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WO2018067819A1 - Compositions et méthodes de traitement de cancers - Google Patents

Compositions et méthodes de traitement de cancers Download PDF

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Publication number
WO2018067819A1
WO2018067819A1 PCT/US2017/055345 US2017055345W WO2018067819A1 WO 2018067819 A1 WO2018067819 A1 WO 2018067819A1 US 2017055345 W US2017055345 W US 2017055345W WO 2018067819 A1 WO2018067819 A1 WO 2018067819A1
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subject
biomarkers
cancer
metastasis
median
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PCT/US2017/055345
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Charles Theuer
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Tracon Pharmaceuticals, Inc.
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Publication of WO2018067819A1 publication Critical patent/WO2018067819A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • 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
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • 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
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • Endoglin also known as, inter alia, CD105 or edg-1, is a type I homodimeric membrane glycoprotein which is expressed at high levels in proliferating vascular endothelial cells. However, there is some expression of endoglin by the vascular endothelium of normal tissues. Human endoglin is known to specifically bind transforming growth factor- ⁇ (TGF- ⁇ ), and the deduced amino acid sequence of endoglin has strong homology to ⁇ -glycan, a type of TGF- ⁇ receptor.
  • TGF- ⁇ transforming growth factor- ⁇
  • a method of treating a cancer or a metastasis thereof in a subject in need thereof comprising detecting whether one or more biomarkers are present in a sample from the subject by contacting the sample with one or more antibodies that bind to the one or more biomarkers and detecting binding between the one or more biomarkers and the one or more antibodies; comparing a baseline value of the one or more biomarkers of the subject to a baseline value of a healthy subject; and administering to the subject one or more doses of a pharmaceutical composition that comprises a vascular endothelial growth factor (VEGF) inhibitor or a VEGF receptor (VEGFR) inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody when the baseline value of the one or more biomarkers in the subject to be treated are above or below a median or mean level in a subject with the cancer or a metastasis thereof.
  • VEGF vascular endothelial growth factor
  • VEGFR VEGF receptor
  • a method of selecting a subject for treatment for a cancer or a metastasis thereof comprising: detecting whether one or more biomarkers are present in a sample from the subject by contacting the sample with one or more antibodies that bind to the one or more biomarkers and detecting binding between the one or more biomarkers and the one or more antibodies; comparing a baseline value of the one or more biomarkers of the subject to a baseline value of a healthy subject; and selecting the subject for treatment with one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor or a VEGFR inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody when the baseline value of the one or more biomarkers in the subject to be treated are above or below a median or mean level in the subject with the cancer or a metastasis thereof.
  • Also provided herein is a method of treating a cancer or a metastasis thereof in a subject in need thereof, comprising detecting whether one or more biomarkers are present in a sample from the subject diagnosing the subject with a cancer or metastasis when the presence of the one or more biomarkers in the sample are detected; and administering to the subject one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor or a VEGFR inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody when a baseline value of the one or more biomarkers in the subject to be treated is above a median or mean level in a subject with the cancer or a metastasis thereof.
  • a method of selecting a subject for treatment for a cancer or a metastasis thereof comprising: detecting whether one or more biomarkers are present in a sample from the subject, wherein detecting comprises contacting a sample from the subject with one or more one or more antibodies that bind to the one or more biomarkers and detecting binding between the one or more biomarkers and the one or more antibodies; and selecting the subject for treatment with one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor or a VEGFR inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody when the baseline value of the one or more biomarkers in the subject to be treated are above or below a median or mean level in the subj ect with the cancer or a metastasis thereof.
  • Detection in such methods can be an enzyme assay including, but not limited to, an Enzyme Linked Immunosorbent Assay (ELISA), a competitive ELISA, fluorescent activated cell sorter (FACS), etc.
  • ELISA Enzyme Linked Immunosorbent Assay
  • FACS fluorescent activated cell sorter
  • Detection can occur prior to treatment, during treatment, or after completion of treatment at one or more time points.
  • a cancer to be treated includes, but is not limited to, a breast cancer, a lung cancer, a brain cancer, a sarcoma, a carcinoma, or a metastasis of any of such cancers.
  • a carcinoma can be, for example, a renal cell carcinoma which can be, in some instances, an advanced renal cell carcinoma.
  • the carcinoma is a renal cell carcinoma which can be, in some instances, a metastatic renal cell carcinoma.
  • the carcinoma is a hepatocellular carcinoma or a choriocarcinoma.
  • the cancer or metastasis thereof is a brain cancer such as, for example, a glioblastoma multiforme (GBM).
  • GBM glioblastoma multiforme
  • the cancer or metastasis thereof is a breast cancer such as, for example, a Luminal A, a Luminal B, a Luminal B-like, a Triple negative or a HER2 type breast cancer.
  • a subject can be treated for a length of time sufficient to prolong the life expectancy of the subject; or to partially or completely treat the cancer or metastasis thereof.
  • a subject can be administered treatment for about 1, about 2, about 3, about 4, about 5, about 6, about 7 or more days.
  • a subject can be administered treatment for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12 or more weeks.
  • a subject can be administered treatment for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12 or more months.
  • a subject can be administered treatment for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12 or more years.
  • the days, weeks, months or years of treatment can be consecutive. Alternatively, the days, weeks, months or years of treatment may not be consecutive. For example, if the subject enters remission, then treatment can be discontinued; if the subject shows presence of one or more abnormal biomarkers after being in remission, treatment can be reinstated. In other instances, a subject to be treated with the recited methods may have received surgery or treatment with a different anti-tumor agent.
  • composition comprising the anti-endoglin antibody and the
  • composition comprising the VEGF inhibitor or the VEGFR inhibitor can be administered simultaneously.
  • the pharmaceutical composition comprising the anti-endoglin antibody and the pharmaceutical composition comprising the VEGF inhibitor or the VEGFR inhibitor can be administered sequentially.
  • the pharmaceutical composition comprising the anti- endoglin antibody and the pharmaceutical composition comprising the VEGF inhibitor or the VEGFR inhibitor can be administered separately.
  • a VEGF inhibitor or a VEGFR inhibitor can be, for example, Axitinib, Pazopanib, Bevacizumab (AVASTIN®), ranibizumab (LUCENTIS®), aflibercept (VEGF-Trap; EYLEA®), sunitinib (SUTENT®), brivanib (BMS-582664), sorafenib
  • EXAVAR® pegaptanib
  • MACUGEN® pegaptanib
  • SU5416 SU5416
  • a VEGF inhibitor to be administered includes, but is not limited to, axitinib (N-methyl -2-[3-((7i)-2-pyridin-2-yl -vinyl)- lH-indazol-6-ylsulfanyl]-benzamide).
  • Axitinib can be administered by any appropriate means including, for example, orally,
  • a VEGF inhibitor to be administered includes, but is not limited to, pazopanib (5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methyl-benzenesulfonamide).
  • Pazopanib can be administered by any appropriate means including, for example, orally, subcutaneously, intravenously, or in an implant.
  • an anti-endoglin antibody to be administered to a subject can be an isolated antibody that is, for example, a monoclonal antibody, a humanized antibody, a deimmunized antibody, a humanized and deimmunized antibody, a mouse-human chimeric antibody, a grafted antibody, a bi-specific antibody, a multi-specific antibody or a human antibody.
  • the anti-endoglin antibody can be formulated in a pharmaceutical composition with one or more pharmaceutically carriers or excipients.
  • the anti-endoglin antibody can be administered by any appropriate means including, for example, subcutaneously, intravenously, or in an implant.
  • the anti-endoglin antibody comprises an antigen-binding fragment that specifically binds to endoglin.
  • Antigen-binding fragments include, but are not limited to, a Fab fragment, a Fab' fragment, a F(ab)2 fragment, a F(ab')2 fragment, a Fv fragment, a scFv fragment, or a single chain binding polypeptide.
  • the anti-endoglin antibody can be an IgG, an IgM, an IgE, an IgA, or an IgD, or is derived therefrom.
  • the antibody can be an IgGl, an IgG2, an IgG3, or an IgG4.
  • the antibody can be an IgG2a antibody or an IgG2b antibody.
  • Anti-endoglin antibodies to be utilized in the present methods include antibodies that bind to, and inhibit and/or neutralize the activity of endoglin.
  • An anti-endoglin antibody can be, for example, a polyclonal antibody, a monoclonal antibody, a chimeric antibody, a humanized antibody, a deimmunized antibody, a human antibody, an affinity matured antibody or a combination thereof. Where combinations are contemplated, one would understood that, for example, a chimeric or humanized antibody could be deimmunized to reduce a T cell response when administered to a human subject.
  • an isolated anti-endoglin antibody comprises a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 1 and a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 3.
  • an isolated anti-endoglin antibody comprises a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 1, a light chain constant region having an amino acid sequence set forth as SEQ ID NO: 2, a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 3 and a gamma 1 ( ⁇ ) constant region having an amino acid sequence set forth as SEQ ID NO: 4.
  • an isolated anti-CD 105 antibody comprises a V L CDR1 having an amino acid sequence set forth as SEQ ID NO: 10; a VL CDR2 having an amino acid sequence set forth as SEQ ID NO: 11 or 12; a V L CDR3 having an amino acid sequence set forth as SEQ ID NO: 13; a VH CDRl having an amino acid sequence set forth as SEQ ID NO: 5; a VH CDR2 having an amino acid sequence set forth as SEQ ID NO: 6, 7, or 8; and a VH CDR3 having an amino acid sequence set forth as SEQ ID NO: 9.
  • an isolated humanized, de-immunized anti-CD105 antibody can comprise a heavy chain variable region having the amino acid sequence set forth as SEQ ID NO: 14, 15, 16, 17, or 18; and a light chain variable region having the amino acid sequence set forth as SEQ ID NO: 19, 20, 21, 22, or 23.
  • an antibody for use in the described methods competes with an antibody described herein and, preferably, has a synergistic effect when administered with the VEGF and VEGFR inhibitors described herein.
  • Treatment can reduce a size of a cancer or a metastasis thereof by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or more compared to administration of a placebo or compared to baseline.
  • the method comprises detecting one or more biomarkers, wherein the one or more biomarkers are higher than the mean or median levels of the biomarkers in a subject with that cancer type.
  • the method comprises detecting two or more biomarkers, wherein the two or more biomarkers are higher than the median or mean levels of the biomarkers in a subject with that cancer type.
  • the method comprises detecting one or more biomarkers, wherein the median or mean levels of one or more biomarkers are lower than the levels of the biomarkers in a subject with that cancer type.
  • the method comprises detecting two or more biomarkers, wherein the levels of two or more biomarkers are lower than the median or mean levels of the biomarkers in a subject with that cancer type.
  • the method comprises detecting two or more biomarkers, wherein at least one of the biomarkers is lower than the mean or median level of the biomarker in subjects with that cancer type and at least one of the biomarkers is higher than the median or mean level of the biomarker in a subject with that cancer type.
