make a final solution at 0.3 mg/ml adjusted to pH 8. Tamibarotene was administered at 3 mg/kg in a 10 ml/kg volume PO twice a day for 28 days.
- ATRA Tretinoin
- ATRA was formulated by using a DMSO stock solution (40mg/ml), diluted 1/100 into PBS to make a final solution at 0.4 mg/ml adjusted to pH 8.
- ATRA was administered at 4 mg/kg in a 10 ml/kg volume PO twice a day for 28 days.
- mice in the combination arm were given the same dosing schedules, volumes, and formulations for each agent.
- Mice in the vehicle arm were given the same dosing schedules, volumes, and formulations, but lacking SY-1425 or ATRA and daratumumab. Tumor volumes were measured twice weekly over the course of the study.
- Daratumumab was administered i.v at 1 mg/kg once a week on week 1 and week 3.
- mice per arm were sacrificed prior to dosing to collect tumor. Each tumor was embedded into FFPE block for H.E. staining, and IHC staining with Human CD38. The remaining tumors were harvested at termination of the study and, each half tumor was embedded into FFPE block as described in the previous example, with the 2 nd half being snap frozen.
- tumor tissue from different treatment regimens is IHC stained for human CD38.
- Treatment with SY-1425 alone or in combination with daratumumab shows greater CD38 staining than ATRA alone, ATRA in combination with daratumumab, or vehicle control.
- Example 10 A combination of Tamibarotene and Daratumumab is superior to a combination of ATRA and Daratumumab in inhibiting the growth of a multiple myeloma cell line xenograft.
- mice were ⁇ -irradiated (200 rads) 24 h before tumor cell inoculation.
- Each mouse was inoculated subcutaneously at the right flank region with MM.1S tumor cells (1 x 10 7 ) in 0.1 ml of PBS for tumor development. The treatments were started when the mean tumor size reaches approximately 150 (100-200) mm 3 . The date of tumor cell inoculation was denoted as day 0.
- Tumor volumes were measured twice per week in two dimensions using a caliper, as described in the previous Example. Dosages and dosing of tamibarotene, ATRA and daratumumab and preparation of tumors for analysis were as described in the previous example. The results of these studies are shown in FIG. 16, where treatment with SY-1425 alone or in combination with daratumumab were the only treatment to demonstrate significant inhibition of MM IS xenograft growth over the vehicle control.
- Example 11 A combination of Tamibarotene and an anti-mouse CD38 antibody is superior to a combination of ATRA and the anti-mouse CD38 antibody in inhibiting the growth of a lymphocytic leukemia cell line xenograft.
- L1210 tumor cells were maintained in vitro as suspension culture in DMEM medium supplemented with 10% heat inactivated fetal bovine serum at 37°C in an atmosphere of 5% CO 2 in air. The tumor cells were routinely subcultured twice weekly. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
- Each mouse was inoculated subcutaneously at the right lower flank region with L1210 tumor cells (2xl0 5 ) in 0.1 ml of PBS for tumor development. The treatments were started when the mean tumor size reaches approximately 50-100 mm 3 . The date of tumor cell inoculation is denoted as day 0.
- Tumor volumes were measured twice per week in two dimensions using a caliper, as described in the previous Example. Dosages and dosing of tamibarotene and ATRA and preparation of tumors for analysis were as described in the previous example.
- Anti-CD38 (Rat mAb CD38, NIMR-5) was formulated in PBS to a solution of 1 mg/ml. It was administered i.v at 10 mg/kg BIW for 4 weeks.
- CD38 antibody acting synergistic ally with SY-1425 as compared to with ATRA This can be seen by comparing the difference in effect between SY1425 alone and SY-1425 + anti-CD38 antibody versus the difference between ATRA alone and ATRA + anti-CD38 antibody.
- the differential decrease in tumor growth caused by adding the anti-CD38 antibody to SY-1425 was greater than the differential decrease caused by adding that antibody to ATRA.
- Embodiments or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
- the invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
- the invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
- the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed embodiments is introduced into another embodiment.
- any embodiment that is dependent on another embodiment can be modified to include one or more limitations found in any other embodiment that is dependent on the same base embodiment.
- elements are presented as lists, e.g. , in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides methods that define cellular populations that are sensitive to RARA agonists and identify patient subgroups that will benefit from treatment with RARA agonists in combination with another therapy, more specifically an anti-CD38 therapy. The invention also provides packaged pharmaceutical compositions that comprise a RARA agonist and instructions for determining if such combination therapy is suitable for use in treatment.
Description
METHODS OF TREATING PATIENTS WITH A RETINOIC ACID RECEPTOR-a AGONIST AND AN ANTI-CD38 ANTIBODY
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of and priority to International Patent
Application No. PCT/US2017/055562, filed on October 6, 2017 and to U.S. Provisional Patent Application No. 62/449,450, filed January 23, 2017, and U.S. Provisional Patent Application No. 62/564,690, filed September 28, 2017, each of which is hereby incorporated by reference herein in its entirety. BACKGROUND OF THE INVENTION
[0002] Retinoids are a class of compounds structurally related to vitamin A, comprising natural and synthetic compounds. Several series of retinoids have been found clinically useful in the treatment of dermatological and oncological diseases. Retinoic acid and its other naturally occurring retinoid analogs (9-cis retinoic acid, all-trans 3,4-didehydro retinoic acid, 4-oxo retinoic acid and retinol) are pleiotropic regulatory compounds that modulate the structure and function of a wide variety of inflammatory, immune and structural cells. They are important regulators of epithelial cell proliferation, differentiation and morphogenesis in lungs. Retinoids exert their biological effects through a series of hormone nuclear receptors that are ligand inducible transcription factors belonging to the
steroid/thyroid receptor super family.
[0003] The retinoid receptors are classified into two families, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), each consisting of three distinct subtypes (α, β, and γ). Each subtype of the RAR gene family encodes a variable number of isoforms arising from differential splicing of two primary RNA transcripts. All-trans retinoic acid is the physiological hormone for the retinoic acid receptors and binds with
approximately equal affinity to all the three RAR subtypes, but does not bind to the RXR receptors for which 9-cis retinoic acid is the natural ligand. Retinoids have anti-inflammatory effects, alter the progression of epithelial cell differentiation, and inhibit stromal cell matrix production. These properties have led to the development of topical and systemic retinoid therapeutics for dermatological disorders such as psoriasis, acne, and hypertrophic cutaneous
scars. Other applications include the control of acute promyelocytic leukemia, adeno- and squamous cell carcinoma, and hepatic fibrosis.
[0004] A limitation in the therapeutic use of retinoids has stemmed from the relative toxicity observed with the naturally occurring retinoids, all-trans retinoic acid and 9-cis retinoic acid. These natural ligands are non-selective in terms of RAR subtype and therefore have pleiotropic effects throughout the body, which are often toxic.
[0005] Various retinoids have been described that interact selectively or specifically with the RAR or RXR receptors or with specific subtypes (α, β, γ) within a class. RARA specific agonists have held high promise for the treatment of cancers and many have entered human clinical trials. However, only one RARA specific agonist, tamibarotene, has ever been approved for the treatment of cancer. Moreover, tamibarotene is only approved in Japan and only for the treatment of acute promyelocytic leukemia, despite trials in the US and Europe. The disconnect between the theoretical efficacy of RARA agonists in cancer and the dearth of regulatory approvals for such agents raises the question of why such agonists are not effective and safe in humans. Therefore, there is a need to better understand why RARA agonists have not met their therapeutic potential.
[0006] Cluster of differentiation 38 (CD38) is a protein expressed on the surface, primarily on white blood cells, and considered a cell surface marker indicative of differentiation initiation. It functions as a cyclic ADP-ribose hydrolase which plays a role in cell signaling (Mehta, K. & Cheema, S., Leuk. Lymphoma, 32, 441-449 (1999)). It is generally found to be highly expressed in cells of the B-cell and plasma cell lineage. In multiple myeloma a subset of patients have high CD38 expression, which has led to the development of anti-CD38 therapeutic antibodies, such as daratumumab (Lokhorst, H. M. et al., N. Engl. J. Med., 373, 1207-1219 (2015); de Weers, M. et al., /. Immunol, 186, 1840- 1848 (2011)). Thus, cancer cells which express CD38 can be selectively targeted for elimination by the immune system using these therapeutic antibodies. In multiple myeloma daratumumab is most effective in high CD38-expressing tumor cells (CD38hl) while lower levels of CD38 expression cause the therapeutic antibody to have less to no effect (Nijhof, I. S. et al., Blood, 128, 959-970 (2016)). This is why normal white blood cells or multiple myeloma cells that are initially low in CD38 expression (or becomes low as a mechanism of resistance) do not get efficiently cleared by anti-CD38 treatment.
[0007] CD38 expression in AML is considered to be generally low (CD38lD), but moderate in expression in a subset of patients (CD38dim). Naturally-occurring CD38hi AML cells are not typical and the percent positivity in AML is generally low. Thus, AML is
believed unlikely to respond to anti-CD38 treatment, a finding that has been demonstrated with daratumumab monotherapy (Dos Santos, C. et al., Blood, 124, 2312-2312 (2014).
[0008] Recent advances in genomic technology and the understanding of gene regulatory circuits has led to the discovery of super enhancers. Whereas many genes in a given tissue or cancer type may be regulated by the presence of enhancers in proximity to the gene coding region, a small minority of these represent a highly asymmetric and
disproportionately large loading of transcriptional marks and machinery relative to all other active genes. Recent discoveries suggest that such enhancers are tied to genes of special relevance to the function and survival of the cell harboring them. As such, an association of a super enhancer with a gene indicates the relative significance of said gene to the survival of that cell.
