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WO1996005220A1 - Compounds for use in treatment of carcinomas - Google Patents

Compounds for use in treatment of carcinomas Download PDF

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Publication number
WO1996005220A1
WO1996005220A1 PCT/GB1995/001892 GB9501892W WO9605220A1 WO 1996005220 A1 WO1996005220 A1 WO 1996005220A1 GB 9501892 W GB9501892 W GB 9501892W WO 9605220 A1 WO9605220 A1 WO 9605220A1
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WO
WIPO (PCT)
Prior art keywords
amino acid
residue
negatively charged
xaa
glu
Prior art date
Application number
PCT/GB1995/001892
Other languages
French (fr)
Inventor
Denis Raymond Stanworth
Valerie Jones
Original Assignee
Peptide Therapeutics Limited
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 Limited filed Critical Peptide Therapeutics Limited
Priority to AU32266/95A priority Critical patent/AU3226695A/en
Publication of WO1996005220A1 publication Critical patent/WO1996005220A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0819—Tripeptides with the first amino acid being acidic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • 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 compounds, particularly a class of peptides for 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, by administering compounds which can neutralise, block or reduce triggering of the release of histamine by the action of IgE on mast cells.
  • the present inventors have found that the compounds 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 compounds, particularly a class of peptides, which prevent "triggering" of histamine release by mast cell degranulation and consequently inhibit carcinoma proliferation.
  • the present invention can provide use of a compound comprising a first negatively charged atom or group and a second negatively charged atom or group, separated by a spacing group effective conformationally to position said negatively charged atoms or groups so that they will neutralise the lysine residues of the amino acid sequence Lys Thr Lys at positions 497-499 of the Ce4 constant domain of human IgE, in the manufacture of a medicament for the treatment of carcinomas, especially mammary adenocarcinomas.
  • the present invention can provide use of a peptide of the following formula I (in which the left-hand side represents the N-terminus and the right-hand side the C- terminus) :
  • R 1 represents a residue of an amino acid or of a sequence of two or more amino acids, which may be the same or different;
  • R 2 represents a residue of an amino acid or of a sequence of two or more amino acids, which may be the same or different; (but preferably any amino acid residue of R 1 or R 2 adjacent to an Xaa residue is neither positively nor negatively charged) ;
  • Xaa 1 represents a residue of a negatively charged amino acid, preferably Glu;
  • Sp represents a spacing residue, preferably of a non-charged amino acid, preferably Pro, or of a non-charged dipeptide, which provides the spacing required for the negatively charged groups of the Xaa residues to be sufficiently proximal to the lysine residues of the amino acid sequence Lys Thr Lys at positions 497-499 of the Ce4 constant domain of human IgE to neutralise them;
  • Xaa 2 represents a residue of a negatively charged amino acid, preferably Glu; and m and n denote the number of amino acids in R 1 and 2 R respectively and each of m and n independently is 0 or an integer of from 1 to 22, and the sum of m plus n is from 0 to 22; and their terminal functional derivatives, in the manufacture of a medicament for the treatment of carcinomas especially mammary adenocarcinomas.
  • the present invention can provide a method of treatment for carcinomas, especially mammary adenocarcinomas, comprising administering an effective dose of the compound, peptide or medicament described herein.
  • terminal functional derivative includes any derivative formed by reaction of the terminal amino or carboxyl group and which does not alter adversely the character imparted to the peptide by the other amino acid residues.
  • any conventional derivative especially N- acetyl and/or C-amide, can be used in this invention.
  • the peptides used in this invention have a length of from 3 to 25 amino acid residues (or spacing equivalent when Sp is not an amino acid or dipeptide residue) , preferably 3 to 20 and most preferably 3 to 10.
  • peptides used in this invention should contain two negatively charged amino acids spaced apart by an appropriate spacer group.
  • the nature of the spacer group is in principle immaterial so long as it performs the function of spacing the negative charges on the negatively charged amino acids, so that they lie adjacent to the positive charges on the lysines of the IgE chain referred to above.