  • the one or more biomarkers to be detected in the current methods include, but are not limited to angiogenin 2 (ANG-2), placental growth factor (PIGF), bone morphogenetic protein 9 (BMP-9), intercellular adhesion molecule 1 (ICAM-1), basic fibroblast growth factor (bFGF), interleukin 6 (IL-6), hepatocyte growth factor (HGF), transforming growth factor beta 1 (TGF- ⁇ ⁇ ), osteopontin (OPN), platelet derived growth factor AA (PDGF-AA), TGF-P2, stromal cell-derived factor 1 (SDF-1), PDGF-BB, transforming growth factor beta receptor 3 (TGFP-R3), tissue inhibitor of metalloproteinase-1 (TEVlP-1), Thrombospondin 2 (TSP-2), vascular cell adhesion molecule 1 (VCAM-1) and a combination thereof.
  • ANG-2 angiogenin 2
  • PIGF placental growth factor
  • BMP-9 bone morphogenetic protein 9
  • the methods detect one or more biomarkers selected from the group consisting of vascular endothelial growth factor A (VEGF-A), Endoglin, VEGF-D, vascular endothelial growth factor receptor 1 (VEGF-Rl), VEGF-R2, VEGF-R3, and a combination thereof; and detect one or more biomarkers selected from the group consisting of ANG-2, PIGF, BMP-9, ICAM-1, bFGF, IL-6, HGF, TGF- ⁇ , osteopontin (OPN), PDGF-AA, TGF-P2, SDF-1, PDGF-BB, TGFP-R3, ⁇ -1, TSP-2, VCAM-1 and a combination thereof.
  • VEGF-A vascular endothelial growth factor A
  • VEGF-D vascular endothelial growth factor receptor 1
  • VEGF-Rl vascular endothelial growth factor receptor 1
  • VEGF-Rl vascular endothelial growth factor receptor 1
  • the method comprises detecting TGFP-R3, where a subject having a plasma concentration of TGF -R3 at baseline that is above the median or mean level in a subject with the specific cancer type is selectively enrolled into a clinical trial of a VEGF inhibitor and an anti-endoglin antibody.
  • the method comprises detecting TGF -R3, where a subject having a plasma concentration of TGFP-R3 at baseline that is above the median or mean level in a subject with the specific cancer type is selected for treatment with a VEGF inhibitor and an anti-endoglin antibody.
  • the method comprises detecting TGF -R3, where a subject having a plasma concentration of TGFP-R3 of above the median or a mean level in a subject with the specific cancer type is administered one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody.
  • the method comprises detecting osteopontin, where a subject having a plasma concentration of osteopontin at baseline that is below the median or a mean value in a subject with the specific cancer type is selectively enrolled in a clinical trial of a VEGF inhibitor and an anti-endoglin antibody.
  • the method comprises detecting osteopontin, where a subject having a plasma concentration of osteopontin at baseline that is below the median or mean value in a subject with the specific cancer type is selected for treatment with a VEGF inhibitor and an anti-endoglin antibody.
  • the method comprises detecting osteopontin, where a subject having a plasma concentration of osteopontin at baseline that is below the median or mean value in a subject with the specific cancer type is administered one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody.
  • the method comprises detecting ANG-2, VEGF-R2, TGFP-R3, and osteopontin, wherein a subject having (i) a plasma concentration at baseline that is above the median or mean level in a subject with the specific cancer type of ANG-2, VEGF-R2, or TGFp-R3, or (ii) a plasma concentration of osteopontin at baseline that is above the median or mean level in a subject with the specific cancer type; or (iii) a combination of any of these biomarkers is selectively enrolled in a clinical trial of a VEGF inhibitor and an anti-endoglin antibody.
  • the method comprises detecting ANG-2, VEGF-R2, TGFP-R3, or osteopontin, wherein a subject having (i) a plasma concentration at baseline that is above the median or mean level in a subject with the specific cancer type of ANG-2, VEGF-R2, or TGFp-R3, or (ii) a plasma concentration of osteopontin at baseline that is above the median or mean level in a subject with the specific cancer type; or (iii) a combination of any of these biomarkers is selectively enrolled in a clinical trial of a VEGF inhibitor and an anti-endoglin antibody; or is selected for treatment with a VEGF inhibitor and an anti-endoglin antibody.
  • the method comprises detecting ANG-2, wherein a subject having a plasma concentration at baseline that is above the median or mean level in a subject with the specific cancer type of ANG-2 is selectively enrolled in a clinical trial of a VEGF inhibitor and an anti- endoglin antibody; or is selected for treatment with a VEGF inhibitor and an anti-endoglin antibody.
  • the method comprises detecting VEGF-R2, wherein a subj ect having a plasma concentration at baseline that is above the median or mean level in a subject with the specific cancer type of VEGF-R2 is selectively enrolled in a clinical trial of a VEGF inhibitor and an anti-endoglin antibody; or is selected for treatment with a VEGF inhibitor and an anti-endoglin antibody.
  • the method comprises detecting, TGFp-R3, wherein a subj ect having a plasma concentration at baseline that is above the median or mean level in a subject with the specific cancer type of TGFp-R3is selectively enrolled in a clinical trial of a VEGF inhibitor and an anti-endoglin antibody; or is selected for treatment with a VEGF inhibitor and an anti-endoglin antibody.
  • the method comprises detecting osteopontin, wherein a subject having a plasma concentration at baseline that is above the median or mean level in a subject with the specific cancer type of osteopontin is selectively enrolled in a clinical trial of a VEGF inhibitor and an anti-endoglin antibody; or is selected for treatment with a VEGF inhibitor and an anti-endoglin antibody.
  • the method comprises detecting ANG-2, VEGF-R2, TGFP-R3, and osteopontin, wherein a subject with renal cell carcinoma having (i) a plasma concentration at baseline that is above the median or mean level in a subject with the specific cancer type of ANG-2, VEGF-R2, or TGFP-R3, or (ii) a plasma concentration of osteopontin at baseline that is below the median or mean level in a subject with the specific cancer type; or (iii) a combination of any of these biomarkers is administered one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody.
  • the method comprises detecting ANG-2, VEGF-R2, TGFP-R3, or osteopontin, wherein a subject with renal cell carcinoma having (i) a plasma concentration at baseline that is above the median or mean level in a subject with the specific cancer type of ANG-2, VEGF-R2, or TGFP-R3, or (ii) a plasma concentration of osteopontin at baseline that is below the median or mean level in a subject with the specific cancer type; or (iii) a combination of any of these biomarkers is selected for treatment with one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody.
  • the method comprises detecting ANG-2, wherein a subject with renal cell carcinoma having a plasma concentration at baseline that is above the median or mean level in a subject with the specific cancer type of ANG-2 is selected for treatment with one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody.
  • the method comprises detecting VEGF-R2, wherein a subj ect with renal cell carcinoma having a plasma concentration at baseline that is above the median or mean level in a subject with the specific cancer type of VEGF-R2 is selected for treatment with one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody.
  • the method comprises detecting TGF -R3, wherein a subject with renal cell carcinoma having a plasma concentration at baseline that is above the median or mean level in a subject with the specific cancer type TGF -R3 is selected for treatment with one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody.
  • the method comprises detecting osteopontin, wherein a subject with renal cell carcinoma having a plasma concentration at baseline that is above the median or mean level in a subject with the specific cancer type osteopontin is selected for treatment with one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody.
  • a method comprises detecting ICAM-1, wherein a subject having a plasma concentration of ICAM-1 below a median or mean level in a subject with a cancer or a metastasis thereof is selected for treatment with a VEGF inhibitor and an anti-endoglin antibody.
  • compositions of a VEGF inhibitor and an anti-endoglin antibody can be administered as described below.
  • a method comprises detecting TSP-2, wherein a subject having a plasma concentration of TSP-2 below a median or mean level in a subject with a cancer or a metastasis thereof at baseline is selected for treatment with a VEGF inhibitor and an anti-endoglin antibody.
  • Compositions of a VEGF inhibitor and an anti-endoglin antibody can be administered as described below.
  • the median level of TGF beta-R3 can be from about 10 to about 250 ng/ml and the median level of OPN can be from about 0.1 to about 75 ng/ml or the median level of TGF beta-R3 can be from about 115 to about 238 ng/ml and the median level of OPN can be from about 0.2 to about 59 ng/ml. In one non-limiting instance, the median level of TGF beta-R3 can be about 182 ng/mL and the medium level of OPN can be about 1.2 ⁇ g/ml.
  • the method comprises detecting ICAM-1 and TSP-2, wherein a subject having a plasma concentration at baseline that is below the median or the mean level of ICAM-1 or TSP-2 is selected for treatment with a VEGF inhibitor and an anti-endoglin antibody.
  • the subject has a soft tissue carcinoma.
  • the median level of ICAM-1 can be from about 250 to about 2000 ng/ml and the median level of TSP-2 can be from about 25 to about 400 ng/ml or the median level of ICAM-1 can be from about 293 to about 1 154 ng/ml and the median level of TSP-2 can be from about 58 to about 281 ng/ml. In one non-limiting instance, the median level of ICAM-1 can be about 658 ng/mL and the medium level of TSP-2 can be about 82 ng/ml.
  • composition comprising an anti-endoglin antibody, for use in combination therapy to treat a subject selected by a method described herein, wherein the anti-endoglin antibody is to be administered with a VEGF or a VEGF receptor inhibitor.
  • FIGS 1A-C OPN ( Figure 1A), TGF -R3 ( Figure IB) and SDF-1 ( Figure 1C) were differentially expressed markers at baseline in renal cell carcinoma responders versus non- responders.
  • FIGS 2A-B ICAM-1 ( Figure 1A) and TSP-2 ( Figure IB) were differentially expressed markers at baseline in soft tissue sarcoma responders versus non-responders.
  • Figure 3 provides a humanized 02-VK1-39 variable (V L ) light chain having the monoclonal murine chimeric TRC105 VL CDRs (underlined) grafted between the framework regions (FRs) 1-3 of the human sequence 02-VK1-39 and a framework region 4 from the human JK4 sequence (SEQ ID NO: 52; all in bold). Variations that can be made to the human FRs are indicated at positions 1, 3, 4, 5, 36, 46, 47, 60, 70, 71, 100, and 106 of the sequence utilizing the Kabat numbering system (shown in italics beneath the humanized sequence).
  • Figure 4 provides a humanized VH3-15 variable (VH) heavy chain having the monoclonal murine monoclonal murine chimeric TRC105 VH CDRs (underlined) grafted between the framework regions (FRs) 1-3 of the human sequence VH3-15 and a framework region 4 from the human JH4 sequence (all in bold) (SEQ ID NO: 53).
  • VH variable
  • One or more variations that can be made to the human FRs are indicated at positions 49, 76, 77, 78, 82a, 89, 94, 108, 109, and 113 of the sequence utilizing the Kabat numbering system (shown in italics beneath the humanized sequence).
  • Figures 5A-B provide an amino acid sequence alignment of exemplary mouse and humanized VK chains (Figure 5A) and VH chains ( Figure 5B).
  • Sequence identifiers are SEQ ID NOS: 1 and 54-57, respectively, from top to bottom in Figure 5A and SEQ ID NOS: 3 and 58-60, respectively, from top to bottom in Figure 5B.
  • Figures 6A-B provide an amino acid sequence alignment of exemplary mouse and super- humanized VK chains (Figure 6A) and V H chains ( Figure 6B).
  • Sequence identifiers are SEQ ID NOS: 1 and 54-57, respectively, from top to bottom in Figure 6A and SEQ ID NOS: 3 and 58-60, respectively, from top to bottom in Figure 6B.