SUMMARY OF THE INVENTION
[0009] The present disclosure provides methods for treating a subject suffering from a hematological cancer (e.g., multiple myeloma (MM), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma
(DLBCL), Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), or T-cell acute lymphoblastic leukemia (TALL)) by administering to the subject a combination of a retinoid (e.g., a retinoic acid receptor alpha- specific agonist, e.g., tamibarotene) and an anti-CD38 antibody (e.g., daratumumab). In some aspects, the method is employed when the hematological cancer is: a) unresponsive to a CD38 inhibitor as a monotherapy; and/or b) characterized as CD38", CD38lD, or CD38dim.
[0010] In a first embodiment, the invention provides a method for treating a subject having a hematological cancer that is unresponsive to a treatment with an anti-CD38 antibody in the absence of a retinoid, wherein the method comprises co-administering to the subject a retinoid and an anti-CD38 antibody. In some aspects of this first embodiment, the subject is only selected for treatment if their hematological cancer has been unresponsive to a prior treatment with an anti-CD38 antibody as a monotherapy (i.e., in the absence of coadministration of a retinoid). In some aspects of the first embodiment, the subject is suffering from a hematological cancer selected from multiple myeloma (MM), acute myeloid leukemia
(AML), myelodysplastic syndrome (MDS), anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), or T-cell acute lymphoblastic leukemia (TALL). In some more specific aspects of the first embodiment, the subject is suffering from a hematological cancer selected from anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, or T-cell acute lymphoblastic leukemia (TALL). In some aspects of the first embodiment, the subject is suffering from a hematological cancer selected from multiple myeloma (MM), non-acute promyelocytic myeloid leukemia (non-APL AML), myelodysplastic syndrome (MDS), or chronic lymphocytic leukemia (CLL).
[0011] In some aspects of the first embodiment, the retinoid is a RARA-specific agonist. In more specific aspects of the first embodiment, the retinoid is tamibarotene. In other aspects of the first embodiment, the anti-CD38 antibody is daratumumab.
[0012] In some aspects of the first embodiment, the subject is administered a retinoid (e.g., a RARA agonist, e.g., tamibarotene) for a period of time prior to administration of an anti-CD38 antibody (e.g., daratumumab); and is co-administered the anti-CD38 antibody only when the CD38 level in the subject (e.g., in the subject's hematological cancer cells) is determined to be CD38hl following initial administration of the retinoid (e.g., tamibarotene). In some aspects of the first embodiment, the CD38 level in the subject is determined at one or more different times following the initial administration of the retinoid (e.g., tamibarotene). In some aspects of the first embodiment, the CD38 level in the subject is determined at one or more times between 6 hours and two weeks following the initial administration of the retinoid (e.g., tamibarotene). In some aspects of the first embodiment, the CD38 level in the subject is determined between 6 and 120 hours following the initial administration of the retinoid (e.g., tamibarotene). In some aspects of the first embodiment, the CD38 level in the subject is determined at one or more of the following time period following initial administration of the retinoid (e.g., tamibarotene): 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, and 14 days. In some aspects of the first embodiment, the CD38 level in the subject is determined between 6 and 72 hours following the initial administration of the retinoid (e.g., tamibarotene).
[0013] In some aspects of the first embodiment, a sample of a subject's diseased
cells is tested for CD38 induction prior to any treatment. Typically, this would involve obtaining a sample of the subject's diseased cells; growing such cells ex vivo; optionally measuring a baseline level of CD38 induction in those cells; treating the ex vivo cells with a retinoid (e.g., tamibarotene); and determining the level of CD38 induction following such treatment. If the CD38 level in this sample of the subject's diseased cells is determined to be CD38hl after treatment with the retinoid, then the subject is determined to be a candidate for the retinoid (e.g., tamibarotene)/anti-CD38 antibody (e.g., daratumumab) combination treatment.
[0014] In some aspects of the first embodiment, the anti-CD38 antibody (e.g., daratumumab) is administered prior to or after administration of the retinoid (e.g., a RARA agonist, e.g., tamibarotene). In some aspects of the first embodiment, when the CD38 level in the diseased cells of a subject is determined to be inducible by a retinoid using the ex vivo technique described above, the treatment regimen does not require any specific order of administering the retinoid and the anti-CD38 antibody. Thus, it may be advantageous to administer the anti-CD38 antibody prior to the retinoid so as to limit or eliminate any side effects of the antibody and/or to optimize the pharmacokinetics of each agent. In some aspects of the first embodiment, the anti-CD38 antibody (e.g., daratumumab) is administered between 6 and 120 hours prior to administration of the retinoid (e.g., a RARA agonist, e.g., tamibarotene).
[0015] In a second embodiment, the invention provides a method for treating a subject having a hematological cancer that is characterized as CD38", CD38lD or CD38dim, wherein the method comprises co-administering to the subject a retinoid and an anti-CD38 antibody. In some aspects of this second embodiment, the subject is only selected for treatment if they have a hematological cancer that is characterized as CD38", CD38lD or CD38dim. In some aspects of the second embodiment, the subject is suffering from a hematological cancer selected from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, or T-cell acute lymphoblastic leukemia (TALL). In some more specific aspects of the second embodiment, the subject is suffering from a hematological cancer selected from anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, or T-cell acute
lymphoblastic leukemia (TALL). In some aspects of the second embodiment, the subject is suffering from a hematological cancer selected from multiple myeloma (MM), non-acute promyelocytic myeloid leukemia (non-APL AML), myelodysplastic syndrome (MDS), or chronic lymphocytic leukemia (CLL).
[0016] In some aspects of the second embodiment, the retinoid is a RARA-specific agonist. In more specific aspects of the second embodiment, the retinoid is tamibarotene, ATRA, or a derivative thereof (e.g., fenretinide). In other aspects of the second embodiment, the anti-CD38 antibody is daratumumab.
[0017] In still other aspects of the second embodiment, the CD38 level in the subject (e.g., in the subject's hematological cancer cells) is determined prior to administration of the therapy.
[0018] In some aspects of the second embodiment, a sample of a subject's diseased cells is tested for CD38 induction prior to any treatment as described for the fourth embodiment. If the CD38 level in this sample of the subject's diseased cells is determined to be CD38hl after treatment with the retinoid, then the subject is determined to be a candidate for the retinoid (e.g., tamibarotene)/anti-CD38 antibody (e.g., daratumumab) combination treatment.
[0019] In yet other aspects of the second embodiment, the subject is administered a retinoid (e.g., a RARA agonist, e.g., tamibarotene) for a period of time prior to administration of the anti-CD38 antibody (e.g., daratumumab); and is co-administered the anti-CD38 antibody only when the CD38 level in the subject (e.g., in the subject's hematological cancer cells) is determined to be CD38hl following initial administration of the retinoid (e.g., tamibarotene).
[0020] In some aspects of the first embodiment, the CD38 level in the subject is determined at one or more different times following the initial administration of the retinoid (e.g., tamibarotene). In some aspects of the first embodiment, the CD38 level in the subject is determined at one or more times between 6 hours and two weeks following the initial administration of the retinoid (e.g., tamibarotene). In some aspects of the first embodiment, the CD38 level in the subject is determined between 6 and 120 hours following the initial administration of the retinoid (e.g., tamibarotene). In some aspects of the first embodiment, the CD38 level in the subject is determined at one or more of the following time period following initial administration of the retinoid (e.g., tamibarotene): 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, and 14 days. In some aspects of the first embodiment, the CD38 level in the subject is determined between 6 and 72 hours
following the initial administration of the retinoid (e.g., tamibarotene).
[0021] In some aspects of the second embodiment, the anti-CD38 antibody (e.g., daratumumab) is administered prior to or after administration of the retinoid (e.g., a RARA agonist, e.g., tamibarotene). In some aspects of the second embodiment, when the CD38 level in the diseased cells of a subject is determined to be inducible by a retinoid using the ex vivo technique described above, the treatment regimen does not require any specific order of administering the retinoid and the anti-CD38 antibody. Thus, it may be advantageous to administer the anti-CD38 antibody prior to the retinoid so as to limit or eliminate any side effects of the antibody and/or to optimize the pharmacokinetics of each agent. In some aspects of the second embodiment, the anti-CD38 antibody (e.g., daratumumab) is administered between 6 and 120 hours prior to administration of the retinoid (e.g., a RARA agonist, e.g., tamibarotene).
[0022] In some aspects of both the first and second embodiments, the determination of whether a subject's hematological cancer is CD38", CD3810, CD38dim or CD38hi is made by analyzing the subject's blood cells (e.g., bone marrow, PBMCs and/or enriched PBMCs) using an anti-human CD38 antibody in conjunction with a fluorescence-activated cell sorter (FACS).
[0023] In a third embodiment, the invention provides a method for treating a subject having a hematological cancer, wherein the method comprises co-administering to the subject a retinoid and an anti-CD38 antibody. In some aspects of the third embodiment, the subject is suffering from a hematological cancer selected from multiple myeloma (MM), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, or T-cell acute lymphoblastic leukemia (TALL). In some more specific aspects of the third embodiment, the subject is suffering from a hematological cancer selected from anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma
(DLBCL), Hodgkin lymphoma, or T-cell acute lymphoblastic leukemia (TALL). In some aspects of the third embodiment, the subject is suffering from a hematological cancer selected from multiple myeloma (MM), non-acute promyelocytic myeloid leukemia (non-APL AML), myelodysplastic syndrome (MDS), or chronic lymphocytic leukemia (CLL).
