WO1996005231A1 - Peptides et anticorps et leur utilisation dans le traitement des carcinomes - Google Patents
Peptides et anticorps et leur utilisation dans le traitement des carcinomes Download PDFInfo
- Publication number
- WO1996005231A1 WO1996005231A1 PCT/GB1995/001893 GB9501893W WO9605231A1 WO 1996005231 A1 WO1996005231 A1 WO 1996005231A1 GB 9501893 W GB9501893 W GB 9501893W WO 9605231 A1 WO9605231 A1 WO 9605231A1
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- WIPO (PCT)
- Prior art keywords
- phe
- gly
- lys
- ser
- seq
- Prior art date
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 32
- 201000009030 Carcinoma Diseases 0.000 title claims abstract description 21
- 102000004196 processed proteins & peptides Human genes 0.000 title abstract description 9
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims abstract description 36
- 229960001340 histamine Drugs 0.000 claims abstract description 18
- 201000008274 breast adenocarcinoma Diseases 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 9
- 108010089230 histamine-releasing peptide Proteins 0.000 claims abstract description 9
- 230000002163 immunogen Effects 0.000 claims abstract description 9
- KLNGALQMFAURPH-NOQNJSOHSA-N kinetensin (1-8) Chemical compound C([C@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C)NC(=O)[C@@H](N)[C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CN=CN1 KLNGALQMFAURPH-NOQNJSOHSA-N 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 5
- 125000002091 cationic group Chemical group 0.000 claims abstract description 4
- 150000001413 amino acids Chemical class 0.000 claims description 18
- 239000003446 ligand Substances 0.000 claims description 7
- 125000000539 amino acid group Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 210000003630 histaminocyte Anatomy 0.000 abstract description 19
- 230000035755 proliferation Effects 0.000 abstract description 8
- 239000000427 antigen Substances 0.000 abstract description 5
- 102000036639 antigens Human genes 0.000 abstract description 5
- 108091007433 antigens Proteins 0.000 abstract description 5
- 238000002649 immunization Methods 0.000 abstract description 5
- 206010028980 Neoplasm Diseases 0.000 description 10
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 6
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 230000004614 tumor growth Effects 0.000 description 6
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 108010081551 glycylphenylalanine Proteins 0.000 description 5
- 108010064235 lysylglycine Proteins 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- GRVMHFCZUIYNKQ-UFYCRDLUSA-N Phe-Phe-Val Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O GRVMHFCZUIYNKQ-UFYCRDLUSA-N 0.000 description 4
- 208000003455 anaphylaxis Diseases 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- 102000014914 Carrier Proteins Human genes 0.000 description 2
- 108010078791 Carrier Proteins Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 201000008275 breast carcinoma Diseases 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- RIQBRKVTFBWEDY-RHYQMDGZSA-N Arg-Lys-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O RIQBRKVTFBWEDY-RHYQMDGZSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- FEUPVVCGQLNXNP-IRXDYDNUSA-N Gly-Phe-Phe Chemical compound C([C@H](NC(=O)CN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 FEUPVVCGQLNXNP-IRXDYDNUSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- FHIAJWBDZVHLAH-YUMQZZPRSA-N Lys-Gly-Ser Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O FHIAJWBDZVHLAH-YUMQZZPRSA-N 0.000 description 1
- GKZIWHRNKRBEOH-HOTGVXAUSA-N Phe-Phe Chemical compound C([C@H]([NH3+])C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)C1=CC=CC=C1 GKZIWHRNKRBEOH-HOTGVXAUSA-N 0.000 description 1
- WEDZFLRYSIDIRX-IHRRRGAJSA-N Phe-Ser-Arg Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=CC=C1 WEDZFLRYSIDIRX-IHRRRGAJSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000002788 anti-peptide Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000008614 cellular interaction Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- MYNGUEUQZPRWDB-UHFFFAOYSA-M sodium;5-(3-methylbutoxy)-4-oxo-8-prop-2-enylchromene-2-carboxylate Chemical compound [Na+].O1C(C([O-])=O)=CC(=O)C2=C1C(CC=C)=CC=C2OCCC(C)C MYNGUEUQZPRWDB-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
- C07K16/4283—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig
- C07K16/4291—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig against IgE
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to peptides and antibodies and their use in the treatment of carcinomas.
- Amino acids and amino acid residues are represented herein by their standard codes as identified by IUPAC-IUB Biochemical Nomenclature Commission and represent D and L amino acids, their analogues or derivatives.