  • Figure 7 provides an amino acid sequence alignment and comparison of exemplary mouse and humanized and super-humanized V K chains and V H chains.
  • the sequences are SEQ ID NOS 61-63, respectively, from top to bottom.
  • Figure 8 illustrates the lead humanized deimmunized heavy chain variable region with CDRs in bold and underlined (SEQ ID NO: 64). Variations that can be made are indicated at the identified positions of the sequence utilizing the Kabat numbering system (shown in italics beneath the humanized sequence). Variations may be made as a single mutation or as more than one mutation, and variations can be made with mutations in any combination.
  • Figure 9 illustrates the lead humanized deimmunized light chain variable region with CDRs in bold and underlined (SEQ ID NO: 65). Variations that can be made are indicated at the identified positions of the sequence utilizing the Kabat numbering system (shown in italics beneath the humanized sequence). Variations may be made as a single mutation or as more than one mutation, and variations can be made with mutations in any combination.
  • references to “a method” include one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure.
  • the term "about” includes equal to, and a range that takes into account experimental error in a given measurement and can refer to plus or minus 5, 4, 3, 2 or 1% or anywhere in-between such as, for example, ⁇ 0.1%, ⁇ 0.2%, ⁇ 0.3%, ⁇ 0.4%, ⁇ 0.5%, ⁇ 0.6%, ⁇ 0.7%, ⁇ 0.8%, ⁇ 0.9%, 1.0%, ⁇ 1.1%, ⁇ 1.2%, ⁇ 1.3%, ⁇ 1.4%, ⁇ 1.5%, ⁇ 1.6%, ⁇ 1.7%, ⁇ 1.8%, ⁇ 1.9%, ⁇ 2.0%, 2.1%, ⁇ 2.2%, ⁇ 2.3%, ⁇ 2.4%, ⁇ 2.5%, ⁇ 2.6%, ⁇ 2.7%, ⁇ 2.8%, ⁇ 2.9%, ⁇ 3.0%, 3.1%, ⁇ 3.2%, ⁇ 3.3%, ⁇ 3.4%, ⁇ 3.5%, ⁇ 3.6%, ⁇ 3.7%, ⁇ 3.8%, ⁇ 3.9%, ⁇ 4.0%, 4.1%, ⁇ 4.2%, ⁇
  • a “baseline value" of a biomarker described herein refers to a value or range described herein.
  • substantially pure refers to material which is at least 50% pure (i.e., free from contaminants), more preferably at least 90% pure, more preferably at least 95% pure, more preferably at least 98% pure, more preferably at least 99% pure.
  • Antibodies can be isolated and purified from the culture supernatant or ascites mentioned above by saturated ammonium sulfate precipitation, euglobulin precipitation method, caproic acid method, caprylic acid method, ion exchange chromatography (DEAE or DE52), or affinity chromatography using anti-Ig column or a protein A, G or L column using art-recognized conventional methods.
  • An antibody can be conjugated to, or recombinantly engineered with, an affinity tag (e.g., a purification tag) for purification.
  • affinity tags are known in the art and include, but are not limited to, a polyhistidine tag (e.g., a 6x His tag; SEQ ID NO: 26). SUBJECT SELECTION AND MONITORING
  • the methods described herein may be used to identify a subject having a cancer or a metastasis thereof for inclusion in a clinical trial for treatment with one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody.
  • the methods described herein may be used to identify a subject having a cancer or a metastasis thereof for treatment with one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody.
  • the methods may also be used to identify whether the cancer or metastasis thereof is being effectively treated with the described methods.
  • a method of treating a cancer or a metastasis thereof in a subject in need thereof comprising detecting whether one or more biomarkers are present in a sample from the subject prior to treatment by contacting the sample with one or more antibodies that bind to the one or more biomarkers and detecting binding between the one or more biomarkers and the one or more antibodies; comparing a baseline value of the one or more biomarkers of the subject to a baseline value of a healthy subject; and administering to the subject one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody when the baseline value of the one or more biomarkers in the subject to be treated are above a median or mean level in a subject with the cancer or metastasis thereof.
  • Also provided herein is a method of treating a cancer or a metastasis thereof in a subject in need thereof, comprising detecting whether one or more biomarkers are present in a sample from the subject prior to treatment; diagnosing the subject with a cancer or metastasis when the presence of the one or more biomarkers in the sample are detected; and administering to the subject one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody when a baseline value of the one or more biomarkers in the subject to be treated is above or below a median or mean level in subjects with a specific cancer type.
  • a level of one or more biomarkers in a sample from the subject can be obtained prior to treatment and, in some instances, samples may be additionally obtained and tested at one or more time points during treatment.
  • the methods include detection of one biomarker, two biomarkers, three biomarkers, four biomarkers, five biomarkers, six biomarkers, seven biomarkers, eight biomarkers, nine biomarkers, ten biomarkers or more at one or more times prior to, during, and/or following treatment.
  • the method comprises detecting one or more biomarkers, wherein the one or more baseline biomarkers are above a median or mean level in subjects with a specific cancer type.
  • the method comprises detecting two or more biomarkers, wherein the two or more baseline biomarkers are above a median or mean level in subjects with a the specific cancer type.
  • the method comprises detecting one or more baseline biomarkers, wherein the one or more biomarkers are lower than a median or mean level in subjects with a specific cancer type.
  • the method comprises detecting two or more biomarkers, wherein the two or more biomarkers are lower than a median or mean level in subjects with a the specific cancer type.
  • the method comprises detecting two or more biomarkers, wherein at least one of the baseline biomarkers is lower than a median or mean level in subjects with a specific cancer type and at least one of the biomarkers is at least two-fold higher than the level of the level of the biomarker in a healthy subject.
  • Detection of one or more biomarkers in sample obtained from a subject can be achieved using any conventionally known means such as, for example, an enzyme assay.
  • Enzyme assays include, but are not limited to, an Enzyme Linked Immunosorbant Assay (ELISA). Detection can be achieved by exposing a sample from a subject to one or more commercially available antibodies and/or to an antibody described herein that specifically bind to a biomarker and comparing the results to a standard curve and a negative control. Assays useful in the described methods are discussed in more detail in the Examples below.
  • One or more biomarkers to be detected in the current methods include, but are not limited to angiogenin 2 (ANG-2), placental growth factor (PIGF), bone morphogenetic protein 9 (BMP-9), intercellular adhesion molecule 1 (ICAM-1), basic fibroblast growth factor (bFGF), interleukin 6 (IL-6), hepatocyte growth factor (HGF), transforming growth factor beta 1 (TGF- ⁇ ), osteopontin (OPN), platelet derived growth factor AA (PDGF-AA), TGF-P2, stromal cell-derived factor 1 (SDF-1), PDGF-BB, transforming growth factor beta receptor 3 (TGFP-R3), tissue inhibitor of metalloproteinase-1 (TIMP-1), Thrombospondin 2 (TSP-2), vascular cell adhesion molecule 1 (VCAM-1) and a combination thereof.
  • ANG-2 angiogenin 2
  • PIGF placental growth factor
  • BMP-9 bone morphogenetic protein 9
  • IAM-1 intercellular adh
  • the methods detect one or more biomarkers selected from the group consisting of vascular endothelial growth factor A (VEGF-A), Endoglin, VEGF-D, vascular endothelial growth factor receptor 1 (VEGF-Rl), VEGF-R2, VEGF-R3, and a combination thereof; and detect one or more biomarkers selected from the group consisting of ANG-2, PIGF, BMP-9, ICAM-1, bFGF, IL-6, HGF, TGF- ⁇ , osteopontin (OPN), PDGF-AA, TGF-P2, SDF-1, PDGF-BB, TGFP-R3, ⁇ -1, TSP-2, VCAM-1 and a combination thereof.
  • VEGF-A vascular endothelial growth factor A
  • VEGF-D vascular endothelial growth factor receptor 1
  • VEGF-Rl vascular endothelial growth factor receptor 1
  • VEGF-Rl vascular endothelial growth factor receptor 1
  • VEGF-A vascular endothelial growth factor A
  • VEGF-D vascular endothelial growth factor A
  • An amino acid sequence of human endoglin to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 28.
  • An amino acid sequence of a human soluble endoglin to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 51.
  • VEGF-A vascular endothelial growth factor receptor 1
  • Rl to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 48.
  • amino acid sequence of human VEGF-R2 to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 47.
  • amino acid sequence of human VEGF-R3 to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 29.
  • An amino acid sequence of human ANG-2 to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 30.
  • amino acid sequence of human PIGF to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 3 1.
  • amino acid sequence of human BMP-9 to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 32.
  • amino acid sequence of human ICAM-1 to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 33.
  • amino acid sequence of human bFGF to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 34.
  • amino acid sequence of human IL-6 to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 35.
  • amino acid sequence of human HGF to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 36.
  • amino acid sequence of human TGF- ⁇ ⁇ to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 37.
  • An amino acid sequence of human osteopontin (OPN) to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 38.
  • An amino acid sequence of human PDGF-AA to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 39.
  • amino acid sequence of human TGF-P2 to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 40.
  • amino acid sequence of human SDF-1 to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 41.
  • amino acid sequence of human PDGF-BB to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 42.
  • amino acid sequence of human TGFP-R3 to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 43.
  • amino acid sequence of human TIMP-1 to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 44.
  • amino acid sequence of human TSP-2 to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 45.
  • amino acid sequence of human VCAM-1 to be detected by the methods described herein is, for example, set forth as SEQ ID NO: 46.
  • the method comprises detecting TGFP-R3, where a subject having a plasma concentration of TGFp-R3 above a median or mean level in subjects with a specific cancer type is selectively enrolled into a clinical trial of a VEGF inhibitor and an anti- endoglin antibody.
  • the method comprises detecting TGFp-R3, where a subject having a plasma concentration of TGFP-R3 at baseline that is above a median or mean level in subjects with a specific cancer type is administered one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody.
  • the method comprises detecting osteopontin, where a subject having a plasma concentration of osteopontin below a median or mean level in subjects with a specific cancer type at baseline is selectively enrolled in a clinical trial of a VEGF inhibitor and an anti- endoglin antibody.
  • the method comprises detecting osteopontin, where a subject having a plasma concentration of osteopontin below a median or mean level in subjects with a specific cancer type at baseline is administered one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody.
  • the method comprises detecting ANG-2, VEGF-R2, TGFP-R3, and osteopontin, wherein a subject having (i) a plasma concentration above a median or mean level in subjects with a specific cancer type of ANG-2, VEGF-R2, or TGFp-R3, or (ii) a plasma concentration of osteopontin below a median or mean level in subjects with a specific cancer type; or (iii) a combination of any of these biomarkers is selectively enrolled in a clinical trial of a VEGF inhibitor and an anti-endoglin antibody; or is selected for treatment with a VEGF inhibitor and an anti-endoglin antibody.
  • the method comprises detecting ANG-2, VEGF-R2, TGFP-R3, or osteopontin, wherein a subject having (i) a plasma concentration above a median or mean level in subjects with a specific cancer type of ANG-2, VEGF-R2, or TGF -R3, or (ii) a plasma concentration of osteopontin below a median or mean level in subjects with a specific cancer type; or (iii) a combination of any of these biomarkers is selectively enrolled in a clinical trial of a VEGF inhibitor and an anti-endoglin antibody; or is selected for treatment with a VEGF inhibitor and an anti-endoglin antibody.