[0024] In some aspects of the third embodiment, the retinoid is a RARA-specific agonist. In more specific aspects of the first embodiment, the retinoid is tamibarotene. In other aspects of the third embodiment, the anti-CD38 antibody is daratumumab.
[0025] In some aspects of the third embodiment, the anti-CD38 antibody (e.g., daratumumab) is administered prior to or after administration of the retinoid (e.g., a RARA agonist, e.g., tamibarotene). In some aspects of the first embodiment, it may be advantageous to administer the anti-CD38 antibody prior to the retinoid so as to limit or eliminate any side effects of the antibody and/or to optimize the pharmacokinetics of each agent. In some aspects of the first embodiment, the anti-CD38 antibody (e.g., daratumumab) is administered between 6 and 120 hours prior to administration of the retinoid (e.g., a RARA agonist, e.g., tamibarotene).
[0026] In any and all embodiments, in some aspects, the present invention features a method for treating a subject having a hematological cancer (e.g., non-APL AML, MDS or MM), wherein the composition comprises an agonist of RARA (e.g., tamibarotene) co- administered with an antibody specific for CD38 (e.g., daratumumab). In some aspects, tamibarotene is administered orally. In some aspects, the subject is administered
tamibarotene at a dosage of between 6 mg/m2/day and 12 mg/m2/day, wherein said dosage is divided into two doses. In some aspects, the anti-CD38 antibody is administered no more than once a week at a dose of between 10-20 mg/kg body weight of the subject.
[0027] The details of one or more embodiments of the invention are set forth herein.
Other features, objects, and advantages of the invention will be apparent from the Detailed Description, the Figures, the Examples, and the Embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] Figs. 1 A- IF depict the effect of tamibarotene ("SY1425") on CD38 levels in various AML cell lines. Figs. 11A-11D demonstrate the effect of tamibarotene on different cell lines as measured by FITC cell sorting. Fig. HE is a graphical representation of the CD38 mRNA levels in various cell lines before and after treatment with tamibarotene. Fig. 1 IF is a graphical representation of the % of cells that are positive for CD38 as determined by FITC cell sorting.
[0029] Figs. 2A-2D depict the effect of tamibarotene and daratumumab ("Dara"), alone or in combination, on NK cell proliferation and tumor cell death in various NK cell/ AML cell line co-cultures, as observed by phase contrast microscopy.
[0030] Figs. 3A-3C depict the effect of a control antibody or Dara alone or in combination with tamibarotene on the number of apoptotic cells in NK cell/ AML co-culture for various AML cell lines.
[0031] Fig. 4 depicts the effect of a control antibody or Dara alone or in
combination with tamibarotene on interferon-gamma secretion in a NK cell/ AML co-culture for the various AML cell lines depicted in Figs. 3A-3C.
[0032] Figs. 5A-5B depict the effect of a control antibody or Dara alone or in combination with tamibarotene on CD38 levels in two different multiple myeloma cell line (MM1S; Fig. 5A) (HUNS1; Fig. 5B) as measured by FITC cell sorting.
[0033] Fig. 6 depicts the effect of a control antibody or Dara alone or in
combination with tamibarotene on the number of apoptotic cells in two different multiple myeloma cell line co-cultured with NK cells.
[0034] Fig. 7 depicts the effect of a control antibody or Dara alone or in combination with tamibarotene on interferon-gamma secretion in a NK cell/multiple myeloma co-culture for the various multiple cell lines depicted in Figs. 5A-5B and 6.
[0035] Fig. 8A depicts the effect of tamibarotene treatment on the expression of
CD38 in various AML and MDS patient samples after 24 or 48 hours. Fig. 8B depicts the effect of tamibarotene treatment on the expression of CD38 in various AML and MDS patient samples after 24 or 48 hours as measured by FACS, as well as the expression of RARA and IRF8 mRNA as measured by qPCR.
[0036] Figs. 9A-9D compares the effect of tamibarotene treatment on CD38 levels in an AML cell line, an AML patient sample, and a multiple myeloma cell line, as well as the baseline CD38 level in a CD38hl multiple myeloma patient sample.
[0037] Figs 10A-10D compare the effect of tamibarotene and all-trans retinoic acid
(ATRA) on CD38 levels in a mouse MV4-11 xenograft model after one week (Figs. 10A and 10B) and three weeks (Figs. IOC and 10D). Tumor cells were tested for the presence of CD38 by both FACS (Figs. 10A and IOC) and immunohistochemical (IHC) staining (Figs. 10B and 10D).
[0038] Fig. 11 compares the effect of tamibarotene and all-trans retinoic acid
(ATRA) on CD38 levels in a mouse THP-1 xenograft model after one week as measured by FACS.
[0039] Fig. 12 compares the effect of tamibarotene and all- trans retinoic acid (ATRA) on CD38 levels in a mouse Kasumi-1 xenograft model after one week as measured by FACS.
[0040] Fig. 13 compares the effect of tamibarotene and all- trans retinoic acid
(ATRA) on CD38 levels in mouse THP-1, Kasumi-1 and MV4-11 xenograft models after one week as measured by IHC.
[0041] Fig. 14 depicts the effect of various treatments on the size of a xenograft
MV-411 tumor over time in a mouse.
[0042] Fig. 15A-15E depict sections of xenograft MV-411 tumors removed from mice following various treatments and stained with anti-human CD38 antibody.
[0043] Fig. 16 depicts the effect of various treatments on the size of a xenograft MM1S tumor over time in a mouse.
[0044] Fig. 17 depicts the effect of various treatments on the size of a xenograft
L1210 tumor over time in a mouse.
DEFINITIONS
[0045] As used herein, the terms "administer," "administering," or
"administration," as used herein refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing an inventive compound, or a pharmaceutical composition thereof.
[0046] As used herein, the term the term "agonist" may be used to refer to an agent, condition, or event whose presence, level, degree, type, or form correlates with increased level or activity of another agent (i.e. , the agonized agent). In general, an agonist may be or include an agent of any chemical class including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and/or any other entity that shows the relevant activating activity. In some embodiments, an agonist may be direct (in which case it exerts
its influence directly upon its target); in some embodiments, an agonist may be indirect (in which case it exerts its influence by other than binding to its target; e.g. , by interacting with a regulator of the target, so that level or activity of the target is altered).
[0047] The term "biological sample" refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g. , cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsied tissue (e.g. , obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample. Biological samples also include those biological samples that are transgenic, such as transgenic oocyte, sperm cell, blastocyst, embryo, fetus, donor cell, or cell nucleus. In some aspects, a biological sample from a subject suffering from a hematological cancer (e.g., AML, MDS, CLL or MM) is a bone marrow aspirate. In other aspects, a biological sample from a subject suffering from a hematological cancer is a fractionated whole blood sample. In more specific aspects, a biological sample from a subject suffering from a hematological cancer is a PBMC fraction from the subject's whole blood (a "PBMC sample"). In still more specific aspects, a PBMC sample from a subject suffering from a hematological cancer is further enriched for specific blasts using various enrichment techniques such as antibody-linked bead enrichment protocols, fluorescent label cell sorting, or other techniques known in the art (an "enriched PBMC sample").
[0048] As used herein, the term "biomarker" refers to an entity whose presence, level, or form, correlates with a particular biological event or state of interest, so that it is considered to be a "marker" of that event or state. To give but a few examples, in some embodiments, a biomarker may be or comprises a marker for a particular disease state or stage, or for likelihood that a particular disease, disorder or condition may develop. In some embodiments, a biomarker may be or comprise a marker for a particular disease or therapeutic outcome, or likelihood thereof. Thus, in some embodiments, a biomarker is predictive, in some embodiments, a biomarker is prognostic, in some embodiments, a biomarker is diagnostic, of the relevant biological event or state of interest. A biomarker may be an entity of any chemical class. For example, in some embodiments, a biomarker may be or comprise a nucleic acid, a polypeptide, a lipid, a carbohydrate, a small molecule, an
inorganic agent (e.g. , a metal or ion), or a combination thereof. In some embodiments, a biomarker is a cell surface marker. In some embodiments, a biomarker is intracellular. In some embodiments, a biomarker is found outside of cells (e.g. , is secreted or is otherwise generated or present outside of cells, e.g. , in a body fluid such as blood, urine, tears, saliva, cerebrospinal fluid, etc. In some embodiments, term refers to a gene expression product that is characteristic of a particular tumor, tumor subclass, stage of tumor, etc. Alternatively or additionally, in some embodiments, a presence or level of a particular marker correlates with activity (or activity level) of a particular signaling pathway, for example that may be characteristic of a particular class of tumors. The statistical significance of the presence or absence of a biomarker may vary depending upon the particular biomarker. In some embodiments, detection of a biomarker is highly specific in that it reflects a high probability that the tumor is of a particular subclass. Such specificity may come at the cost of sensitivity (e.g. , a negative result may occur even if the tumor is a tumor that would be expected to express the biomarker).
[0049] The terms "co-administer" or "co- administering" as used herein in the context of the administration of therapies (e.g., a RARA agonist and an antibody specific for CD38), indicates that one therapy may be used in combination with another therapy or therapies during the course of the subject's affliction with the disorder. In some
embodiments, the administration of therapies is simultaneous or concurrent, meaning that the delivery of one treatment is still occurring when the delivery of the second begins. In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered. Here, a RARA agonist and an antibody specific to CD38 can be administered simultaneously, in the same or in separate compositions, or sequentially. For sequential administration, the RARA agonist can be administered first, and the antibody specific to CD38 can be administered second, or the
order of administration can be reversed.
