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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 PDF

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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
Authority
WO
WIPO (PCT)
Prior art keywords
phe
gly
lys
ser
seq
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB1995/001893
Other languages
English (en)
Inventor
Denis Raymond Stanworth
Valerie Jones
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Pasteur Holding Ltd
Original Assignee
Peptide Therapeutics Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Peptide Therapeutics Ltd filed Critical Peptide Therapeutics Ltd
Priority to AU32267/95A priority Critical patent/AU3226795A/en
Publication of WO1996005231A1 publication Critical patent/WO1996005231A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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).
PCT/GB1995/001893 1994-08-12 1995-08-10 Peptides et anticorps et leur utilisation dans le traitement des carcinomes Ceased WO1996005231A1 (fr)

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
GB9416321A GB9416321D0 (en) 1994-08-12 1994-08-12 Peptides and antibodies and their use in treatment of carcinomas
GB9416321.9 1994-08-12

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 Ceased 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)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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

Patent Citations (1)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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
AU3226795A (en) 1996-03-07
GB9416321D0 (en) 1994-10-05

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