- mast cells are known to participate in the development of anaphylaxis mediated by IgE.
- Ionov suggested that the ability of mast cell inhibitors to impede tumour growth is connected with the inhibition of anaphylactic reactions in tumour-bearing organisms.
- IgE antibodies specific to tumour antigens appear in an organism. These antibodies induce anaphylactic reactions at the line of demarcation between tumour and healthy tissues. This has been confirmed by finding degranulation of mast cells at their sites of contact with tumour cells and by elevated histamine concentrations in tumour bearing animals. Ionov presumes these anaphylactic reactions are able to promote tumour growth.
- mast cell-stabilising agent (Fisons FPL 55618) had significant benefits in reducing tumour growth of rat mammary adenocarcinoma in vivo. This observation supports the concept that mast cell/tumour cell interactions are important for the growth and invasive properties of the model breast carcinoma used.
- carcinoma proliferation especially that of mammary adenocarcinoma can be treated by inhibiting mast cell degranulation mediated by IgE.
- IgE mast cell degranulation mediated by IgE
- the present inventors have found that antibodies and antigens of the type described by Stanworth can be used to treat carcinomas.
- the treatment is based on the inventors concept of the link between the effect of inhibition of IgE reactions and the effect that mast cell degranulation is inhibited and the consequential effect that carcinoma proliferation is inhibited.
- This radical approach differs fundamentally from those suggested or hinted at in the prior art in two ways:
- the invention does not attempt to block the direct consequence of mast cell degranulation (i.e. by histamine- blocking agents) .
- the invention can provide for the use of immunoactive peptides (antigens) for active immunisation to produce antibodies which prevent "triggering" of histamine release by mast cell degranulation and consequently inhibit carcinoma proliferation.
- the invention can also provide for the use of antibodies for passive immunisation, which antibodies prevent "triggering" of histamine release by mast cell degranulation and consequently inhibit carcinoma proliferation.
- the present invention can provide use of an immunogen comprising a covalent conjugate of a residue of a histamine-releasing peptide having a cationic N terminus and a hydrophobic C terminus, together with a residue capable of eliciting antibodies against this peptide in the manufacture of a medicament for the treatment of carcinomas, especially mammary adenocarcinomas.
- residue as used herein includes within its scope single amino acids and functional sequences of amino acids.
- the C terminus of this immunogen is blocked by amidation to prolong its half life. This enables a shorter peptide to be used.
- the C terminus comprises the sequence Phe-Phe.
- the N terminus comprises the sequence Lys-Thr-Lys and is separated from the C terminus by from 2 to 6 predominantly non-polar and non-hydrophobic amino acid residues,* preferably Gly-Ser-Gly.
- the residue of a histamine-releasing peptide has the sequence Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe-Val-Phe (SEQ ID NO:l) or has a sequence selected from the group which comprises:
- Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe-Val-Phe-Ser-Arg (SEQ ID NO:5) or an amidated or non-amidated histamine-releasing analogue thereof.
- the present invention can provide use of a ligand comprising an antibody domain specific for any histamine- releasing peptide described herein and being reactive with a sequence of amino acids of the heavy chain of IgE which mediates histamine release in the manufacture of a medicament for the treatment of carcinomas especially mammary adenocarcinomas.
- This ligand may comprise a monoclonal or polyclonal, wholly, semi or non-synthetic antibody or a fragment thereof.
- the present invention can provide a method of treatment for carcinomas, especially mammary adenocarcinomas, comprising administering an effective dose of the immunogen, ligand or medicament described herein.
- Figures 1 and 2 are growth curves of 2540 ICI8, a murine mammary adenocarcinoma cell line, treated with F30 peptide ( ys-Thr-Lys- Gly-Ser-Gly-Phe-Phe-Val-Phe-NH 2 (SEQ ID NO:6)) conjugated to carrier protein (PPD) and treated with F19 (an unrelated peptide which comprises a sequence of amino acid residues of human y- chain polypeptide) conjugated to carrier protein (PPD) .
- F30 peptide ys-Thr-Lys- Gly-Ser-Gly-Phe-Phe-Val-Phe-NH 2 (SEQ ID NO:6) conjugated to carrier protein (PPD)
- F19 an unrelated peptide which comprises a sequence of amino acid residues of human y- chain polypeptide
- Figure 3 is a growth curve of,2546 ICI10, another murine mammary adenocarcinoma cell line, treated with F30 conjugated to PPD and with F19 conjugated to PPD.