[0050] As used herein, the terms "condition," "disease," and "disorder" are used interchangeably.
[0051] An "effective amount" of a compound described herein, such a RARA agonist and/or an antibody specific for CD38, refers to an amount sufficient to elicit the desired biological response, i.e. , treating the condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound described herein, such a RARA agonist and/or an antibody specific for CD38, may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In some embodiments, an effective amount encompasses therapeutic and prophylactic treatment. In other embodiments, an effective amount encompasses only therapeutic treatment. For example, in treating cancer, an effective amount of an inventive compound or composition may reduce the tumor burden or stop the growth or spread of a tumor.
[0052] A "subject" to which administration is contemplated includes, but is not limited to, humans (i.e. , a male or female of any age group, e.g. , a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g. , young adult, middle-aged adult, or senior adult)) and/or other non-human animals, for example, mammals (e.g. , primates (e.g. , cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g. , commercially relevant birds such as chickens, ducks, geese, and/or turkeys). In certain embodiments, the animal is a mammal. The animal may be a male or female and at any stage of development. A non-human animal may be a transgenic animal. In certain embodiments, the subject is a human.
[0053] A "therapeutically effective amount" of a compound described herein, such a RARA agonist and/or an antibody specific for CD38, is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. In some embodiments, a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.
[0054] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a "pathological condition" (e.g. , a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein. In some embodiments, "treatment," "treat," and "treating" require that signs or symptoms of the disease disorder or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g. , in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
RARA Agonists and Antibodies Targeting CD38
[0055] The present invention features methods of treating a subject having cancer
(e.g., non-APL AML, MDS or MM) with a RARA agonist in combination with an antibody specific for CD38, for example, when a biomarker for RARA or IRF8 is identified
RARA Asonists
[0056] The choice of RARA agonist with which to treat a patient identified as having a super enhancer associated with a RARA gene may be made from any RARA agonist known in the art. It is preferable that the RARA agonist utilized in the methods of the invention be specific for RARA and have significantly less (at least 10X less, at least 100X less, at least 1,000X less, at least 10,000X less, at least 100,000X less) agonistic activity against other forms of RaR, e.g., RaR-β and RaR-γ.
[0057] In some embodiments, the RARA agonist is selected from a compound disclosed in or any compound falling within the genera set forth in any one of the following United States patents: US 4,703,110, US 5,081,271, US 5,089,509, US 5,455,265, US 5,759,785, US 5,856,490, US 5,965,606, US 6,063,797, US 6,071,924, US 6,075,032, US 6,187,950, US 6,355,669, US 6,358,995, and US 6,387,950, each of which is incorporated by reference.
[0058] In some embodiments, the RARA agonist is selected from any of the following known RARA agonists set forth in Table 1, or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the foregoing:
Table 1. Exemplary RARA Agonists useful in the invention.
Structure Code Name(s)
Am-580; CD- 336; Ro-40- 6055
AM- 80;
INNO-507; NSC-608000; OMS-0728; TM-411; TOS- 80; TOS-80T; Z-208;
tamibarotene
Am-555S; TAC-101; amsilarotene
ER-34617
0 ER-38930
[0059] In some embodime tamibarotene. In some
[0060] CD38 is a transmembrane glycoprotein involved in a number of metabolic functions including the catabolism of extracellular nucleotides, receptor-mediated adhesion, regulation of migration, and a variety of signaling events. Antibodies targeting CD38 may modulate any one of these functions, thus contributing to the efficacy of a RARA agonist in the treatment of a cancer. In some embodiments, the antibody specific for CD38 may recognize and/or bind to any portion of fragment of CD38. The antibody specific for CD38
may comprise a monoclonal antibody, a humanized antibody, or a human antibody.
Exemplary antibodies that are specific for CD38 include isatuximab, daratumumab,
MOR202, Ab79, Abl9, and EPR4106. In some embodiments, the antibody specific for CD38 is daratumumab.
Therapeutic Regimens
[0061] In some embodiments, the subject to be treated with a RARA agonist (e.g. , tamibarotene) and an antibody specific for CD38 is suffering from relapsed or refractory non- APL AML. A subject is classified as having relapsed or refractory non-APL AML if they: a) do not demonstrate a partial response after a first cycle of induction chemotherapy; or b) do not demonstrate a complete response after a second cycle of induction chemotherapy; or c) relapse after conventional chemotherapy; or d) relapse are undergoing a single stem cell transplantation. In some embodiments, the subject to be treated with a RARA agonist (e.g. , tamibarotene) and an antibody specific for CD38 is suffering from refractory MM.
[0062] In other embodiments, the subject to be treated with a RARA agonist (e.g. , tamibarotene) is an elderly unfit subject. The term "elderly unfit" as used herein means the subject is a human at least 60 years of age and who is determined by a physician to not be a candidate for standard induction therapy.
[0063] In some embodiments, the subject is co-administered a RARA agonist (e.g., tamibarotene) and an antibody specific to CD38 (e.g., daratumumab). In some embodiments, the RARA agonist (e.g., tamibarotene) is administered simultaneously with the antibody specific to CD38 (e.g., daratumumab). In some embodiments, the RARA agonist (e.g., tamibarotene) and the antibody specific to CD38 (e.g., daratumumab) are administered within about 1 hour to about 48 hours of one another. In some embodiments, the RARA agonist (e.g., tamibarotene) and an antibody specific to CD38 (e.g., daratumumab) are administered within about 1 minute, about 2 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 36 hours, or about 48 hours of one another.
[0064] In some embodiments, a patient population includes one or more subjects
(e.g. , comprises or consists of subjects) who received previous therapy for treatment of cancer (e.g. , non-APL AML, MDS or MM). In some embodiments, a patient population includes one or more subjects (e.g. , comprises or consists of subjects) who have not received
previous therapy for treatment of cancer (e.g. , non-APL AML, MDS or MM). In some embodiments, a patient population comprises or consists of patients who have not received previous therapy for treatment of non-APL AML, MDS or MM.
[0065] In some embodiments, a patient who received previous therapy may have received previous therapy selected from the group consisting of chemotherapy,
immunotherapy, radiation therapy, palliative care, surgery, and combinations thereof. In some embodiments, a patient has received a transplant. In some embodiments, a patient has received standard cytotoxic chemotherapy. In some embodiments, standard cytotoxic chemotherapy includes cytarabine and/or an anthracycline. In some embodiments, standard cytotoxic chemotherapy may include additional chemotherapy and/or hematopoietic stem cell transplantation (HSTC). In some embodiments, a patient has received hypomethylating agents. In some embodiments, a patient has received lenalidomide.
[0066] In some embodiments, a patient population includes one or more subjects
(e.g., comprises or consists of subjects) who have received and/or are receiving other therapy, e.g. , so that a RARA agonist therapy (e.g., tamibarotene) composition is administered in combination with the other therapy (e.g. chemotherapy agents), in addition to an antibody specific for CD38. In some embodiments, such other therapy may comprise or consist of therapy for cancer (e.g., as described herein), pain, nausea, constipation, for treatment of one or more side effects (e.g., pruritus, hair loss, sleeplessness, etc.) associated with cancer therapy, etc., or any combination thereof. The present invention provides a method of treating non-APL AML, MDS or MM, which comprises treating a patient identified as having non- APL AML, MDS or MM, with a therapeutically effective amount of RARA agonist therapy (e.g., tamibarotene) or a pharmaceutically acceptable salt thereof and an antibody specific for CD38.
[0067] In some embodiments, the invention provides a method for treating a patient for non-APL AML, MDS or MM previously treated with a treatment regimen comprising chemotherapy by administering to such a patient a therapeutically effective amount of a RARA agonist (e.g., tamibarotene) and an antibody specific CD38. In some embodiments, the present disclosure provides a method for treating a patient for non-APL AML, MDS or MM where no standard therapies exist. In some embodiments, the present disclosure provides a method for treating a patient that is not suited for standard therapy.
[0068] In some embodiments, a patient or patient population may not be (e.g. , may exclude) a patient who has a previous history of hypersensitivity to an ingredient of tamibarotene. In some embodiments, a patient or patient population may not be (e.g. , may
exclude) a patient who is receiving vitamin A formulations. In some embodiments, a patient or patient population may not be (e.g. , may exclude) a patient who has hypervitaminosis A.
[0069] In some embodiments, a patient or patient population may not be (e.g. , may exclude) an elderly patient. In some embodiments, a patient or patient population may be or include one or more elderly patients. In some embodiments, an elderly patient may be monitored more frequently to detect potential adverse events (including for example, low levels of serum albumin and/or elevated concentrations of free drug in plasma, etc.) as compared with one or more younger patients. In some embodiments, the administration of the RARA agonist and/or the antibody specific CD38 may be reduced, suspended, and/or terminated for an elderly patient determined to display one or more signs of such an adverse event.
Dose Forms and Dosing Regimens
[0070] In general, each active agent (e.g., a RARA agonist or an antibody specific for CD38) for use in accordance with the present invention is formulated, dosed, and administered in a therapeutically effective amount using pharmaceutical compositions and dosing regimens that are consistently with good medical practice and appropriate for the relevant agent(s) and subject. In principle, therapeutic compositions can be administered by any appropriate method known in the art, including, without limitation, oral, mucosal, by- inhalation, topical, buccal, nasal, rectal, or parenteral (e.g., intravenous, infusion, intratumoral, intranodal, subcutaneous, intraperitoneal, intramuscular, intradermal, transdermal, or other kinds of administration). In some embodiments, a RARA agonist (e.g., tamibarotene) will be administered orally. In some embodiments, an antibody specific for CD38 will be administered intravenously.