  • the method comprises detecting ANG-2, VEGF-R2, TGF -R3, and osteopontin, wherein a subject having (i) a plasma concentration above a median or mean level in subjects with a specific cancer type of ANG-2, VEGF-R2, or TGFP-R3, or (ii) a plasma concentration of osteopontin below a median or mean level in subjects with a specific cancer type; or (iii) a combination of any of these biomarkers is administered one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody.
  • the method comprises detecting ANG-2, VEGF-R2, TGF -R3, or osteopontin, wherein a subject having (i) a plasma concentration above a median or mean level in subjects with a specific cancer type of ANG-2, VEGF-R2, or TGF -R3, or (ii) a plasma concentration of osteopontin below a median or mean level in subjects with a specific cancer type; or (iii) a combination of any of these biomarkers is administered one or more doses of a pharmaceutical composition that comprises a VEGF inhibitor and one or more doses of a pharmaceutical composition that comprises an anti-endoglin antibody; or is selected for treatment with a VEGF inhibitor and an anti-endoglin antibody.
  • sample denotes a sample taken or isolated from a subject.
  • sample includes, but are not limited to, a biofluid sample; blood; serum; plasma; urine; a tissue sample; and/or a biopsy sample, etc.
  • sample also includes a mixture of the above-mentioned samples.
  • sample also includes untreated or pretreated (or pre-processed) biological samples.
  • a sample can contain cells from a subject.
  • biofluid refers to any fluid obtained from a biological source and includes, but is not limited to, blood, urine, biopsies, and bodily secretions.
  • a sample can be obtained by removing a sample from a subject, but can also be
  • sample can be freshly collected or a previously collected sample.
  • the sample can be an untreated sample.
  • untreated sample refers to a sample that has not had any prior sample pre-treatment except for dilution and/or suspension in a solution.
  • Exemplary methods for treating a sample include, but are not limited to, centrifugation, filtration, sonication, homogenization, heating, freezing and thawing, and combinations thereof.
  • the test sample can be a frozen test sample, e.g., a frozen tissue. The frozen sample can be thawed before employing methods, assays and systems described herein. After thawing, a frozen sample can be centrifuged before being subjected to methods, assays and systems described herein.
  • the sample is a clarified test sample, for example, prepared by centrifugation and collection of a supernatant comprising the clarified sample.
  • a sample can be a pre-processed sample, for example, supernatant or filtrate resulting from a treatment selected from the group consisting of
  • centrifugation centrifugation, filtration, thawing, purification, and any combinations thereof.
  • the sample can be treated with a chemical and/or biological reagent.
  • Chemical and/or biological reagents can be employed to protect and/or maintain the stability of the sample during processing.
  • the skilled artisan is well aware of methods and processes appropriate for preprocessing of biological samples required for determination of the biomolecules/biomarkers as described herein.
  • the methods described herein can further comprise a step of obtaining a sample from a subject.
  • the subject can be a human subject. It will be understood that a sample can be obtained from a subject utilizing any art-appropriate means.
  • the methods described herein can comprise creating a report based on the levels as described herein.
  • the report denotes raw values the levels described herein in the test sample (plus, optionally, the level in a reference sample) or it indicates a percentage or fold increase or decrease as compared to a reference level, a base line level, and/or provides a prognosis regarding the subject's treatment responsiveness.
  • the one or more biomarkers described herein can be detected using any conventionally described assay including, but not limited to, an enzyme assay.
  • Enzyme assays include, but are not limited to, an Enzyme Linked Immunosorbant Assay (ELISA), a competitive ELISA, fluorescent activated cell sorter (FACS), etc.
  • ELISA Enzyme Linked Immunosorbant Assay
  • FACS fluorescent activated cell sorter
  • Antibodies that may be used to detect the one or more biomarkers include commercially available antibodies from, for example, Life Technologies, Roche, Amgen, Genentech,
  • Endoglin is a 180 kDa homodimeric transmembrane protein.
  • CD105 is constitutively phosphorylated in endothelial cells, mainly on serine and threonine residues, and this phosphorylation is due to the constitutively active TGF- ⁇ RII within the cell.
  • TGF- ⁇ binding to CD 105 results in down-regulation of phosphorylation, similar to effects seen with protein kinase C inhibitors.
  • the sequences of human CD 105 (SEQ ID NO: 28) and murine CD 105 (SEQ ID NO: 27) are not identical.
  • the human CD 105 amino acid sequence contains the tripeptide arginine-glycine- aspartic acid (RGD) located in an exposed region of the extracellular domain.
  • RGD arginine-glycine- aspartic acid
  • the RGD peptide is a key recognition structure found on ECM proteins such as fibronectin, vitronectin, von Willebrand factor (vWF), type I collagen, and fibrinogen and is recognized by cell surface integrins.
  • antibody refers to an immunoglobulin (Ig) whether naturally, or partly or wholly synthetically produced.
  • Ig immunoglobulin
  • the term also covers any polypeptide or protein having a binding domain which is, or is homologous to, an antigen-binding domain.
  • the term further includes "antigen-binding fragments" and other interchangeable terms for similar binding fragments such as described below.
  • Antibodies useful in the present invention encompass, but are not limited to, monoclonal antibodies, polyclonal antibodies, antibody fragments ⁇ e.g., Fab, Fab', F(ab') 2 , Fv, Fc, etc.), chimeric antibodies, bispecific antibodies, multispecific antibodies, deimmunized antibodies, heteroconjugate antibodies, single chain (ScFv), mutants thereof, fusion proteins comprising an antibody portion ⁇ e.g., a domain antibody), humanized antibodies, human antibodies, and/or any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies.
  • an antibody for use in the methods described herein is a chimeric and deimmunized antibody.
  • an antibody for use in the methods described herein is a humanized and deimmunized antibody.
  • Native antibodies and native immunoglobulins are usually heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is typically linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain ("V H " or "VH”) followed by a number of constant domains ("CH" or "CH").
  • V H variable domain
  • CH constant domain
  • Each light chain has a variable domain at one end ("VL” or “VL”) and a constant domain (“CL” or “CL”) at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light-chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light- and heavy-chain variable domains.
  • synthetic polynucleotide means that the corresponding polynucleotide sequence or portion thereof, or amino acid sequence or portion thereof, is derived, from a sequence that has been designed, or synthesized de novo, or modified, compared to an equivalent naturally-occurring sequence.
  • polynucleotides antibodies or antigen binding fragments
  • synthetic genes can be prepared by methods known in the art, including but not limited to, the chemical synthesis of nucleic acid or amino acid sequences.
  • Synthetic genes are typically different from naturally-occurring genes, either at the amino acid, or polynucleotide level, (or both) and are typically located within the context of synthetic expression control sequences.
  • Synthetic gene polynucleotide sequences may not necessarily encode proteins with different amino acids, compared to the natural gene; for example, they can also encompass synthetic polynucleotide sequences that incorporate different codons but which encode the same amino acid ⁇ i.e. , the nucleotide changes represent silent mutations at the amino acid level).
  • variable domain refers to the variable domains of antibodies that are used in the binding and specificity of each particular antibody for its particular antigen.
  • variability is not evenly distributed throughout the variable domains of antibodies. Rather, it is concentrated in three segments called hypervariable regions (also known as CDRs) in both the light chain and the heavy chain variable domains. More highly conserved portions of variable domains are called the "framework regions" or "FRs.”
  • the variable domains of unmodified heavy and light chains each contain four FRs (FR1, FR2, FR3 and FR4), largely adopting a ⁇ -sheet configuration interspersed with three CDRs which form loops connecting and, in some cases, part of the ⁇ -sheet structure.
  • the CDRs in each chain are held together in close proximity by the FRs and, with the CDRs from the other chain, contribute to the formation of the antigen -binding site of antibodies (see Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991), pages 647-669).
  • hypervariable region refers to the amino acid residues of an antibody which are responsible for antigen-binding.
  • the CDRs comprise amino acid residues from three sequence regions which bind in a complementary manner to an antigen and are known as CDR1, CDR2, and CDR3 for each of the VH and VL chains.
  • the CDRs typically correspond to approximately residues 24-34 (CDRLl), 50-56
  • CDRL2 and 89-97 (CDRL3)
  • CDRL3 Cyclone-Linked Rease-Linked Rease-Linked Rease-Linked Rease-Linked Rease-Linked Rease-Linked Rease-Linked Rease-Linked Rease-Linked Rease-Linked Rease-Linked Rease-Linked Rease-Linked Rease-Linked Rease-97
  • CDRH3 residues 31 -35
  • CDRH2 50-65
  • CDRH3 95-102
  • the Kabat numbering system accounts for such insertions with a numbering scheme that utilizes letters attached to specific residues ⁇ e.g., 27 A, 27B, 27C, 27D, 27E, and 27F of CDRLl in the light chain) to reflect any insertions in the numberings between different antibodies.
  • the CDRs typically correspond to approximately residues 26-32 (CDRLl), 50-52 (CDRL2) and 91 -96 (CDRL3)
  • the CDRs typically correspond to approximately residues 26-32 (CDRH1), 53-55 (CDRH2) and 96-101 (CDRH3) according to Chothia and Lesk, J. Mol. Biol, 196: 901-917 (1987)).
  • framework region refers to framework amino acid residues that form a part of the antigen binding pocket or groove.
  • the framework residues form a loop that is a part of the antigen binding pocket or groove and the amino acids residues in the loop may or may not contact the antigen.
  • Framework regions generally comprise the regions between the CDRs. In the light chain variable domain, the FRs typically correspond to
  • FRs typically correspond to approximately residues 0-30 (FRH1), 36-49 (FRH2), 66-94 (FRH3), and 103-133 according to Kabat et al, Sequences of Proteins of
  • the FRs typically correspond to approximately residues 0-25 (FRL1), 33-49 (FRL2) 53-90 (FRL3), and 97-109 (FRL4)
  • the FRs typically correspond to approximately residues 0-25 (FRH1), 33-52 (FRH2), 56-95 (FRH3), and 102-1 13 (FRH4) according to Chothia and Lesk, J. Mol. Biol, 196: 901-917 (1987)).
  • Constant domains (Fc) of antibodies are not involved directly in binding an antibody to an antigen but, rather, exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity via interactions with, for example, Fc receptors (FcR). Fc domains can also increase bioavailability of an antibody in circulation following administration to a patient. Substitution of a murine Fc domain with a human Fc domain can also reduce side HAMA reactions.
  • immunoglobulins can be assigned to different classes. There are five major classes of
  • immunoglobulins IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.
  • the heavy-chain constant domains (Fc) that correspond to the different classes of immunoglobulins are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
  • the "light chains" of antibodies from any vertebrate species can be assigned to one of two clearly distinct types, called kappa or (" ⁇ ") and lambda or (“ ⁇ "), based on the amino acid sequences of their constant domains.
  • antigen-binding portion of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen.
  • antigen-binding fragments included within such terms include, but are not limited to, a Fab fragment, a Fab' fragment, a F(ab) 2 fragment, a F(ab') 2 fragment, a Fv fragment, a scFv fragment, or a single chain binding
  • polypeptide The structures of such antigen-binding fragments described herein are known in the art.