- Figure 4 is a bar graph showing tumour weights of 2540 ICI8 after 41 days following treatment with F19 and F30 conjugated to PPD.
- Figure 5 is a bar graph showing tumour weights of 2546 ICI10 after 30 days following treatment with F19 and F30 conjugated to PPD.
- mice with mammary adenocarcinoma were immunised with human e-chain decapeptide (having the sequence Lys-Thr-Lys-Gly- Ser-Gly-Phe-Phe-Val-Phe-NH 2 ) conjugated to PPD according to the regimen reported in The Lancet (1990) 1279-81. Accordingly, 200 ⁇ l of a 1:1 mixture of peptide-PPD conjugate (1 mg/ml solution in buffer) and CFA (Difco) were injected subcutaneously into rats having mammary adenocarcinomas. Further subcutaneous injections at 14 and 21 days of 200 ⁇ l of 1:1 mixture of the same peptide-PPD conjugate with IFA (Difco) .
- Tail bleeds were taken at days 0, 7, 14, 21 and 28 and the resultant sera was stored frozen at -20°C before anti-peptide antibody assays were carried out by ELISA.
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- Health & Medical Sciences (AREA)
- Immunology (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Cette invention se rapporte à l'utilisation de peptides immunoactifs (antigènes) pour une immunisation active, afin de produire des anticorps qui empêchent le déclenchement de la libération d'histamine par la dégranulation des mastocytes et qui, par voie de conséquence, inhibent la prolifération des carcinomes. Cette invention se rapporte également à l'utilisation d'anticorps pour une immunisation passive, anticorps qui empêchent le déclenchement de la libération d'histamine par la dégranulation des mastocytes et qui, par voie de conséquence, inhibent la prolifération des carcinomes. Cette invention se rapporte à l'utilisation d'un immunogène comprenant un conjugué covalent d'un résidu d'un peptide libérant l'histamine ayant une terminaison N cationique et une terminaison C hydrophobe, conjointement avec un résidu capable de dresser des anticorps contre ce peptide, dans la fabrication d'un médicamant pour le traitement des carcinomes, en particulier les adénocarcinomes mammaires. De préférence, le résidu d'un peptide libérant l'histamine possède la séquence Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe-Val-Phe (numéro d'identification de séquence: 1).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU32267/95A AU3226795A (en) | 1994-08-12 | 1995-08-10 | Peptides and antibodies and their use in treatment of carcinomas |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9416321.9 | 1994-08-12 | ||
| GB9416321A GB9416321D0 (en) | 1994-08-12 | 1994-08-12 | Peptides and antibodies and their use in treatment of carcinomas |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996005231A1 true WO1996005231A1 (fr) | 1996-02-22 |
Family
ID=10759787
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1995/001893 WO1996005231A1 (fr) | 1994-08-12 | 1995-08-10 | Peptides et anticorps et leur utilisation dans le traitement des carcinomes |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU3226795A (fr) |
| GB (1) | GB9416321D0 (fr) |
| WO (1) | WO1996005231A1 (fr) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000040229A3 (fr) * | 1999-01-06 | 2001-07-19 | Maxim Pharm Inc | Reponse tumoricide synergique induite par l'histamine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990015878A1 (fr) * | 1989-06-15 | 1990-12-27 | National Research Development Corporation | Peptides et anticorps immunoactifs et leur utilisation dans les traitements anti-allergiques |
-
1994
- 1994-08-12 GB GB9416321A patent/GB9416321D0/en active Pending
-
1995
- 1995-08-10 WO PCT/GB1995/001893 patent/WO1996005231A1/fr active Application Filing
- 1995-08-10 AU AU32267/95A patent/AU3226795A/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990015878A1 (fr) * | 1989-06-15 | 1990-12-27 | National Research Development Corporation | Peptides et anticorps immunoactifs et leur utilisation dans les traitements anti-allergiques |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000040229A3 (fr) * | 1999-01-06 | 2001-07-19 | Maxim Pharm Inc | Reponse tumoricide synergique induite par l'histamine |
| US6498181B1 (en) | 1999-01-06 | 2002-12-24 | Maxim Pharmaceuticals | Synergistic tumorcidal response induced by histamine |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9416321D0 (en) | 1994-10-05 |
| AU3226795A (en) | 1996-03-07 |
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