[0071] In some embodiments, a dosing regimen for a particular active agent may involve intermittent or continuous administration, for example to achieve a particular desired pharmacokinetic profile or other pattern of exposure in one or more tissues or fluids of interest in the subject receiving therapy.
[0072] In some embodiments, different agents administered in combination may be administered via different routes of delivery and/or according to different schedules.
Alternatively, or additionally, in some embodiments, one or more doses of a first active agent is administered substantially simultaneously with, and in some embodiments via a common route and/or as part of a single composition with, one or more other active agents.
[0073] Factors to be considered when optimizing routes and/or dosing schedule for a given therapeutic regimen may include, for example, the particular indication being treated, the clinical condition of a subject (e.g., age, overall health, prior therapy received and/or response thereto, etc.) the site of delivery of the agent, the nature of the agent, the mode and/or route of administration of the agent, the presence or absence of combination therapy, and other factors known to medical practitioners. For example, in the treatment of cancer, relevant features of the indication being treated may include, among other things, one or more of cancer type, stage, location, etc.
[0074] In some embodiments, one or more features of a particular pharmaceutical composition and/or of a utilized dosing regimen may be modified over time (e.g., increasing or decreasing amount of active in any individual dose, increasing or decreasing time intervals between doses, etc.), for example in order to optimize a desired therapeutic effect or response.
[0075] In general, type, amount, and frequency of dosing of active agents in accordance with the present invention are governed by safety and efficacy requirements that apply when relevant agent(s) is/are administered to a mammal, preferably a human. In general, such features of dosing are selected to provide a particular, and typically detectable, therapeutic response as compared with what is observed absent therapy.
[0076] In context of the present invention, an exemplary desirable therapeutic response may involve, but is not limited to, inhibition of and/or decreased tumor growth, tumor size, metastasis, one or more of the symptoms and side effects that are associated with a tumor, as well as increased apoptosis of tumor cells, therapeutically relevant decrease or increase of one or more cell marker or circulating markers and the like. Such criteria can be readily assessed by any of a variety of immunological, cytological, and other methods that are disclosed in the literature.
[0077] In some embodiments, it may be desirable to tailor dosing regimens, and particularly to design sequential dosing regimens, based on timing and/or threshold expression levels of inducible markers, whether for particular types of tumors, particular tumors, particular patient populations (e.g., carrying genetic markers), and/or particular patients. In some such embodiments, therapeutic dosing regimens may be combined with or adjusted in light of detection methods that assess expression of one or more inducible markers prior to and/or during therapy.
[0078] In some embodiments, a RARA agonist (e.g. , tamibarotene) therapy regimen comprises at least one (or includes or consists of exactly one) dose of about 1 mg/m2, 2
mg/m2, 3 mg/m2, 4 mg/m2, 5 mg/m2, 6 mg/m2, 7 mg/m2, 8 mg/m2, 9 mg/m2, 10 mg/m2, 11 mg/m2, 12 mg/m2, 13 mg/m2, 14 mg/m2, 15 mg/m2, 16 mg/m2, or a dose between any two of these values of a RARA agonist (e.g. , tamibarotene). In some embodiments, a RARA agonist (e.g. , tamibarotene) therapy regimen comprises a dose of between 1 mg/m2 and 50 mg/m2. In some embodiments, a RARA agonist (e.g. , tamibarotene) therapy regimen comprises a dose of between 5 mg/m2 and 25 mg/m2. In some embodiments, a RARA agonist (e.g. , tamibarotene) therapy regimen comprises a dose of between 5 mg/m2 and 15 mg/m2. In some embodiments, a RARA agonist (e.g. , tamibarotene) therapy regimen comprises a dose of 12 mg/m2. In some embodiments, a RARA agonist (e.g. , tamibarotene) therapy regimen comprises a dose of 6 mg/m2.
[0079] In some embodiments, a RARA agonist (e.g., tamibarotene) therapy regimen comprises a plurality of doses of a tamibarotene composition. In some such embodiments, a tamibarotene therapy regimen comprises, for example 2, 5, 10, 20, 30, 60, 90, 180, 365 doses or a number of doses between any two of these values and/or comprises a repeated pattern of doses (e.g. , at least one cycle of two daily doses, which cycle may be repeated, optionally with a period of alternative administration, or optionally no administration, separating different cycles). In some embodiments, a tamibarotene therapy regimen is administered twice a day. In some embodiments, a tamibarotene therapy regimen is administered once a day. In some embodiments, a tamibarotene therapy regimen comprises a total dose of 6 mg/m2 to 12 mg/m2, divided as twice daily oral dosing.
[0080] In some embodiments, an antibody specific for CD38 (e.g. , daratumumab) therapy regimen comprises at least one (or includes or consists of exactly one) dose of about 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, or a dose between any two of these values of a an antibody specific for CD38 (e.g. , daratumumab). In some embodiments, an antibody specific for CD38 (e.g. , daratumumab) therapy regimen comprises a dose of between 1 mg/kg and 100 mg/kg. In some embodiments, an antibody specific for CD38 (e.g. , daratumumab) therapy regimen comprises a dose of between 5 mg/kg and 50 mg/kg. In some embodiments, an antibody specific for CD38 (e.g. , daratumumab) therapy regimen comprises a dose of between 10 mg/kg and 20 mg/kg.
[0081] In some embodiments, an antibody specific for CD38 (e.g. , daratumumab) therapy regimen comprises a plurality of doses of a daratumumab composition. In some such embodiments, a daratumumab therapy regimen comprises, for example 2, 5, 10, 20, 30, 60,
90, 180, 365 doses or a number of doses between any two of these values and/or comprises a repeated pattern of doses (e.g. , at least one cycle of two daily doses, which cycle may be repeated, optionally with a period of alternative administration, or optionally no
administration, separating different cycles). In some embodiments, a daratumumab therapy regimen is administered once a week. In some embodiments, a daratumumab therapy regimen is administered no more than once a week. In some embodiments, a daratumumab therapy regimen is administered once every two weeks. In some embodiments, a daratumumab therapy regimen comprises a total dose of 10 mg/kg to 20 mg/kg no more than once a week. Formulations
[0082] A pharmaceutical composition, as used herein, refers to a mixture of a compound, such as tamibarotene or an antibody specific for CD38, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates
administration of the compound to an organism. Pharmaceutical compositions containing a compound may be administered in therapeutically effective amounts by any conventional form and route known in the art including, but not limited to: intravenous, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, and topical administration.
[0083] For oral administration, a compound can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers or excipients well known in the art. Such carriers permit the compounds described herein to be formulated as tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Generally, excipients such as fillers, disintegrants, glidants, surfactants, recrystallization inhibitors, lubricants, pigments, binders, flavoring agents, and so forth can be used for customary purposes and in typical amounts without affecting the properties of the compositions. In some embodiments, the excipient is one or more of lactose hydrate, corn starch, hydroxypropyl cellulose and/or magnesium stearate. In some embodiments, tamibarotene may be formulated with one or more of lactose hydrate, corn starch, hydroxypropyl cellulose and/or magnesium stearate.
[0084] The identification of acceptable formulations of tamibarotene can be achieved by various methods known in the art, for example as described in US 20100048708, which is incorporated herein by reference.
Packaged Pharmaceutical Compositions
[0085] The packaged pharmaceutical compositions of the present invention comprise a written insert or label comprising instructions to use the RARA agonist and the antibody targeting CD38 in a subject suffering from a cancer. The instructions may be adhered or otherwise attached to a vessel comprising the RARA agonist and the antibody targeting CD38. Alternatively, the instructions and the vessel comprising the RARA agonist will be separate from one another, but present together in a single package, box or other type of container.
[0086] The instructions in the packaged pharmaceutical composition will typically be mandated or recommended by a governmental agency approving the therapeutic use of the RARA agonist and the antibody targeting CD38. The instructions may optionally comprise dosing information, the types of cancer for which treatment with the RARA agonist and/or and the antibody targeting CD38 were approved, physicochemical information about the RARA agonist and/or and the antibody targeting CD38; pharmacokinetic information about the RARA agonist and/or and the antibody targeting CD38; or drug-drug interaction information. In some aspects, the instructions direct that the composition be administered to a subject diagnosed as suffering from non-APL AML. In some aspects, the instructions direct that the composition be administered to a subject diagnosed as suffering from non-APL MM. In some aspects, the pharmaceutical composition comprises tamibarotene. In some aspects, the pharmaceutical composition comprises AGN-195183. In some aspects, the pharmaceutical composition comprises daratumumab. In some embodiments, the pharmaceutical composition comprises both tamibarotene and daratumumab.
EXAMPLES
[0087] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.