  • the positive charge in lysine lies on the amino group nitrogen atom of a 4-aminobutyl side chain. Computer modelling by the inventors predicts that these nitrogens lie about 1.4 nm apart, and that a range of separations between about 1.0 and 1.5 nm might be effective.
  • the spacing between the negatively charged oxygens in the 2-carboxyethyl side-chains of glutamate is about 1.3 nm.
  • the spacing group is the single amino acid residue proline. If another amino acid were included in the spacing group, i.e. if it were a dipeptide, the spacing between the negative charges on the glutamates would increase by about the length of two C-N bonds, roughly 0.3 nm, to 1.6 nm, which may be a little too great for the best neutralising effect.
  • the spacing group might have to be made correspondingly longer, i.e. usually a dipeptide residue. It would be possible for the peptides to have different negatively charged residues, such as one glutamate and one aspartate, but this particular combination may give rise to some spacing problems as the single amino acid spacer is a little short, while the dipeptide spacer is a little long, although it is likely that the effects of the invention would be obtained in some degree with either. Using these guidelines, the person of average skill in the art will be able to obtain the benefits of this invention for a variety of different peptides.
  • the amino acids herein can have the (D) or (L) configuration, but are preferably selected from the 20 naturally occurring (L-) amino acids.
  • the preferred negatively charged amino acids are aspartic (Asp) or glutamic (Glu) .
  • the spacing group Sp preferably comprises (consists of when it is a single amino acid residue or includes when it is a dipeptide residue) proline (Pro) or a ring-substituted derivative thereof.
  • the peptides are thought to bind to the patient's IgE, after the IgE has supposedly undergone a conformational change thereby blocking its subsequent action of triggering mast cells. Such triggering initiates release of histamine.
  • the two negatively charged amino acid residues should be presented to the IgE. Accordingly, the peptide should not contain any amino acids which are likely to interfere with such presentation or cause the peptide to bind to other proteins.
  • the spacing group preferably does not comprise cysteine, which might cause binding to other proteins.
  • the peptide need not be any longer than a tripeptide, as in preferred peptides Glu Pro Glu and Glu Gly Glu, but it can have additional, flanking amino acid(s) at either or both side of the essential motif Xaa 1 Sp Xaa 2 .
  • any flanking amino acids be the same within each flank or both flanks, e.g. as in another peptide of the invention, having the sequence:
  • peptides of a more natural structure such as that of sequence: Ser His Ala lie Arg Ser lie Thr Glu Pro Glu Thr Ala 1 5 10
  • the peptides of the invention may be prepared by standard methods, e.g. the well-known Fmoc. method.
  • the peptides used in the invention are preferably administered as such, i.e. without any carrier such as a conjugated protein or a branched peptide type of carrier, as it is not desirable that the patient should raise antibodies against them. It may well be desirable, however, that they be administered in a slow release or depot form, for example in liposomes or nanoparticles (isobutyl and isodecylcyanoacrylate carriers used for anti- cancer drugs) .
  • the peptides used in the invention may be administered by any of the conventional routes of giving drugs, for example orally, by intravenous or intramuscular injection or as eyedrops or as a nasal spray.
  • compositions manufactured according to the invention comprise a compound, such as a peptide, and a carrier or diluent.
  • Oral preparations include solid forms such as tablets, pills, lozenges and capsules, and liquid forms such as solutions in containers and sprays, e.g. nasal and throat sprays, all of which can be formulated in any conventional way.
  • Injectable preparations include sterile solutions, especially in physiological saline. If the peptides are readily soluble, they can be administered very easily in a liquid form.
  • each dose typically containing from 0.01 to 1 mg. of the peptide.
