WO1996005231A1 - Peptides and antibodies and their use in treatment of carcinomas - Google Patents
Peptides and antibodies and their use in treatment of carcinomas Download PDFInfo
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- 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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- 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
The invention provides 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 also provides 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 invention provides 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. Preferably, the residue of a histamine-releasing peptide has the sequence Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe-Val-Phe (SEQ ID NO:1).
Description
Peptides and Antibodies and their Use in Treatment of
Carcinomas
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.
Scott, K.G. , Annals of the New York Academy of Sciences 103 (1963) 285-312, conducted studies in rodents and man in attempts to elucidate the relationship between developing cancer cells and the normal cells of the host. It was suggested that release of peptides by tumour cells appears to be capable of affecting adjacent tissues during early stages of tumour growth and to be capable of affecting remote cells, such as mast cells, as tumour cells develop. Tumour cells were found to release peptides which lead to mast cell degranulation and consequential 5-HT and histamine release. Certain tumours were shown to be partially dependent upon histamine and 5-HT for growth. Scott noted that serotonin and/or histamine blockers could possess moderate anti- cancer activity.
Ionov, I.D., Int. J. , Radiat. Biol. ££ (1991) 287-291, found that the mast cell activity inhibitor, disodium chromoglycate, significantly depressed tumour growth alone and in combination with cytostatic methotrexate. It was indicated that mast cell inhibitors might be considered plausible for tumour therapy.
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. Furthermore, it has been shown experimentally that during development of a tumour 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.
Dabbaus, M.K. et al, One-day Workshop of the British Connective Tissue Society, 14th November 1990, indicated that the proliferation of certain mammary carcinomas was accompanied by mast cell degranulation. A 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.
According to the present invention, carcinoma proliferation especially that of mammary adenocarcinoma can be treated by inhibiting mast cell degranulation mediated by IgE. Surprisingly it has been found that by administering or eliciting antibodies to IgE carcinoma proliferation can be inhibited.
Stanworth et al, WO 90/15878, have shown that it is possible in vitro and in vivo to produce or elicit with an immunogen an
antibody to the "effector site" of the Fc region of IgE. The antibody can bind to the Fc region of IgE and can consequently prevent mast cell activity including degranulation when cell bound IgE is cross-linked to its specific allergen. This can occur even when IgE is present in the circulation, bound by its Fc region to a mast cell.
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:
1) The invention does not attempt to directly stabilise mast cells to block the degranulation process;
2) The invention does not attempt to block the direct consequence of mast cell degranulation (i.e. by histamine- blocking agents) .
In complete contrast to the prior art, 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.
It is expected that these antigens and antibodies could be used both in preventative immunisation and in acute therapy.
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.
The term residue as used herein includes within its scope single amino acids and functional sequences of amino acids.
Preferably the C terminus of this immunogen is blocked by amidation to prolong its half life. This enables a shorter peptide to be used. Preferably the C terminus comprises the sequence Phe-Phe.
Preferably 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.
Preferably, 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 (SEQ ID NO:2)
Arg-Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe (SEQ ID NO:3)
Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe-Val (SEQ ID NO:4)
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.
In a second aspect, 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.
In a third aspect, 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.
The present invention will be further described with reference to the drawings of which:
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-NH2 (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) .
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.
Six Balb/c mice with mammary adenocarcinoma were immunised with human e-chain decapeptide (having the sequence Lys-Thr-Lys-Gly- Ser-Gly-Phe-Phe-Val-Phe-NH2) conjugated to PPD according to the regimen reported in The Lancet (1990) 1279-81. Accordingly, 200 μl 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 μl of 1:1 mixture of the same peptide-PPD conjugate with IFA (Difco) .
A control group of six Balb/c mice, having mammary adenocarcinomas, were similarly immunised with human γ-chain peptide (F19)-PPD conjugate.
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.
Tumour growth in immunised and control animals was monitored regularly.
The results of these experiments are shown in Figures 1 to 5.