Example 1. RARA mRNA -dependent CD38 induction in AML cell lines by
tamibarotene
[0088] We monitored the induction of cell surface CD38 expression following tamibarotene treatment by measuring cell surface mean fluorescent intensity (MFI) staining
by CD38-FITC antibody. Fig. 1A shows that 72h tamibarotene treatment at a concentration of 50 nmol/L does not induce CD38 expression in a RARA mRNA low cell line, Kasumi (CD38 ). Fig. IB demonstrates that following 72h tamibarotene treatment of RARA mRNA high cell line, MV411, the entire cell population expresses high levels of CD38 (CD38hl). Furthermore, in Fig. 1C, OCI-AML3 (RARA mRNA high), at baseline, has low CD38 MFI (CD38DIM). Upon tamibarotene treatment, CD38 expression is further induced and the cell population shifts to CD38hl. Fig. ID shows 72h tamibarotene treatment does not induce CD38 expression in another RARA mRNA low cell line, OCI-M1 (CD38 ). These data indicate that CD38hl induction by tamibarotene can be predicted by RARA mRNA level. These results are depicted as a bar graph in Fig. IE, which shows the level of CD38 mRNA expression detected in each cell line before and after treatment. Fig. IF shows the percentage of CD38hi cells based on FACS are shown before and after tamibarotene treatment. In Figs. IE and IF the APL cell line, NB4, is also shown. Example 2. RARA mRNA predicts NK cell mediated cytotoxicity of AML cell line, MV411, following tamibarotene and daratumumab combination therapy
[0089] To functionally evaluate the efficacy of a tamibarotene and daratumumab combination, AML cell lines with differential RARA mRNA levels were treated with tamibarotene for 72 hours then co-cultured with human NK cells with daratumumab or control antibody. NK cell proliferation and tumor cell death were then imaged in phase contrast during a 38h co-culture time course. Figs. 2A-2D are representative images of phase contrast images of RARA mRNA high MV411 cell line in co-culture assay with the following treatment conditions: Fig. 2A) 72h DMSO MV411 cell line pretreatment and 38h co-culture control antibody treatment. Fig. 2B) 72h SY1425 (50nM) MV411 cell line pretreatment and 38h co-culture control antibody treatment. Fig. 2C) 72h DMSO MV411 cell line pretreatment and 38h co-culture daratumumab treatment. Fig. 2D) 72h SY1425 (50nM) MV411 cell line pretreatment and 38h co-culture daratumumab treatment.
Example 3. RARA mRNA level predicts NK cell mediated cytotoxicity of AML cell lines following tamibarotene and daratumumab combination therapy
[0090] Kinetic measurement of NK cell-mediated tumor cell death by annexin V staining of tumor cells supports the finding that tamibarotene and daratumumab treatment combination result in increased tumor cell death in only some AML cell lines (Figs. 3A-3C) in comparison to single agent treatment. These data in combination with the increased
induction of CD38 expression in RARA mRNA high AML cell lines (i.e. OCI-AML3 and MV411), but not in RARA mRNA low AML cell lines (i.e., OCI-Ml) (Figs. IB-ID) support the conclusion that tamibarotene induces CD38hl phenotype in a RARA mRNA-dependent manner, which is required for efficient NK cell-mediated tumor cell death following daratumumab treatment.
Example 4. NK cell activation in co-culture assay only occurs post tamibarotene and daratumumab combination treatment as determined by NK cell IFN gamma secretion.
[0091] Interferon gamma (IFNy) secretion is an indication of NK cell activation. IFNy secretion was quantitated 38h post AML cell line and NK cell co-culture following the indicated treatment conditions (Fig. 4). Significantly increased levels of IFNy are observed following combination treatment with tamibarotene and daratumumab only in the RARA mRNA high AML cell lines (MV411 and OCI-AML3) and NK cell co-culture assay in comparison to single agent treatment conditions. In addition, these are the only cell lines that demonstrate the CD38hl phenotype following tamibarotene treatment. These data further support the Annexin V quantitation (Figs. 2A-2D and 3) indicating efficient NK cell activation requires the combination treatment.
Example 5. Tamibarotene increases the intensity of CD38 expression in multiple myeloma cells.
[0092] Daratumumab is clinically approved for the treatment of multiple myeloma
(MM). However, only a fraction of these patients responds due to low levels of CD38 expression. We demonstrate here that tamibarotene increases the CD38hl phenotype in an already CD38hi multiple myeloma cell line (MM1S) (Fig. 5 A) and can increase a CD38" multiple myeloma cell line to a dim state (HUNS1) (Fig. 5B). Based on the previous AML experiments, we predict that this will may increase the response of CD38hl high subjects to CD38 therapeutic antibody directed immune-mediated death.
Example 6. Tamibarotene increase in CD38ffl phenotype further sensitizes MM cell line to daratumumab dependent NK cell-mediated cytotoxicity.
[0093] To investigate if treatment of MM cell lines with tamibarotene will increase sensitivity to CD38 antibody treatment, we repeated the NK cell co-culture assay described previously with HUNS1 and MM IS MM cell lines. Fig. 6 demonstrates that following tamibarotene and daratumumab combination treatment, MM IS tumor cell death is increased
in comparison to single agent anti-CD38 antibody treatment as quantitated by Annexin V staining. We further confirm this by directly monitoring NK cell activation by ΙΡ γ secretion after 38h treatment in this assay (Fig. 7). The multiple myeloma cell line that achieved high CD38 intensity, MM1S, showed strong cell killing in response to combination treatment.
Example 7. Tamibarotene induces CD38ffl phenotype in primary non-APL AML and MPS patient samples.
[0094] To confirm tamibarotene induction of CD38hl levels in AML cell lines can be extrapolated to AML and MDS patient samples, we cultured PBMCs obtained from 15 different AML or MDS patients with 50nM tamibarotene or with DMSO as a negative control. We tested viability and CD38 induction 24h and 48h post-treatment as measured by flow cytometry. Samples that had at least 10% viability were analyzed for CD38 levels. The results are shown in Fig. 8A. The majority of patient samples (11/15) showed an increase in CD38hl cells 24 hours after treatment. One patient sample showed no response
(Patient 4) and three patient samples did not meet viability criteria after 24h (Patients 2, 6 and 10). After 48h, four additional patient samples that had shown CD38 induction after 48h no longer met viability criteria and were excluded (patients 3, 7, 9 and 14). All of the remaining patient samples except for non-responder Patient 4 showed further induction of CD38 level after 48 h.
[0095] We then measured both RARA and IRF8 mRNA levels in a subset of these patients (Patients 1, 5, 11, 12 and 13), which represented patients that showed some response, were still viable after 48 h, and represented both AML and MDS. As shown in Fig. 8B, those patient samples that showed higher levels of either RARA mRNA and/or IRF8 mRNA as measured by RNA qPCR (the lower the dCq value, the higher the level of mRNA) demonstrated a greater percentage of CD38hl upon tamibarotene treatment as compared to samples with lower RARA mRNA and/or IRF8 mRNA.
[0096] The CD38 induction levels observed for AML patient samples correlated well with results obtained from high RARA RNA AML cell lines (e.g., compare tamibarotene-induced CD38 MFI in patient sample AML_1 with AML cell line MV411 in Fig. 9C-9D). For both, tamibarotene caused an increase in the CD38hl phenotype similar to that observed in daratumumab-sensitive multiple myeloma cell lines and multiple myeloma patients (e.g., compare patient sample MM_1 with multiple myeloma cell line MM1S in Fig. 9A-9B). Based on this correlation, the inventors believe that high RARA mRNA AML patients will
benefit from a combination treatment of a RARA-specific agonist, such as tamibarotene, and an anti-CD38 antibody, such as daratumumab.
Example 8. Tamibarotene Causes a Greater Increase in CD38 Induction than ATRA in AML cell line xenografts having high RARA or IRF8 Levels.
[0097] It has been reported that ATRA causes a greater induction in CD38 levels than tamibarotene in HL-60 cells, an AML cell lines typically characterized as APL (A Uruno et al., 2011, J Leuk Biol, 90, pp 235-247). We wanted to compare the CD38 induction effects of ATRA versus tamibarotene in non-APL AML cell lines having varying levels of either RARA or IRF8 mRNA. In this experiment, we used mouse xenografts of MV411, THP-1, or Kasumi-1. MV411 has a high level of RARA mRNA and IRF8 mRNA (i.e., above a threshold), while THP-1 has a high level of IRF-8 mRNA. Kasumi-1 cells are considered to have levels of IRF8 and RARA that are below the threshold.
[0098] Each of the cell lines were maintained in vitro as suspension cultures in the appropriate medium (THP-1 cells: RPMI1640 medium supplemented with 10% heat inactivated fetal bovine serum and 0.05mM β-mercaptoethanol; MV4-11 cells: IMDM medium supplemented with 10% heat inactivated fetal bovine serum; Kasumi-1 cells:
RPMI1640 medium supplemented with 20% heat inactivated fetal bovine serum), at 37°C in an atmosphere of 5% CO2 in air. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
[0099] All mice were γ-irradiated (200 rads) 24 h before tumor cell inoculation.
Each mouse was inoculated subcutaneously at the right flank region with the appropriate tumor cell line (THP-1 cells: lx 107 cells in 0.1 ml of PBS (1:1 Matrigel); MV4-11 cells: 5 x 106 cells in 0.1 ml of PBS (1:1 Matrigel); Kasumi-1 cells: 1 x 107 cells in 0.1 ml of PBS (1:1 Matrigel)) for tumor development. Treatment with tamibarotene, ATRA or vehicle was started when the mean tumor size reached approximately 100-200 mm3. The mice were divided into 3 groups of nine and each was orally administered drug (ATRA 4 mg/kg;
tamibarotene 3 mg/kg) or vehicle alone BID for up to 28 days. The date of tumor cell inoculation was denoted as day 0. Tumor volumes were measured twice per week in two dimensions using a caliper, and the volume expressed in mm3 using the formula: V = 0.5 a x b2 where a and b are the length and width of the tumor, respectively. Three mice per group were sacrificed on day 7, 14, and 21 after grouping (4-week study total). Half of the tumor was collected for embedding into a FFPE block for immunohistochemistry staining (IHC), and the other half of tumor was collected for CD38 FACS analysis of the tumor cells.