  • the Y residue could simply be an aliphatic chain, as in a 1,5-pentylenediamine N,N-di- (3-propionate) , but preferably has some rigidity to mimic the planar carbonyl groups in peptide linkages and possibly additional rigidity as conferred by the pyrrolidine ring in the preferred proline spacer amino acid. This may be provided by at least one carbocyclic or heterocyclic ring within Y, as in 1,2- cyclopentylene and 1,2-pyrrolidinylene compounds or in bicyclic ring systems.
  • the compounds must, of course, be non-toxic and stable to rapid metabolic degradation. They may be organic or organometallic in nature .
  • non-peptide compounds are in principle no different from that of the peptides, as described above, but variations and limitations may be necessary according to the type of compound chosen.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

The invention provides for the use of compounds, particularly a class of peptides, which prevent 'triggering' of histamine release by mast cell degranulation and consequently inhibit carcinoma proliferation. The present invention provides use of a compound comprising a first negatively charged atom or group and a second negatively charged atom or group, separated by a spacing group effective conformationally to position said negatively charged atoms or groups so that they will neutralise the lysine residues of the amino acid sequence Lys Thr Lys at positions 497-499 of the C⊂4 constant domain of human IgE, in the manufacture of a medicament for the treatment of carcinomas, especially mammary adenocarcinomas. The present invention provides use of a peptide of following formula (I) (in which the left-hand side represents the N-terminus and the right-hand side the C-terminus): R1m Xaa?1 Sp Xaa2 R2¿n (SEQ ID NO:1) wherein, R1 represents a residue of an amino acid or of a sequence of two or more amino acids, which may be the same or different; R2 represents a residue of an amino acid or of a sequence of two or more amino acids, which may be the same or different; (but preferably any amino acid residue of R1 or R2 adjacent to an Xaa residue is neither positively nor negatively charged); Xaa1 represents a residue of a negatively charged amino acid, preferably Glu; Sp represents a spacing residue, preferably of a non-charged amino acid, preferably Pro, or of a non-charged dipeptide, which provides the spacing required for the negatively charged groups of the Xaa residues to be sufficiently proximal to the lysine residues of the amino acid sequence Lys Thr Lys at positions 497-499 of the C⊂4 constant domain of human IgE to neutralise them; Xaa2 represents a residue of a negatively charged amino acid, preferably Glu; and m and n denote the number of amino acids in R?1 and R2¿ respectively and each of m and n independently is 0 or an integer of from 1 to 22, and the sum of m plus n is from 0 to 22; and their terminal functional derivatives, in the manufacture of a medicament for the treatment of carcinomas especially mammary adenocarcinomas.

Description

Compounds for Use in Treatment of Carcinomas
The present invention relates to compounds, particularly a class of peptides for 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. 6_0_ (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, by administering compounds which can neutralise, block or reduce triggering of the release of histamine by the action of IgE on mast cells.
Stanworth et al, GB 9320897.3 have suggested that it is possible to block the "effector site" of the Fc region of IgE. Certain compounds 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 the compounds 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 compounds, particularly a class of peptides, which prevent "triggering" of histamine release by mast cell degranulation and consequently inhibit carcinoma proliferation.
The present invention can provide use of a compound comprising a first negatively charged atom or group and a second negatively charged atom or group, separated by a spacing group effective conformationally to position said negatively charged atoms or groups so that they will neutralise the lysine residues of the amino acid sequence Lys Thr Lys at positions 497-499 of the Ce4 constant domain of human IgE, in the manufacture of a medicament for the treatment of carcinomas, especially mammary adenocarcinomas.