  • chimeric forms of non-human (e.g., murine) antibodies include chimeric antibodies which contain minimal sequence derived from a non-human Ig.
  • chimeric antibodies are murine antibodies in which at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin, are inserted in place of the murine Fc.
  • Fc immunoglobulin constant region
  • the term "monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e. , the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to conventional (polyclonal) antibody preparations, which can include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.
  • the modifier "monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • monoclonal antibodies can be made by the hybridoma method first described by Kohler et al. , Nature 256:495 (1975), or can be made by recombinant DNA methods (see, e.g. , U. S. Pat. No. 4,816,567).
  • the monoclonal antibodies can be isolated from phage antibody libraries using the techniques described in Clackson et al, Nature 352:624-628 (1991) and Marks et al , J. Mol. Biol. 222:581-597 (1991), for example.
  • binding refers to binding agents, antibodies or fragments thereof that are specific to a sequence of amino acid residues (i.e., a "binding site” or an “epitope"), yet if are cross-reactive to other peptides/proteins, are not toxic at the levels at which they are formulated for administration to human use.
  • binding refers to a direct association between two molecules, due to, for example, covalent, electrostatic, hydrophobic, and ionic and/or hydrogen- bond interactions under physiological conditions, and including interactions such as salt bridges and water bridges and any other conventional binding means.
  • the term "preferentially binds" means that the binding agent binds to the binding site with greater affinity than it binds unrelated amino acid sequences.
  • Affinity can be at least 1-fold greater, at least 2-fold greater, at least 3 -fold greater, at least 4-fold greater, at least 5 -fold greater, at least 6- fold greater, at least 7-fold greater, at least 8-fold greater, at least 9-fold greater, 10-fold greater, at least 20-fold greater, at least 30-fold greater, at least 40-fold greater, at least 50-fold greater, at least 60-fold greater, at least 70-fold greater, at least 80-fold greater, at least 90-fold greater, at least 100- fold greater, or at least 1000-fold greater than the affinity of the binding agent for unrelated amino acid sequences.
  • the term “avidity” refers to the resistance of a complex of two or more agents to dissociation after dilution. Avidities can be determined by methods such as a Scatchard analysis or any other technique familiar to one of skill in the art.
  • affinity refers to the equilibrium constant for the reversible binding of two agents. Apparent affinities can be determined by methods such as an enzyme linked immunosorbent assay (ELISA) or any other technique familiar to one of skill in the art.
  • ELISA enzyme linked immunosorbent assay
  • An antibody, or antigen-binding fragment thereof, described herein may have a dissociation constant (IQ) of from about 1 femptomolar (fM) to about 500 nM, from about 1 pM to about 500 nM, from about 1 pM to about 250 nM, from about 1 picomolar (pM) to about 200 nM, from about 1 pM to about 150 nM, from about 1 pM to about 100 nM, from about 1 pM to about 50 nM, from about 1 pM to about 25 nM, from about 1 pM to about 10 nM, from about 1 pM to about 1 nM, from about 1 pM to about 70 pM, from about 1 pM to about 500 pM, from about 1 pM to about 250 pM, from about 1 pM to about 125 pM, from about 1 pM to about 100 pM, from 1 pM to about 75 pM, from 1 pM
  • An antibody, or antigen-binding fragment thereof, described herein may have a dissociation constant (K d ) of less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 250 pM, less than about 200 pM, less than about 100 pM, less than about 75 pM, less than about 50 pM, less than about 30 pM, less than about 25 pM, less than about 20 pM, less than about 18 pM, less than about 15 pM, less than about 10 pM, less than about 7.5 pM, less than about 5 pM, less than about 2.5 pM, less than about 1 pM, less than about 900 fM, less than about 800 fM, less than about 700 fM, less than about 600 fM, less than
  • An antibody, or antigen-binding fragment thereof, described herein may have an affinity (K A ) for hepcidin or a hepcidin peptide of from about 10 '9 to about 10 "14 , from about 10 '10 to about 10 "14 , from about 10 "11 to about 10 "14 , from about 10 "12 to about 10 “14 , from about 10 "13 to about 10 " 14 , from about 10 "10 to about 10 "11 , from about 10 '11 to about 10 "12 , from about 10 '12 to about 10 '13 , or 10 -13 to about 10 -14 .
  • affinity matured antibodies are also provided herein.
  • affinity matured antibodies can be produced by procedures known in the art (Marks et al, 1992, Bio/Technology, 10:779-783; Barbas et a!., 1994, Proc Nat. Acad. Sci, USA 91 :3809-3813; Schier et al, 1995, Gene, 169: 147-155; Ydion et al, 1995, J. Immunol, 155: 1994-2004; Jackson et al, 1995, J. Immunol, 154(7) 3310-9; Hawkins et al, 1992, J. Mol. Biol, 226:889-896; and WO2004/058184).
  • epitopope refers to that portion of an antigen or other
  • binding interactions can be manifested as an intermolecular contact with one or more amino acid residues of one or more CDRs.
  • Antigen binding can involve, for example, a CDR3 or a CDR3 pair or, in some cases, interactions of up to all six CDRs of the VH and VL chains.
  • An epitope can be a linear peptide sequence (i.e., "continuous") or can be composed of noncontiguous amino acid sequences (i.e. , "conformational” or “discontinuous”).
  • An antibody can recognize one or more amino acid sequences; therefore an epitope can define more than one distinct amino acid sequence. Epitopes recognized by antibodies can be determined by peptide mapping and sequence analysis techniques well known to one of skill in the art. Binding interactions are manifested as intermolecular contacts with one or more amino acid residues of a CDR.
  • the term "specific” refers to a situation in which an antibody will not show any significant binding to molecules other than the antigen containing the epitope recognized by the antibody.
  • the term is also applicable where, for example, an antigen binding domain is specific for a particular epitope which is carried by a number of antigens, in which case the antibody will be able to bind to the various antigens carrying the epitope.
  • the terms "preferentially binds” or “specifically binds” mean that the antibodies bind to an epitope with greater affinity than it binds unrelated amino acid sequences, and, if cross-reactive to other polypeptides containing the epitope, are not toxic at the levels at which they are formulated for administration to human use.
  • such affinity is at least 1-fold greater, at least 2-fold greater, at least 3-fold greater, at least 4-fold greater, at least 5- fold greater, at least 6-fold greater, at least 7-fold greater, at least 8-fold greater, at least 9-fold greater, 10-fold greater, at least 20-fold greater, at least 30-fold greater, at least 40-fold greater, at least 50-fold greater, at least 60-fold greater, at least 70-fold greater, at least 80-fold greater, at least 90-fold greater, at least 100-fold greater, or at least 1000-fold greater than the affinity of the antibody for unrelated amino acid sequences.
  • immunoreactive binds
  • preferentially binds and “specifically binds” are used interchangeably herein.
  • binding refers to a direct association between two molecules, due to, for example, covalent, electrostatic, hydrophobic, and ionic and/or hydrogen-bond interactions under physiological conditions, and includes interactions such as salt bridges and water bridges, as well as any other conventional means of binding.
  • isolated when applied to polypeptides means a polypeptide or a portion thereof which, by virtue of its origin or manipulation: (i) is present in a host cell as the expression product of a portion of an expression vector; or (ii) is linked to a protein or other chemical moiety other than that to which it is linked in nature; or (iii) does not occur in nature, for example, a protein that is chemically manipulated by appending, or adding at least one hydrophobic moiety to the protein so that the protein is in a form not found in nature.
  • isolated it is further meant a protein that is: (i) synthesized chemically; or (ii) expressed in a host cell and purified away from associated and contaminating proteins.
  • the term generally means a polypeptide that has been separated from other proteins and nucleic acids with which it naturally occurs. Typically, the polypeptide is also separated from substances such as antibodies or gel matrices (polyacrylamide) which are used to purify it.
  • Antibodies can be isolated and purified from the culture supernatant or ascites mentioned above by saturated ammonium sulfate precipitation, euglobulin precipitation method, caproic acid method, caprylic acid method, ion exchange chromatography (DEAE or DE52), or affinity chromatography using anti-Ig column or a protein A, G or L column.
  • Antibodies and antigen-binding fragments can be constructed and produced using conventional techniques known in the art.
  • recombinantly prepared antibodies can often be produced in large quantities, particularly when utilizing high level expression vectors.
  • Methods for recombinantly and synthetically producing antibodies, including expressing antibodies, are described in, for example, US Patent No. 8,221,753, issued July 17, 2012, and such methods are incorporated by reference herein. The expression of antibodies and antibody fragments is well established in the art.
  • an antibody, or antigen-binding fragment thereof, described herein are labeled with a reporter label, a therapeutic label, or a combination thereof.
  • Methods of making immunoconjugates are known in the art and are considered herein. Such methods include those described in, for example, US Patent No. 8,221,753, issued July 17, 2012, and such methods are incorporated by reference herein.
  • immunoconjugates refer to conjugates comprised of the humanized anti- endoglin antibodies or fragments thereof according to the present invention and at least one therapeutic label.
  • antitumor agents include, but not limited to, toxins, drugs, enzymes, cytokines, radionuclides, and photodynamic agents.
  • Toxins include, but are not limited to, ricin A chain, mutant Pseudomonas exotoxins, diphtheria toxoid, streptonigrin, boamycin, saporin, gelonin, and pokeweed antiviral protein.
  • Drugs include daunorubicin, methotrexate, and calicheamicins.
  • Radionuclides include radiometals.
  • Cytokines include, but are not limited to, transforming growth factor (TGF)-P, interleukins, interferons, and tumor necrosis factors.
  • TGF transforming growth factor
  • Photodynamic agents include, but are not limited to, porphyrins and their derivatives. Additional therapeutic labels will be known in the art and are also contemplated herein.
  • the methods for complexing the anti-endoglin mAbs or a fragment thereof with at least one antitumor agent are well known to those skilled in the art ⁇ i.e., antibody conjugates as reviewed by Ghetie et ah , 1994, Pharmacol. Ther. 63 :209-34). Such methods may utilize one of several available heterobifunctional reagents used for coupling or linking molecules. Additional radionuclides are further described herein along with additional methods for linking molecules, such as therapeutic labels.
  • antibody, or antigen-binding fragment thereof, described herein are modified to increase half-life and/or to cross the blood brain barrier. Such modification of the antibodies described herein allows for the treatment of a brain cancer.
  • chimeric antibodies that bind CD 105 and decrease and/or inhibit angiogenesis are described herein that exhibit reduced immunogenicity while maintaining and/or improving their specificity.
  • These anti-CD105 antibodies are useful for the diagnosis and treatment of various conditions and diseases as well as for purification and detection of CD 105.
  • Antibodies against CD105 represent an important area for the development of therapies for the treatment of a variety of diseases and conditions which involve, are influenced by, or affected by angiogenesis.
  • Provided herein are antibodies thereof that bind to CD105. Also provided are antibodies, (or antigen -binding fragments) thereof that bind CD 105 and inhibit (partially or fully) or manage/treat (partially or fully) a cancer or a metastasis thereof.