SEQUENCE LISTING
(1) GENERAL INFORMATION:
(i) APPLICANT:
(A) NAME: PEPTIDE THERAPEUTICS LIMITED
(B) STREET: 321 CAMBRIDGE SCIENCE PARK '(C) CITY: CAMBRIDGE
(D) STATE: CAMBRIDGE
(E) COUNTRY: ENGLAND
(F) POSTAL CODE (ZIP) : CB4 4WG
(G) TELEPHONE: 01223 423333 <H) TELEFAX: 01223 423111
(ii) TITLE OF INVENTION: Peptides And Antibodies And Their Use In The Treatment Of Carcinomas
(iii) NUMBER OF SEQUENCES: 6
(iv) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk
(B) COMPUTER: IBM PC compatible
(C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: Patentin Release #1.0, Version #1.30 (EPO)
(vi) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: GB 9416321.9
(B) FILING DATE: 12-AUG-1994
(2) INFORMATION FOR SEQ ID NO: 1:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 10 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1:
Lys Thr Lys Gly Ser Gly Phe Phe Val Phe 1 5 10
(2) INFORMATION FOR SEQ ID NO: 2:
(i) SEQUENCE CHARACTERISTICS: (A) .LENGTH: 8 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2:
Lys Thr Lys Gly Ser Gly Phe Phe l 5
(2) INFORMATION FOR SEQ ID NO: 3:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3:
Arg Lys Thr Lys Gly Ser Gly Phe Phe 1 5
(2) INFORMATION FOR SEQ ID NO: 4:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4:
Lys Thr Lys Gly Ser Gly Phe Phe Val 1 5
(2) INFORMATION FOR SEQ ID NO: 5:
(i) SEQUENCE CHARACTERISTICS:
(A). LENGTH: 12 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5:
Lys Thr Lys Gly Ser Gly Phe Phe Val Phe Ser Arg 1 5 10
(2) INFORMATION FOR SEQ ID NO: 6:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 10 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: Modified-site
(B) LOCATION:10
(D) OTHER INFORMATION: /product= "Phe 10" /note= "Amidated"
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6:
Lys Thr Lys Gly Ser Gly Phe Phe Val Phe
1 5 10
Claims
1. 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.
2. Use of an immunogen comprising a covalent conjugate of a peptide having the amino acid residue sequence Lys-Thr- ys- Gly-Ser-Gly-Phe-Phe-Val-Phe (SEQ ID NO:l) or a sequence selected from the group which comprises:
Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe (SEQ ID N0:2)
Arg-Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe (SEQ ID N0:3)
Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe-Val (SEQ ID N0:4)
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 together with a residue capable of eliciting antibodies against this peptide whilst inhibiting histamine release by this peptide, in the manufacture of a medicament for the treatment of mammary adenocarcinoma.
3. Use of a ligand comprising an antibody domain specific for a histamine-releasing peptide 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.
4. Use of a ligand according to claim 3, wherein the peptide has the amino acid residue sequence Lys-Thr-Lys-Gly-Ser- Gly-Phe-Phe-Val-Phe (SEQ ID N0:1) or a sequence selected from the group which comprises: Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe (SEQ ID NO:2)
Arg-Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe (SEQ IN NO:3)
Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe-Val (SEQ ID NO:4)
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.
5. A method of treatment of carcinoma which consists of administering to a patient an effective amount of an immunogen comprising 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.
6. A method of treatment of mammary adenocarcinoma which consists of administering to a patient an effective amount of an immunogen comprising a peptide having the amino acid residue sequence Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe-Val-Phe (SEQ ID NO:l) or a sequence selected from the group which comprises: Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe (SEQ ID NO:2) Arg-Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe (SEQ ID N0:3) Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe-Val (SEQ ID NO:4) 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 together with a residue capable of eliciting antibodies against this peptide whilst inhibiting histamine release by this peptide.
7. A method of treatment of carcinoma which consists of administering to a patient an effective amount of a ligand comprising an antibody domain specific for a histamine-releasing peptide 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.
8. A method of treatment of mammary adenocarcinoma which consists of administering to a patient an effective amount of a ligand according to claim 7, wherein the peptide has the amino acid sequence Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe-Val-Phe (SEQ ID NO:l) or a sequence selected from the group which comprises: Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe (SEQ ID NO:2)
Arg-Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe (SEQ ID NO:3)
Lys-Thr-Lys-Gly-Ser-Gly-Phe-Phe-Val (SEQ ID NO:4)
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.
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 (en) | 1996-02-22 |
Family
ID=10759787
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1995/001893 WO1996005231A1 (en) | 1994-08-12 | 1995-08-10 | Peptides and antibodies and their use in treatment of carcinomas |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU3226795A (en) |
| GB (1) | GB9416321D0 (en) |
| WO (1) | WO1996005231A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000040229A3 (en) * | 1999-01-06 | 2001-07-19 | Maxim Pharm Inc | Synergistic tumorcidal response induced by histamine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990015878A1 (en) * | 1989-06-15 | 1990-12-27 | National Research Development Corporation | Immunoactive peptides and antibodies and their use in anti-allergy treatment |
-
1994
- 1994-08-12 GB GB9416321A patent/GB9416321D0/en active Pending
-
1995
- 1995-08-10 WO PCT/GB1995/001893 patent/WO1996005231A1/en 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 (en) * | 1989-06-15 | 1990-12-27 | National Research Development Corporation | Immunoactive peptides and antibodies and their use in anti-allergy treatment |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000040229A3 (en) * | 1999-01-06 | 2001-07-19 | Maxim Pharm Inc | Synergistic tumorcidal response induced by 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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