[0100] For embedding into a FFPE block, freshly collected tumor tissue (3-5 mm thickness) was placed in 10% NBF and fixed for 24 hours at room temperature. After rinsing with running water, the specimens were dehydrated in a Vacuum Tissue Processor
(ASP200S, Leica) and then embedded into FFPE blocks using a Leica EG1150 Embedding Station. FFPE blocks were sectioned (3 μιη) on a manual rotary microtome and prepared for IHC staining utilizing a BOND RX autostainer (Leica) following manufacturer's directions and using an anti-CD38 antibody directed against the C-terminus of CD38 (clone SP149; Abeam; Cat. No. abl83326). Antibody was diluted 1:100 in pH 9.0 EDTA buffer and then incubated with tumor slices for 20 minutes. Signal was developed using DAB and the manufacturer's (Leica) Bond Polymer Refine Detection kit.
[0101] As seen in FIG. 10A, after 7 days, tamibarotene-treated MV4-11 xenograft mice showed a mean fluorescence intensity (MFI) of over 200 with over 80% of the tumor cells being CD38hi by FACS analysis. ATRA-treated MV4-11 xenograft mice showed a MFI of slightly over 100 with approximately 70% of the tumor cells being CD38hl.
Immunohistochemical staining of tumor sections with an anti-CD38 antibody confirmed the surprising and unexpected superiority of tamibarotene over ATRA in this xenograft model (FIG. 10B). This trend became even more pronounced at 3 weeks. As shown in FIG. IOC, at three weeks, in tamibarotene-treated MV4-11 xenografts, over 60% of the tumor cells remained CD38hl, with a MFI of around 110, while in ATRA-treated xenografts less than 20% of the tumor cells remained CD38hi with a MFI of around 50. FIG. 10D shows immunohistochemical staining of tumor cells after three weeks, which confirms the superiority of tamibarotene over ATRA.
[0102] As shown in FIG. 11, the superiority of tamibarotene in inducing CD38 after
7 days was also observed in THP-1 cells. Although ATRA-treated xenografts showed a similar percentage of CD38hl cells as compared to tamibarotene, tamibarotene treatment resulted in a higher MFI (over 200) as compared to ATRA (-175). In contrast, Kasumi-1 cells showed very little CD38 induction with either treatment (FIG. 12). An
immunohistochemical comparison of each type of xenograft and each type of treatment after one week is shown in FIG. 13.
Example 9. A combination of Tamibarotene and Daratumumab is superior to a combination of ATRA and Daratumumab in inhibiting the growth of an AML cell line xenograft.
[0103] Subcutaneous MV4-11 xenografts were established in NOD.SCID mice at
Crown Bioscience (Beijing, China), essentially as described in Example 8. Each mouse was inoculated subcutaneously at the right flank region with MV4-11 tumor cells (5 x 106) in 0.1 ml of PBS (1 : 1 matrigel) for tumor development. The treatments were started when the mean tumor size reached approximately 50-150 mm3. The date of tumor cell inoculation was denoted as day 0. During routine monitoring, the animals were checked for any effects of tumor growth and treatments on normal behavior such as mobility, visual estimation of food and water consumption, body weight gain/loss (body weights measured twice per week), eye/hair matting and any other abnormal effect.
[0104] Tumor volumes were measured twice per week in two dimensions using a caliper, and the volume expressed in mm3 using the formula: V = 0.5x a x b2 where a and b are the length and width of the tumor, respectively. The entire procedures of dosing as well as tumor and body weight measurement was conducted in a Laminar Flow Cabinet.
[0105] Tamibarotene was formulated by using a DMSO stock solution (30 mg/ml), diluted 1/100 into PBS to make a final solution at 0.3 mg/ml adjusted to pH 8. Tamibarotene was administered at 3 mg/kg in a 10 ml/kg volume PO twice a day for 28 days. ATRA (Tretinoin) was formulated by using a DMSO stock solution (40mg/ml), diluted 1/100 into PBS to make a final solution at 0.4 mg/ml adjusted to pH 8. ATRA was administered at 4 mg/kg in a 10 ml/kg volume PO twice a day for 28 days.
[0106] Mice in the combination arm were given the same dosing schedules, volumes, and formulations for each agent. Mice in the vehicle arm were given the same dosing schedules, volumes, and formulations, but lacking SY-1425 or ATRA and daratumumab. Tumor volumes were measured twice weekly over the course of the study.
[0107] Daratumumab was formulated in PBS to a solution of O.lmg/ml.
Daratumumab was administered i.v at 1 mg/kg once a week on week 1 and week 3.
[0108] Three mice per arm were sacrificed prior to dosing to collect tumor. Each tumor was embedded into FFPE block for H.E. staining, and IHC staining with Human CD38. The remaining tumors were harvested at termination of the study and, each half tumor was embedded into FFPE block as described in the previous example, with the 2nd half being snap frozen.
[0109] The results of these studies are shown in FIGS. 14 and 15A-14E. In FIG.
14, it can be seen that at day 25 only treatment with a combination of SY-1425 and daratumumab resulted in a significantly smaller tumor size than the vehicle control. In FIG. 15A-15E, tumor tissue from different treatment regimens is IHC stained for human CD38.
Treatment with SY-1425 alone or in combination with daratumumab shows greater CD38 staining than ATRA alone, ATRA in combination with daratumumab, or vehicle control.
Example 10. A combination of Tamibarotene and Daratumumab is superior to a combination of ATRA and Daratumumab in inhibiting the growth of a multiple myeloma cell line xenograft.
[0110] Subcutaneous MM1S xenografts were established in NOD.SCID mice at
Crown Bioscience (Beijing, China). All mice were γ-irradiated (200 rads) 24 h before tumor cell inoculation. Each mouse was inoculated subcutaneously at the right flank region with MM.1S tumor cells (1 x 107) in 0.1 ml of PBS for tumor development. The treatments were started when the mean tumor size reaches approximately 150 (100-200) mm3. The date of tumor cell inoculation was denoted as day 0.
[0111] Tumor volumes were measured twice per week in two dimensions using a caliper, as described in the previous Example. Dosages and dosing of tamibarotene, ATRA and daratumumab and preparation of tumors for analysis were as described in the previous example. The results of these studies are shown in FIG. 16, where treatment with SY-1425 alone or in combination with daratumumab were the only treatment to demonstrate significant inhibition of MM IS xenograft growth over the vehicle control. Example 11. A combination of Tamibarotene and an anti-mouse CD38 antibody is superior to a combination of ATRA and the anti-mouse CD38 antibody in inhibiting the growth of a lymphocytic leukemia cell line xenograft.
[0112] L1210 tumor cells were maintained in vitro as suspension culture in DMEM medium supplemented with 10% heat inactivated fetal bovine serum at 37°C in an atmosphere of 5% CO2 in air. The tumor cells were routinely subcultured twice weekly. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
[0113] Each mouse was inoculated subcutaneously at the right lower flank region with L1210 tumor cells (2xl05) in 0.1 ml of PBS for tumor development. The treatments were started when the mean tumor size reaches approximately 50-100 mm3. The date of tumor cell inoculation is denoted as day 0.
[0114] Tumor volumes were measured twice per week in two dimensions using a caliper, as described in the previous Example. Dosages and dosing of tamibarotene and ATRA and preparation of tumors for analysis were as described in the previous example.
Anti-CD38 (Rat mAb CD38, NIMR-5) was formulated in PBS to a solution of 1 mg/ml. It was administered i.v at 10 mg/kg BIW for 4 weeks.
[0115] The results are shown in FIG. 17, where there is a trend toward the anti-
CD38 antibody acting synergistic ally with SY-1425 as compared to with ATRA. This can be seen by comparing the difference in effect between SY1425 alone and SY-1425 + anti-CD38 antibody versus the difference between ATRA alone and ATRA + anti-CD38 antibody. The differential decrease in tumor growth caused by adding the anti-CD38 antibody to SY-1425 was greater than the differential decrease caused by adding that antibody to ATRA. Equivalents and Scope
[0116] In the embodiments articles such as "a," "an," and "the" may mean one or more than one unless indicated to the contrary or otherwise evident from the context.
Embodiments or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
[0117] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed embodiments is introduced into another embodiment. For example, any embodiment that is dependent on another embodiment can be modified to include one or more limitations found in any other embodiment that is dependent on the same base embodiment. Where elements are presented as lists, e.g. , in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms "comprising" and "containing" are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise
indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
[0118] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the embodiments. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any embodiment, for any reason, whether or not related to the existence of prior art.
[0119] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended embodiments. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following embodiments.
Claims
1. A method of treating a human subject suffering from a disease selected from a hematological cancer and MDS comprising co- administering to the subject tamibarotene and an antibody specific for CD38.
2. The method of claim 1, wherein the antibody specific for CD38 is daratumumab.
3. The method of claim 1 or 2, wherein the subject is administered tamibarotene for a period of time prior to administration of the antibody specific for CD38; and is coadministered the antibody specific for CD38 only when the CD38 level in the subject has been determined to be CD38hl following initial administration of tamibarotene.
4. The method of claim 3, wherein the CD38 level in the subject is determined at one or more of 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, and 14 days following the initial administration of tamibarotene.