  • antibodies that specifically bind CD105 generated using the methods described herein can be tested using the assays provided herein or known in the art for the ability to bind to CD 105 using conventional methods including, but not limited to, ELISA. Affinity of antibodies described herein can also be determined using conventional methods including, but not limited to, BIACORE® or surface plasmon resonance.
  • antibodies that bind CD 105 are also provided herein. Also provided herein are isolated antibodies that specifically bind to CD 105 and inhibit a cancer or a metastasis thereof.
  • an isolated anti-endoglin antibody comprises chain variable region having an amino acid sequence set forth as SEQ ID NO: 1 and a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 3.
  • an isolated anti-endoglin antibody that comprises a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 1, a light chain constant region having an amino acid sequence set forth as SEQ ID NO: 2, a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 3 and a gamma 1 ( ⁇ ) constant region having an amino acid sequence set forth as SEQ ID NO: 4.
  • an isolated anti-CD105 antibody comprises a V L CDR1 having an amino acid sequence set forth as SEQ ID NO: 10; a V L CDR2 having an amino acid sequence set forth as SEQ ID NO: 11 or 12; a VL CDR3 having an amino acid sequence set forth as SEQ ID NO: 13; a VH CDRl having an amino acid sequence set forth as SEQ ID NO: 5; a VH CDR2 having an amino acid sequence set forth as SEQ ID NO: 6, 7, or 8; and a V H CDR3 having an amino acid sequence set forth as SEQ ID NO: 9.
  • an isolated humanized, de-immunized anti-CD105 antibody can comprise a heavy chain variable region having the amino acid sequence set forth as SEQ ID NO: 14, 15, 16, 17, or 18; and a light chain variable region having the amino acid sequence set forth as SEQ ID NO: 19, 20, 21, 22, or 23.
  • An isolated anti-endoglin antibody as described herein binds to human and murine endoglin and also competitively inhibits human BMP binding. However, an isolated anti-endoglin antibody as described herein does not prevent the binding of mouse BMP to mouse endoglin.
  • Antibodies described herein are useful in detection assays or to isolate endoglin from a sample.
  • Antibodies or antigen-binding fragments thereof provided herein are such that they can be conjugated or linked to a therapeutic moiety, a detectable moiety, and/or an affinity tag. Methods for conjugating or linking polypeptides are well known in the art. Associations (binding) between compounds and labels include any means known in the art including, but not limited to, covalent and non-covalent interactions, chemical conjugation as well as recombinant techniques.
  • compositions or formulations that contain an anti-endoglin antibody described herein may be prepared with one or more optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing (2000)), in the form of lyophilized formulations or aqueous solutions.
  • pharmaceutically acceptable carrier or “pharmaceutical acceptable excipient” includes any material which, when combined with an active ingredient, allows the ingredient to retain biological activity and is non-reactive with the subject's immune system.
  • Examples include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsion, and various types of wetting agents.
  • Preferred diluents for aerosol or parenteral administration are phosphate buffered saline or normal (0.9%) saline.
  • Compositions comprising such carriers are formulated by well- known conventional methods ⁇ see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1990; and Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000).
  • Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and may comprise buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine;
  • preservatives such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannito
  • the formulations to be used for in vivo administration may be sterilized. This may be accomplished by, for example, filtration through sterile filtration membranes, or any other art- recognized method for sterilization.
  • Antibody compositions are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle. Other methods for sterilization and filtration are known in the art and are contemplated herein.
  • compositions are formulated to be free of pyrogens such that they are acceptable for administration to a subject.
  • Testing compositions for pyrogens and preparing pharmaceutical compositions free of pyrogens are well understood to one of ordinary skill in the art.
  • the composition is lyophilized, for example, to increase shelf-life in storage.
  • the compositions can be substantially free of pyrogens such that the composition will not cause an inflammatory reaction or an unsafe allergic reaction when administered to a human patient.
  • Testing compositions for pyrogens and preparing compositions substantially free of pyrogens are well understood to one or ordinary skill of the art and can be accomplished using commercially available kits.
  • Acceptable carriers can be a compound that stabilizes, increases or delays absorption or clearance of an anti-endoglin antibody.
  • Such compounds include, for example, carbohydrates, such as glucose, sucrose, or dextrans; low molecular weight proteins; compositions that reduce the clearance or hydrolysis of peptides; or excipients or other stabilizers and/or buffers.
  • Agents that delay absorption include, for example, aluminum monostearate and gelatin. Detergents can also be used to stabilize or to increase or decrease the absorption of the pharmaceutical composition, including liposomal carriers.
  • the compound can be complexed with a composition to render it resistant to acidic and enzymatic hydrolysis, or the compound can be complexed in an appropriately resistant carrier such as a liposome.
  • Means of protecting compounds from digestion are known in the art (see, e.g., Fix (1996) Pharm Res. 13 : 1760 1764; Samanen (1996) J. Pharm. Pharmacol. 48: 1 19 135; and U.S. Pat. No. 5,391,377, describing lipid compositions for oral delivery of therapeutic agents).
  • phrases “pharmaceutically acceptable” refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a subject.
  • unit dose when used in reference to a therapeutic composition refers to physically discrete units suitable as unitary dosage for humans, each unit containing a
  • compositions can be administered in a manner compatible with the dosage formulation, and in a therapeutically effective amount.
  • the quantity to be administered depends on the subject to be treated, capacity of the subject's immune system to utilize the active ingredient, and degree of binding capacity desired. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and are peculiar to each individual. Suitable regimes for initial administration and booster shots are also variable, but are typified by an initial administration followed by repeated doses at one or more hour intervals by a subsequent injection or other administration. Alternatively, continuous intravenous infusion sufficient to maintain concentrations in the blood are contemplated.
  • One embodiment of the present invention contemplates the use of any of the compositions of the present invention to make a medicament for treating a cancer.
  • Medicaments can be formulated based on the physical characteristics of the subject needing treatment, and can be formulated in single or multiple formulations based on the disorder.
  • Medicaments of the present invention can be packaged in a suitable pharmaceutical package with appropriate labels for the distribution to hospitals and clinics wherein the label is for the indication of treating a cancer as described herein in a subj ect.
  • Medicaments can be packaged as a single or multiple units.
  • compositions can be administered in a manner compatible with the dosage formulation, and in a therapeutically effective amount.
  • the quantity to be administered depends on the subject to be treated, capacity of the subject's immune system to utilize the active ingredient, and degree of binding capacity desired. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and are peculiar to each individual. Suitable regimes for initial administration and booster shots are also variable, but are typified by an initial administration followed by repeated doses at one or more hour intervals by a subsequent injection or other administration. Booster doses can also be given at any appropriate interval. Alternatively, continuous intravenous infusion sufficient to maintain concentrations in blood is also contemplated.
  • VEGF and VEGFR inhibitors to be considered for use in the present compositions and methods include, but are not limited to, Axitinib, Pazopanib, Bevacizumab (AVASTIN®), ranibizumab (LUCENTIS®), aflibercept (VEGF-Trap; EYLEA®), sunitinib (SUTENT®), brivanib (BMS-582664), sorafenib (NEXAVAR®), pegaptanib (MACUGEN®), and SU5416.
  • Axitinib, Pazopanib Bevacizumab (AVASTIN®), ranibizumab (LUCENTIS®), aflibercept (VEGF-Trap; EYLEA®), sunitinib (SUTENT®), brivanib (BMS-582664), sorafenib (NEXAVAR®), pegaptanib (MACUGEN®), and SU5416.
  • the inhibitor is a small molecule inhibitor, such as, for example, axitinib, pazopanib, sorafenib, sunitinib, pazopanib, brivanib, etc.
  • the inhibitor is an antagonistic anti-VEGF antibody or an antagonistic anti-VEGFR antibody such as, for example, Bevacizumab (AVASTIN®), ranibizumab (LUCENTIS®), aflibercept (VEGF-Trap; EYLEA®), etc.
  • INLYTA® (Axitinib) is a small molecule indazole derivative, kinase inhibitor of the chemical name N-methyl ⁇ -fS-i ⁇ -pyridin ⁇ -yl-viny ⁇ -lH-indazol-e-ylsulfanylJ-benzamide and a molecular formula of C22H1 8 N4OS.
  • the chemical structure is of Axitinib is shown in Formula I:
  • Compositions/formulations of Axitinib may contain microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, and a dye as inactive ingredients; and may also contain a film coating that includes lactose monohydrate, HPMC 2910/Hypromellose 15cp, titanium dioxide, triacetin (glycerol triacetate) and red iron oxide.
  • Pazopanib (VOTRIENT®) is a potent and selective multi -targeted receptor tyrosine kinase inhibitor that blocks tumor growth and inhibits angiogenesis.
  • Pazopanib has a chemical name of 5- [[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl- benzenesulfonamide.
  • the chemical structure is of Pazo anib is shown in Formula ⁇ :
  • compositions/formulations of Pazopanib can be administered orally once daily without food (at least 13 1 hour before or 2 hours after a meal) with a maximum dosage of 800 mg daily.
  • a cancer to be treated includes, but is not limited to, a breast cancer, a lung cancer, a brain cancer, a sarcoma, a carcinoma, or a metastasis of any of such cancers.
  • the carcinoma is a Renal Cell Carcinoma which can be, in some instances, an advanced Renal Cell Carcinoma. In one non-limiting example, the carcinoma is a Renal Cell Carcinoma which can be, in some instances, a metastatic Renal Cell Carcinoma. In some instances, the carcinoma is a hepatocellular carcinoma or a choriocarcinoma.
  • the cancer or metastasis thereof is a brain cancer such as, for example, a glioblastoma multiforme (GBM).
  • GBM glioblastoma multiforme
  • the cancer or metastasis thereof is a breast cancer such as, for example, a Luminal A, a Luminal B, a Luminal B-like, a Triple negative or a HER2 type breast cancer.
  • a VEGF inhibitor to be administered includes, but is not limited to, Axitinib (N-methyl-2-[3-((£)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide).
  • Axitinib can be administered by any appropriate means including, for example, orally,
  • the anti-endoglin antibody can be administered by any appropriate means including, for example, orally, subcutaneously, intravenously, or in an implant.
  • the anti-endoglin antibody comprises an antigen-binding fragment that specifically binds to endoglin.
  • Antigen-binding fragments include, but are not limited to, a Fab fragment, a Fab' fragment, a F(ab)2 fragment, a F(ab r )2 fragment, a Fv fragment, a scFv fragment, or a single chain binding polypeptide.
  • the anti-endoglin antibody can be an IgG, an IgM, an IgE, an IgA, or an IgD, or is derived therefrom.
  • the antibody can be an IgGl, an IgG2, an IgG3, or an IgG4.
  • the antibody can be an IgG2a antibody or an IgG2b antibody.
  • an isolated anti-endoglin antibody comprises chain variable region having an amino acid sequence set forth as SEQ ID NO: 1 and a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 3.
  • an isolated anti-endoglin antibody comprises a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 1, a light chain constant region having an amino acid sequence set forth as SEQ ID NO: 2, a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 3 and a gamma 1 ( ⁇ ) constant region having an amino acid sequence set forth as SEQ ID NO: 4.