In a second aspect, the present invention can provide use of a peptide of the following formula I (in which the left-hand side represents the N-terminus and the right-hand side the C- terminus) :
R\- Xaa1 Sp Xaa2 R2 n (Formula I)
(SEQ ID NO: 1) wherein:
R1 represents a residue of an amino acid or of a sequence of two or more amino acids, which may be the same or different; R2 represents a residue of an amino acid or of a sequence of two or more amino acids, which may be the same or different; (but preferably any amino acid residue of R1 or R2 adjacent to an Xaa residue is neither positively nor negatively charged) ; Xaa1 represents a residue of a negatively charged amino acid, preferably Glu;
Sp represents a spacing residue, preferably of a non-charged amino acid, preferably Pro, or of a non-charged dipeptide, which provides the spacing required for the negatively charged groups of the Xaa residues to be sufficiently proximal to the lysine residues of the amino acid sequence Lys Thr Lys at positions 497-499 of the Ce4 constant domain of human IgE to neutralise them;
Xaa2 represents a residue of a negatively charged amino acid, preferably Glu; and m and n denote the number of amino acids in R1 and 2R respectively and each of m and n independently is 0 or an integer of from 1 to 22, and the sum of m plus n is from 0 to 22; and their terminal functional derivatives, in the manufacture of a medicament for the treatment of carcinomas especially mammary adenocarcinomas.
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 compound, peptide or medicament described herein.
The term "terminal functional derivative " as used herein includes any derivative formed by reaction of the terminal amino or carboxyl group and which does not alter adversely the character imparted to the peptide by the other amino acid residues. Thus, any conventional derivative, especially N- acetyl and/or C-amide, can be used in this invention.
The peptides used in this invention have a length of from 3 to 25 amino acid residues (or spacing equivalent when Sp is not an amino acid or dipeptide residue) , preferably 3 to 20 and most preferably 3 to 10.
An important feature of the peptides used in this invention is that they should contain two negatively charged amino acids spaced apart by an appropriate spacer group. The nature of the spacer group is in principle immaterial so long as it performs the function of spacing the negative charges on the negatively charged amino acids, so that they lie adjacent to the positive charges on the lysines of the IgE chain referred to above. The positive charge in lysine lies on the amino group nitrogen atom of a 4-aminobutyl side chain. Computer modelling by the inventors predicts that these nitrogens lie about 1.4 nm apart, and that a range of separations between about 1.0 and 1.5 nm might be effective. In one tripeptide Glu Pro Glu, the spacing between the negatively charged oxygens in the 2-carboxyethyl side-chains of glutamate is about 1.3 nm. Here, the spacing group is the single amino acid residue proline. If another amino acid were included in the spacing group, i.e. if it were a dipeptide, the spacing between the negative charges on the glutamates would increase by about the length of two C-N bonds, roughly 0.3 nm, to 1.6 nm, which may be a little too great for the best neutralising effect.
However, if the negatively charged amino acids were aspartates, which have shorter, carboxymethyl, side chains, the spacing group might have to be made correspondingly longer, i.e. usually a dipeptide residue. It would be possible for the peptides to have different negatively charged residues, such as one glutamate and one aspartate, but this particular combination may give rise to some spacing problems as the single amino acid spacer is a little short, while the dipeptide spacer is a little long, although it is likely that the effects of the invention would be obtained in some degree with either. Using these guidelines, the person of average skill in the art will be able to obtain the benefits of this invention for a variety of different peptides.
The amino acids herein can have the (D) or (L) configuration, but are preferably selected from the 20 naturally occurring (L-) amino acids. Thus, the preferred negatively charged amino acids are aspartic (Asp) or glutamic (Glu) . The spacing group Sp preferably comprises (consists of when it is a single amino acid residue or includes when it is a dipeptide residue) proline (Pro) or a ring-substituted derivative thereof. The peptides are thought to bind to the patient's IgE, after the IgE has supposedly undergone a conformational change thereby blocking its subsequent action of triggering mast cells. Such triggering initiates release of histamine. Therefore, it is considered essential to the invention that the two negatively charged amino acid residues, appropriately spaced apart, should be presented to the IgE. Accordingly, the peptide should not contain any amino acids which are likely to interfere with such presentation or cause the peptide to bind to other proteins. Thus, the spacing group preferably does not comprise cysteine, which might cause binding to other proteins.