5. The method of any one of claims 1-4, wherein the subject is suffering from a disease selected from multiple myeloma, non-APL AML, chronic lymphocytic leukemia, and MDS.
6. A method of selecting and treating a human subject suffering from a disease selected from a hematological cancer and MDS comprising the steps of:
a. selecting the subject on the basis of being unresponsive to prior treatment with a CD38 inhibitor as a monotherapy; and
b. co-administering to the selected subject tamibarotene and an antibody specific for CD38.
7. The method of claim 6, wherein the antibody specific for CD38 is daratumumab.
8. The method of claim 6 or 7, wherein the subject is administered tamibarotene for a period of time prior to administration of the antibody specific for CD38; and is coadministered the antibody specific for CD38 only when the CD38 level in the subject has
been determined to be CD38 1 following initial administration of tamibarotene.
9. The method of claim 8, wherein the CD38 level in the subject is determined at one or more of 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, and 14 days following the initial administration of tamibarotene.
10. The method of any one of claims 6-9, wherein the subject is suffering from a disease selected from multiple myeloma, non-APL AML, chronic lymphocytic leukemia, and MDS.
11. A method of selecting and treating a human subject suffering from a disease selected from a hematological cancer and MDS comprising the steps of:
a. selecting the subject on the basis of having been unresponsive to prior
treatment with a CD38 inhibitor as a monotherapy; and
b. co-administering to the selected subject tamibarotene and an antibody specific for CD38.
12. The method of claim 6, wherein the antibody specific for CD38 is daratumumab.
13. The method of claim 6 or 7, wherein the subject is administered tamibarotene for a period of time prior to administration of the antibody specific for CD38; and is coadministered the antibody specific for CD38 only when the CD38 level in the subject has been determined to be CD38hl following initial administration of tamibarotene.
14. The method of claim 8, wherein the CD38 level in the subject was determined between 6 and 72 hours following the initial administration of tamibarotene.
15. The method of any one of claims 6-9, wherein the subject is suffering from a disease selected from multiple myeloma, non-APL AML, chronic lymphocytic leukemia, and MDS.
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762449450P | 2017-01-23 | 2017-01-23 | |
US62/449,450 | 2017-01-23 | ||
US201762564690P | 2017-09-28 | 2017-09-28 | |
US62/564,690 | 2017-09-28 | ||
USPCT/US2017/0055562 | 2017-10-06 | ||
PCT/US2017/055562 WO2018067946A1 (en) | 2016-10-06 | 2017-10-06 | Methods of treating patients with a retinoic acid receptor-alpha agonist and an anti-cd38 antibody |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2018136961A1 true WO2018136961A1 (en) | 2018-07-26 |
Family
ID=62909176
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2018/014904 WO2018136961A1 (en) | 2017-01-23 | 2018-01-23 | METHODS OF TREATING PATIENTS WITH A RETINOIC ACID RECEPTOR-α AGONIST AND AN ANTI-CD38 ANTIBODY |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2018136961A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10697025B2 (en) | 2015-03-31 | 2020-06-30 | Syros Pharmaceuticals, Inc. | Methods of stratifying patients for treatment with retinoic acid receptor-alpha agonists |
US11053552B2 (en) | 2016-04-08 | 2021-07-06 | Syros Pharmaceuticals, Inc. | Methods of stratifying patients for treatment with retinoic acid receptor-α agonists |
RU2826217C1 (en) * | 2019-11-13 | 2024-09-05 | Тайхо Фармасьютикал Ко., Лтд. | Methods of treating diseases and disorders associated with lsd1, lsd1 inhibitors |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160235842A1 (en) * | 2013-07-15 | 2016-08-18 | The Board Of Trustees Of The Leland Stanford Junior University | Medical uses of cd38 agonists |
US20160355888A1 (en) * | 2015-03-31 | 2016-12-08 | Syros Pharmaceuticals, Inc. | Methods of stratifying patients for treatment with retinoic acid receptor-alpha agonists |
-
2018
- 2018-01-23 WO PCT/US2018/014904 patent/WO2018136961A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160235842A1 (en) * | 2013-07-15 | 2016-08-18 | The Board Of Trustees Of The Leland Stanford Junior University | Medical uses of cd38 agonists |
US20160355888A1 (en) * | 2015-03-31 | 2016-12-08 | Syros Pharmaceuticals, Inc. | Methods of stratifying patients for treatment with retinoic acid receptor-alpha agonists |
Non-Patent Citations (5)
Title |
---|
ATANACKOVIC ET AL.: "Immunotherapies targeting CD 38 in Multiple Myeloma", ONCOIMMUNOLOGY, vol. 5, no. 11, 2016, pages 1 - 11, XP055505109 * |
HOFMANN WOLF-K. ET AL.: "Myelodysplastic Syndrome", ANNUAL REVIEW OF MEDICINE, 26 November 2016 (2016-11-26), pages 1 - 5, XP055505130 * |
NIJHOF ET AL.: "Upregulation of CD 38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab", vol. 29, 5 June 2015 (2015-06-05), pages 2039 - 2049, XP002778367 * |
URUNO ET AL.: "All-trans retinoic acid and a novel synthetic retinoid tamibarotene (Am80) differentially regulate CD 38 expression in human leukemia HL-60 cells: possible involvement of protein kinase C-[delta", JOURNAL OF LEUKOCYTE BIOLOGY, vol. 90, August 2011 (2011-08-01), pages 235 - 247, XP002750180 * |
WHAT IS MULTIPLE MYELOMA?, 24 September 2016 (2016-09-24), pages 1 - 2 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10697025B2 (en) | 2015-03-31 | 2020-06-30 | Syros Pharmaceuticals, Inc. | Methods of stratifying patients for treatment with retinoic acid receptor-alpha agonists |
US11447831B2 (en) | 2015-03-31 | 2022-09-20 | Syros Pharmaceuticals, Inc. | Methods of stratifying patients for treatment with retinoic acid receptor-alpha agonists |
US11053552B2 (en) | 2016-04-08 | 2021-07-06 | Syros Pharmaceuticals, Inc. | Methods of stratifying patients for treatment with retinoic acid receptor-α agonists |
RU2826217C1 (en) * | 2019-11-13 | 2024-09-05 | Тайхо Фармасьютикал Ко., Лтд. | Methods of treating diseases and disorders associated with lsd1, lsd1 inhibitors |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Smith et al. | Fibroblasts expressing the thyrotropin receptor overarch thyroid and orbit in Graves' disease | |
Kimura et al. | Lymphatic dysfunction attenuates tumor immunity through impaired antigen presentation | |
Li et al. | Activation of the NLRP3 inflammasome pathway by prokineticin 2 in testicular macrophages of uropathogenic Escherichia coli-induced orchitis | |
US20210030703A1 (en) | Use of caloric restriction mimetics for potentiating chemo-immunotherapy for the treatment of cancers | |
KR20200019619A (en) | Dosing Parameters for CD47 Targeted Therapies for Hematologic Malignancies | |
Juel et al. | Inflammatory cytokines protect retinal pigment epithelial cells from oxidative stress-induced death | |
Kang et al. | The p110δ subunit of PI3K regulates bone marrow-derived eosinophil trafficking and airway eosinophilia in allergen-challenged mice | |
US20100256232A1 (en) | Cancer Therapy | |
Jabbour et al. | The immune microenvironment in cutaneous leishmaniasis | |
TW202015732A (en) | Biomarkers for determining efficacy of immune checkpoint inhibitor | |
Li et al. | AMD3100 inhibits brain-specific metastasis in lung cancer via suppressing the SDF-1/CXCR4 axis and protecting blood-brain barrier | |
Hussain et al. | CXCL13 signaling in the tumor microenvironment | |
JP7235259B2 (en) | Modulation of inflammasome activation of myeloid-derived suppressor cells to treat GVHD or tumors | |
JP2019214576A (en) | Method of screening of compounds using membrane stim1 | |
WO2018136961A1 (en) | METHODS OF TREATING PATIENTS WITH A RETINOIC ACID RECEPTOR-α AGONIST AND AN ANTI-CD38 ANTIBODY | |
KR102423631B1 (en) | Compositions and Combination Therapies for Preventing or Treating Cancer comprising Chemokine Inhibitor, Colony Stimulating Factor Inhibitor, and Immune Checkpoint Inhibitor | |
Tian et al. | Rational design of innate defense regulator peptides as tumor vaccine adjuvants | |
Geller et al. | C‐C chemokine receptor 4 expression in CD8+ cutaneous T‐cell lymphomas and lymphoproliferative disorders, and its implications for diagnosis and treatment | |
US20240408071A1 (en) | Novel combination of serotonin receptor (5-htr2b) antagonist and an immunomodulator and chemotherapeutic drugs for inhibition of cancer | |
WO2011088402A2 (en) | The use of entrained neutrophils to treat metastatic and micrometastatic disease in at risk patients | |
Zheng et al. | The mechanism of EZH2/H3K27me3 downregulating CXCL10 to affect CD8+ T cell exhaustion to participate in the transformation from myelodysplastic syndrome to acute myeloid leukaemia | |
JP7560893B2 (en) | Modified macrophages, compositions and uses thereof | |
Song et al. | Rosiglitazone prevents graft-versus-host disease (GVHD) | |
Luo et al. | Mutant monocyte chemoattractant protein-1 protein (7ND) inhibits osteoclast differentiation and reduces oral squamous carcinoma cell bone invasion | |
JP2019516803A (en) | Pharmaceutical composition and its use in the treatment of autoimmune diseases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18741420 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 18741420 Country of ref document: EP Kind code of ref document: A1 |