  • an isolated anti-CD105 antibody comprises a VL CDRl having an amino acid sequence set forth as SEQ ID NO: 10; a V L CDR2 having an amino acid sequence set forth as SEQ ID NO: 11 or 12; a VL CDR3 having an amino acid sequence set forth as SEQ ID NO: 13; a VH CDRl having an amino acid sequence set forth as SEQ ID NO: 5; a VH CDR2 having an amino acid sequence set forth as SEQ ID NO: 6, 7, or 8; and a V H CDR3 having an amino acid sequence set forth as SEQ ID NO: 9.
  • an isolated humanized, de-immunized anti-CD 105 antibody can comprise a heavy chain variable region having the amino acid sequence set forth as SEQ ID NO: 14, 15, 16, 17, or 18; and a light chain variable region having the amino acid sequence set forth as SEQ ID NO: 19, 20, 21, 22, or 23.
  • Treatment can reduce a size of a cancer or a metastasis thereof by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or more compared to administration of a placebo or compared to baseline.
  • An "individual” or a "subject" to be treated by a method herein may be a mammal, more preferably a human. Mammals also include, but are not limited to, farm animals, sport animals, and pets, including, but not limited to, primates, equines, bovines, alpacas, dogs, cats, rabbits, mice and rats. It will be appreciated that a subject to be treated may be suffering from a cancer, or a metastasis thereof, but may not yet be symptomatic for the disease.
  • a “therapeutically effective dosage” or a “therapeutically effective amount” of a pharmaceutical composition described herein is an amount sufficient to effect beneficial or desired results.
  • beneficial or desired results include results such as lessening the severity or delaying the progression of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
  • an "effective dosage" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved. Accordingly, in some instances, one or more therapeutic agents may be administered to the subject. In other instances, treatment with a pharmaceutical composition described herein is conducted prior to, or after, one or more other treatment modalities described herein. [0210] By “treating" a subject suffering from a cancer or a metastasis thereof, it is meant that the subject's symptoms can be partially alleviated, totally alleviated, or remain static following treatment according to the invention. A subject that has been treated can exhibit a partial or total alleviation of tumor load.
  • a subject suffering from a highly metastatic cancer is treated where additional metastasis either do not occur, or are reduced in number as compared to a subject who does not receive treatment.
  • a subject is treated where the subject' s solid cancer either becomes reduced in size or does not increase in size as compared to a subject who does not receive treatment.
  • the number of cancer cells in a treated subject either does not increase or is reduced as compared to the number of cancer cells in a subj ect who does not receive treatment. Improvement can also be defined, for example, as decreased cell proliferation, decreased numbers of cells, increased apoptosis, and/or increased survival of the subject being treated.
  • a subject can be treated for a length of time sufficient to prolong the life expectancy of the subject; or to partially or completely treat the cancer or metastasis thereof.
  • a subject can be administered treatment for about 1, about 2, about 3, about 4, about 5, about 6, about 7 or more days.
  • a subject can be administered treatment for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12 or more weeks.
  • a subject can be administered treatment for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12 or more months.
  • a subject can be administered treatment for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12 or more years.
  • the days, weeks, months or years of treatment can be consecutive. Alternatively, the days, weeks, months or years of treatment may not be consecutive. For example, if the subject enters remission, then treatment can be discontinued; if the subject shows presence of one or more abnormal biomarkers after being in remission, treatment can be reinstated. In other instances, a subject to be treated with the recited methods may have received surgery or treatment with another anti-tumor agent.
  • the treatment is sustained until a desired suppression of symptoms occurs or until sufficient therapeutic levels are achieved, for example, to reduce pain.
  • Non-limiting doses of an anti-endoglin antibody or antigen-binding fragment include, but are not limited to, about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg per subject, or any integer in between.
  • the one or more dose(s) of an anti-endoglin antibody or antigen-binding fragment can be administered twice a week, weekly, every two weeks, every three weeks, every 4 weeks, every 6 weeks, every 8 weeks, every 12 weeks, or any combination of weeks therein.
  • Dosing cycles are also contemplated such as, for example, administering antibodies or antigen-binding fragments thereof once or twice a week for 4 weeks, followed by two weeks without therapy. Additional dosing cycles including, for example, different combinations of the doses and weekly cycles described herein are also contemplated within the invention.
  • An exemplary dosing regimen of an anti-endoglin antibody comprises administering an initial dose of about 2 mg/kg, followed by a weekly maintenance dose of about 1 mg/kg, or followed by a maintenance dose of about 1 mg/kg every other week. Dosing may continue for a period of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months or more until a cancer is partially or completely eradicated. In some instances, treatment may result in stasis of the cancer, and increases the life expectancy of the subject being treated compared to a subject receiving a placebo.
  • Axitinib may be formulated for administration to a subject in an amount of about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 1 1 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg dose once or twice a day.
  • Axitinib may be administered about every 12 hours and dose adjustments may be made based upon the subject' s safety, tolerability and/or progression of a cancer to be treated.
  • Axitinib may be administered to a subject orally for at least 2 consecutive weeks.
  • the dose to be administered and the timing of administration for a subject may be empirically determined for each subject depending upon the height, weight, age, the state of the cancer to be treated, and other physical characteristics of the subject to be treated in accordance with a physician's
  • an anti-endoglin antibody can be administered at about 8 mg/kg/week and axitinib can be administered at about 5 mg twice a day (BID).
  • an anti-endoglin antibody can be administered at about 10 mg/kg/week and axitinib can be administered at about 5 mg twice a day (BID).
  • an anti-endoglin antibody can be administered at about 8 mg/kg/week and pazopanib can be administered at about 800 mg once a day (qD).
  • an anti-endoglin antibody can be administered at about 10 mg/kg/week and pazopanib can be administered at about 800 mg once a day (qD).
  • dosage regimens may be useful and are contemplated herein, depending on the pattern of pharmacokinetic decay that the treating practitioner wishes to achieve. For example, in some embodiments, dosing from one-four times a week is contemplated. The progress of this therapy is easily monitored by conventional techniques and assays. The dosing regimen can vary over time.
  • an anti-endoglin antibody will depend on the anti-endoglin antibody employed, the type and stage of cancer to be treated, previous surgery and/or therapy, the subject's clinical history and response to the antibody, and the discretion of the attending physician.
  • Empirical considerations such as the half-life, generally will contribute to the determination of the dosage.
  • antibodies that are compatible with the human immune system such as humanized antibodies or fully human antibodies, may be used to prolong half-life of the antibody and to prevent the antibody being attacked by the host's immune system.
  • Frequency of administration may be determined and adjusted over the course of therapy.
  • sustained continuous release formulations of anti-endoglin antibodies may be appropriate.
  • Various formulations and devices for achieving sustained release are known in the art.
  • an indicator of the disease can be followed.
  • the pharmaceutical composition comprising the anti-endoglin antibody and the anti-VEGF agent are administered at the same site.
  • the pharmaceutical composition comprising the anti-endoglin antibody and the anti-VEGF agent are administered at the different sites.
  • the pharmaceutical composition comprising the anti-endoglin antibody and the anti-VEGF agent are administered sequentially.
  • the pharmaceutical composition comprising the anti-endoglin antibody and the anti-VEGF agent are administered concurrently.
  • treatment of cancer includes stasis, partial or total elimination of a cancerous growth or tumor.
  • Treatment or partial elimination includes, for example, a fold reduction in growth or tumor size and/or volume such as about 2-fold, about 3-fold, about 4-fold, about 5- fold, about 10-fold, about 20-fold, about 50-fold, or any fold reduction in between.
  • treatment or partial elimination can include a percent reduction in growth or tumor size and/or volume of about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99%, 100%, or any percentage reduction in between.
  • Treatment efficacy can be assessed by methods well-known in the art.
  • Non-limiting examples of tumors include a carcinoma, a sarcoma, a lung cancer, a breast cancer, or a brain cancer.
  • Tumor is used herein to refer to a cancerous tissue (as compared to expression by normal tissue of the same type). Tumors can include solid tumors and semi-solid tumors. Tumors may also, in some instances, be metastatic.
  • amelioration As used herein, “amelioration” “inhibition,” “treatment” and “treating” refer to, for example, stasis of symptoms, prolongation of survival, partial or full amelioration of symptoms, and partial or full eradication of a condition, disease or disorder associated with a cancer or a metastasis thereof.
  • a cancer or a metastasis thereof is inhibited by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%), or about 100%, following treatment with one or more doses of a humanized and deimmunized antibody compared to treatment with a placebo or compared to a subject that does not receive any treatment.
  • symptoms of a cancer or a metastasis thereof may be ameliorated by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, following treatment with one or more doses of an anti-endoglin antibody compared to treatment with a placebo or compared to a subject that does not receive any treatment.
  • Treatment also refers to resolution of one or more symptoms of a cancer or a metastasis thereof. Treatment also refers to stasis of symptoms where a cancer or a metastasis thereof in a subject does not progress.
  • Pain associated with a cancer or a metastasis thereof may be reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%), about 95%), or about 100%, following treatment with one or more doses of an anti-endoglin antibody compared to treatment with a placebo or compared to a subject that does not receive any treatment.
  • administering is defined herein as a means providing the composition to the subject in a manner that results in the composition being inside the subject's body.
  • Such an administration can be by any route including, without limitation, locally, regionally or systemically by subcutaneous, intravitreal, intradermal, intravenous, intra-arterial, intraperitoneal, or intramuscular administration ⁇ e.g., injection), or by oral administration.
  • Concurrent administration means administration within a relatively short time period from each other; such time period can be less than 2 weeks, less than 7 days, less than 1 day and could even be administered simultaneously.
  • compositions can be administered to a subject in a therapeutically effective amount, i.e., that are effective for producing some desired therapeutic effect by inhibiting a cancer or a metastasis thereof such as described herein which can be associated with endoglin, at a reasonable benefit risk ratio applicable to any medical treatment.
  • a therapeutically effective amount is an amount achieves at least partially a desired therapeutic or prophylactic effect in an organ or tissue.
  • the amount of an anti- endoglin antibody or antigen binding fragment thereof necessary to bring about prevention and/or therapeutic treatment of a cancer or a metastasis thereof is not fixed per se.
  • the amount of anti -endoglin antibody or antigen binding fragment thereof administered may vary with the type of a cancer or a metastasis thereof, extensiveness of the cancer or a metastasis thereof, and size of the mammal suffering from the cancer or a metastasis thereof.
  • two or more anti-endoglin antibodies described herein are administered to a subject in combination. Combination includes concomitant or subsequent administration of the antibodies.
  • compositions can be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular composition employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts.
  • the antibodies and antigen-binding fragments described herein can be administered to a subject in various dosing amounts and over various time frames.
  • a sarcoma is a cancer (malignant tumor) of connective tissue (e.g., bone, cartilage, fat) or other non-epithelial tissue resulting in mesoderm proliferation.
  • a sarcoma to be treated with the recited methods may be a soft tissue sarcoma of endothelium (angiosarcoma), synovial tissues (tissues around joints), muscles (e.g., a
  • a sarcoma to be treated is a bone sarcoma (osteosarcoma).
  • a carcinoma is any malignant cancer that arises from epithelial cells (e.g., breast, colon, pancreas, and others) of the skin or of the lining of the internal organs (e.g., liver or kidney).
  • epithelial cells e.g., breast, colon, pancreas, and others
  • the skin or of the lining of the internal organs e.g., liver or kidney.
  • Carcinomas can, in some instances, invade surrounding tissues and organs and may metastasize, or spread, to lymph nodes and other sites.
  • a carcinoma to be treated by the described methods includes, but is not limited to, an adenocarcinoma; a squamous cell carcinoma; a small cell carcinoma; a sinonasal undifferentiated carcinoma (S UC); an undifferentiated carcinoma; a carcinoma of the prostate; a hepatocellular carcinoma; or a renal cell carcinoma.
  • the carcinoma to be treated is a renal cell carcinoma that can be in some instances, an advanced renal cell carcinoma or a metastasized renal cell carcinoma.
  • a subject having a renal cell carcinoma may be symptomless (asymptomatic) until the disease is in an advanced stage.
  • a subject in need thereof having a lung cancer is administered a therapeutically effective amount of a pharmaceutical composition that comprises an antibody, or antigen-binding fragment thereof described herein.
  • a lung cancer to be treated with the described methods can be, for example, a non-small cell lung cancer, a lung carcinoid tumor, or a small cell lung cancer.
  • a non-small cell lung cancer can be, for example, a squamous cell carcinoma, an adenocarcinoma, or a large cell undifferentiated carcinoma.
  • breast cancer in a method described herein, a subject in need thereof having a breast cancer is administered a therapeutically effective amount of a pharmaceutical composition that comprises an antibody, or antigen-binding fragment thereof described herein.
  • a pharmaceutical composition that comprises an antibody, or antigen-binding fragment thereof described herein.
  • breast cancer also encompasses a phenotype that displays a predisposition towards developing breast cancer in an individual.
  • a breast cancer to be treated using the methods described herein includes any type of breast cancer that can develop in a female subject.
  • the breast cancer may be characterized as Luminal A (ER+ and/or PR+, HER2-, low Ki67), Luminal B (ER+ and/or PR+, HER2+ (or HER2- with high Ki67), Triple negative/basal-like (ER-, PR-, HER2-) or HER2 type (ER-, PR-, HER2+).
  • the breast cancer may be resistant to therapy or therapies such as alkylating agents, platinum agents, taxanes, vinca agents, anti-estrogen drugs, aromatase inhibitors, ovarian suppression agents, endocrine/hormonal agents, bisphophonate therapy agents or targeted biological therapy agents.
  • therapies such as alkylating agents, platinum agents, taxanes, vinca agents, anti-estrogen drugs, aromatase inhibitors, ovarian suppression agents, endocrine/hormonal agents, bisphophonate therapy agents or targeted biological therapy agents.
  • a lobular carcinoma in situ and a ductal carcinoma in situ are breast cancers that have developed in the lobules and ducts, respectively, but have not spread to the fatty tissue surrounding the breast or to other areas of the body.
  • Infiltrating (or invasive) lobular and ductal carcinoma are cancers that have developed in the lobules and ducts, respectively, and have spread to either the breast's fatty tissue and/or other parts of the body.
  • a method of treating breast cancer such as a ductal carcinoma in duct tissue in a mammary gland, a breast cancer that is Her2- and/or ER- and/or PR-.
  • Other cancers of the breast that would benefit from treatment by the methods are medullary carcinomas, colloid carcinomas, tubular carcinomas, and inflammatory breast cancer.
  • Antibodies, or antigen-binding fragments thereof, described herein can be modified so that they are able to cross the blood-brain barrier. Such modification of the antibodies or antigen- binding fragments described herein allows for the treatment of brain diseases such as glioblastoma multiforme (GBM). Exemplary modifications to allow proteins such as antibodies or antigen- binding fragments to cross the blood-brain barrier are described in US Patent Application
  • Brain tumors to be treated using the methods described herein include, but are not limited to, a meningioma, an astrocytoma such as glioblastomas ⁇ e.g., glioblastoma multiforme (GBM)), and a malignant medulloblastoma.
  • a meningioma an astrocytoma such as glioblastomas ⁇ e.g., glioblastoma multiforme (GBM)
  • GBM glioblastoma multiforme
  • analytes also referred to as markers or biomarkers
  • the characteristics of plasma analytes were investigated using a variety of measures. Baseline and on-treatment levels were quantified and changes among analytes were determined at the desired time points (waterfall plots; data not shown).
  • ANG-2 Angiopoietin-2
  • bFGF Basic fibroblast growth factor
  • HGF hepatocyte growth factor
  • PDGF Platelet-derived growth factor
  • TSP Thrombospondin
  • PIGF placenta growth factor
  • VEGF Vascular endothelial growth factor
  • BMP bone morphogenetic protein
  • TGF transforming growth factor
  • ICAM Intercellular Adhesion Molecule
  • IL Interleukin
  • OPN Osteopontin
  • SDF stromal cell -derived factor
  • TEVIP tissue inhibitor of metalloproteinase
  • VCAM Vascular cell adhesion protein.
  • Plasma samples were collected at Baseline (Day 1) prior to initiation of treatment in all studies.
  • mBC metastatic breast cancer
  • GBM glioblastoma multiforme
  • a subject with advanced or metastatic renal cell carcinoma presenting to a treating physician would have a sample of blood taken from a peripheral vein, from which plasma would be obtained.
  • the plasma would be subject to an ELISA to measure concentrations of one or more soluble proteins (e.g., such as those described in Table 1), including angiopoietin, VEGFR2, osteopontin and TGFP-R3.
  • the subject Based on the concentrations of the one or more soluble proteins, including but not limited to, an elevation of TGFP-R3, angiopoietin, or VEGFR2 above the median or mean level of the biomarker in subjects with the specific cancer type and/or a decrease in osteopontin below the median or mean level of the biomarker in subjects with the specific cancer type, the subject would be identified as a subject to be treated with a VEGF inhibitor (including but not limited to axitinib) and an anti-endoglin antibody (including, but not limited to, TRC 105).
  • a VEGF inhibitor including but not limited to axitinib
  • an anti-endoglin antibody including, but not limited to, TRC 105.
  • a subject with advanced or soft tissue sarcoma presenting to a treating physician would have a sample of blood taken from a peripheral vein, from which plasma would be obtained.
  • the plasma would be subject to an ELISA to measure concentrations of one or more soluble proteins (e.g., such as those described in Table 1), including ICAM-1 and TSP-2.
  • the subject Based on the concentrations of the one or more soluble proteins, including but not limited to, a decrease in ICAM-1 or TSP-2 below the median or mean level of the biomarker in subjects with the specific cancer type, the subject would be identified as a subject to be treated with a VEGF inhibitor (including but not limited to pazopanib) and an anti-endoglin antibody (including, but not limited to, TRC 105).
  • a VEGF inhibitor including but not limited to pazopanib
  • an anti-endoglin antibody including, but not limited to, TRC 105.
  • the described methods can be used, in one example, to identify a subject for treatment when ANG-2 is detected.
  • the described methods can be used, in one example, to identify a subject for treatment when ANG-2 is detected in combination with VEGF-R2, OPN and/or TGFp-R3.
  • the described methods can be used, in one example, to identify a subject for treatment when VEGF-R2 is detected.
  • the described methods can be used, in one example, to identify a subject for treatment when VEGF-R2 is detected in combination with ANG-2, OPN and/or TGFP-R3.
  • the described methods can be used, in one example, to identify a subject for treatment when OPN is detected.
  • the described methods can be used, in one example, to identify a subject for treatment when OPN is detected in combination with ANG-2, VEGF-R2 and/or TGFP-R3. [0283] The described methods can be used, in one example, to identify a subject for treatment when TGF -R3 is detected.
  • the described methods can be used, in one example, to identify a subj ect for treatment when TGFP-R3 is detected in combination with ANG-2, VEGF-R2 and/or OPN.

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Abstract

La présente invention concerne une polythérapie destinée au traitement d'un cancer ou d'une métastase de ce dernier. L'invention concerne également des procédés d'évaluation de biomarqueurs avant, pendant et après le traitement d'un sujet. L'invention concerne également des procédés d'identification d'un ou de plusieurs niveaux de base de biomarqueurs chez un sujet et son recrutement dans un essai clinique sur la base du ou des niveaux de base de biomarqueurs. L'invention concerne également des procédés d'identification d'un ou de plusieurs niveaux de base de biomarqueurs chez un sujet, et de prédiction du fait que le sujet est sensible ou non au traitement par un anticorps anti-endogline et un inhibiteur de VEGF ou un inhibiteur du récepteur de VEGF.
PCT/US2017/055345 2016-10-06 2017-10-05 Compositions et méthodes de traitement de cancers WO2018067819A1 (fr)

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WO2018187158A1 (fr) * 2017-04-07 2018-10-11 Tracon Pharmaceuticals, Inc. Polythérapie du cancer par anticorps anti-endogline et agents anti-récepteur de mort programmée
US10336831B2 (en) 2014-11-12 2019-07-02 Tracon Pharmaceuticals, Inc. Use of anti-endoglin antibodies for treating ocular fibrosis
CN112870193A (zh) * 2021-03-11 2021-06-01 大连医科大学附属第二医院 褪黑素在制备治疗对靶向药物耐药的her2阳性乳腺癌的药物中的应用
WO2023133595A2 (fr) 2022-01-10 2023-07-13 Sana Biotechnology, Inc. Méthodes de dosage et d'administration ex vivo de particules lipidiques ou de vecteurs viraux ainsi que systèmes et utilisations associés
WO2024081820A1 (fr) 2022-10-13 2024-04-18 Sana Biotechnology, Inc. Particules virales ciblant des cellules souches hématopoïétiques
WO2024119157A1 (fr) 2022-12-02 2024-06-06 Sana Biotechnology, Inc. Particules lipidiques avec cofusogènes et leurs procédés de production et d'utilisation
WO2024243340A1 (fr) 2023-05-23 2024-11-28 Sana Biotechnology, Inc. Fusogènes en tandem et particules lipidiques associées

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10336831B2 (en) 2014-11-12 2019-07-02 Tracon Pharmaceuticals, Inc. Use of anti-endoglin antibodies for treating ocular fibrosis
WO2018187158A1 (fr) * 2017-04-07 2018-10-11 Tracon Pharmaceuticals, Inc. Polythérapie du cancer par anticorps anti-endogline et agents anti-récepteur de mort programmée
CN112870193A (zh) * 2021-03-11 2021-06-01 大连医科大学附属第二医院 褪黑素在制备治疗对靶向药物耐药的her2阳性乳腺癌的药物中的应用
CN112870193B (zh) * 2021-03-11 2022-07-08 大连医科大学附属第二医院 褪黑素在制备治疗对靶向药物耐药的her2阳性乳腺癌的药物中的应用
WO2023133595A2 (fr) 2022-01-10 2023-07-13 Sana Biotechnology, Inc. Méthodes de dosage et d'administration ex vivo de particules lipidiques ou de vecteurs viraux ainsi que systèmes et utilisations associés
WO2024081820A1 (fr) 2022-10-13 2024-04-18 Sana Biotechnology, Inc. Particules virales ciblant des cellules souches hématopoïétiques
WO2024119157A1 (fr) 2022-12-02 2024-06-06 Sana Biotechnology, Inc. Particules lipidiques avec cofusogènes et leurs procédés de production et d'utilisation
WO2024243340A1 (fr) 2023-05-23 2024-11-28 Sana Biotechnology, Inc. Fusogènes en tandem et particules lipidiques associées

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