The peptide need not be any longer than a tripeptide, as in preferred peptides Glu Pro Glu and Glu Gly Glu, but it can have additional, flanking amino acid(s) at either or both side of the essential motif Xaa1 Sp Xaa2. Referring to Formula I, the nature of any flanking amino acid (m or n=l) or peptide chain (m or n=2 or more) represented by R1 or ^R is not critical to the invention, although an amino acid externally adjacent to either of the negatively charged amino acids, i.e. to the N-terminus of Xaa2 is preferably not negatively charged, especially not Glu or Asp, or positively charged, especially not Lys, Arg or His. From the viewpoint of ease of synthesis, it is preferred that any flanking amino acids be the same within each flank or both flanks, e.g. as in another peptide of the invention, having the sequence:
Ala Ala Ala Glu Pro Glu
1 5
(SEQ ID NO:2)
However, peptides of a more natural structure such as that of sequence: Ser His Ala lie Arg Ser lie Thr Glu Pro Glu Thr Ala 1 5 10
Ala Met Phe lie Tyr Asn Glu 15 20
(SEQ ID NO:3) are favoured as being more likely to adopt a favourable conformation to bring their negatively charged motif, in this case Glu Pro Glu, into a favourable alignment with the Lys Thr Lys motif of the IgE effector site.
The peptides of the invention may be prepared by standard methods, e.g. the well-known Fmoc. method.
The peptides used in the invention are preferably administered as such, i.e. without any carrier such as a conjugated protein or a branched peptide type of carrier, as it is not desirable that the patient should raise antibodies against them. It may well be desirable, however, that they be administered in a slow release or depot form, for example in liposomes or nanoparticles (isobutyl and isodecylcyanoacrylate carriers used for anti- cancer drugs) .
The peptides used in the invention may be administered by any of the conventional routes of giving drugs, for example orally, by intravenous or intramuscular injection or as eyedrops or as a nasal spray.
Pharmaceutical compositions manufactured according to the invention comprise a compound, such as a peptide, and a carrier or diluent. Oral preparations include solid forms such as tablets, pills, lozenges and capsules, and liquid forms such as solutions in containers and sprays, e.g. nasal and throat sprays, all of which can be formulated in any conventional way. Injectable preparations include sterile solutions, especially in physiological saline. If the peptides are readily soluble, they can be administered very easily in a liquid form.
It will usually be desirable to give the peptide in several doses over an extended period, each dose typically containing from 0.01 to 1 mg. of the peptide.
Turning now to the non-peptide compounds for use in treating carcinomas, the compounds should aim to mimic the tripeptide Glu Pro Glu structurally and therefore one class of preferred compounds has the general formula (II) :
MOOC-CH2-CH2-Y-CH2-CHj-COOM (II) wherein M represents a hydrogen atom or a non-toxic cation such as sodium or potassium and Y represents a group which spaces the two 2-carboxyethyl groups apart so that the negative charges (when in anionic form) are separated by a distance of from about 1.0 to less than 1.6 nm. Roughly stated, the length of Y is about equal to six saturated C-C or C-N bond lengths, about 0.15 x 6 = 0.9 nm. The Y residue could simply be an aliphatic chain, as in a 1,5-pentylenediamine N,N-di- (3-propionate) , but preferably has some rigidity to mimic the planar carbonyl groups in peptide linkages and possibly additional rigidity as conferred by the pyrrolidine ring in the preferred proline spacer amino acid. This may be provided by at least one carbocyclic or heterocyclic ring within Y, as in 1,2- cyclopentylene and 1,2-pyrrolidinylene compounds or in bicyclic ring systems.
The compounds must, of course, be non-toxic and stable to rapid metabolic degradation. They may be organic or organometallic in nature .
The formulation and administration of the non-peptide compounds are in principle no different from that of the peptides, as described above, but variations and limitations may be necessary according to the type of compound chosen.
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: Compounds For Use In The Treatment Of Carcinomas
(iii) NUMBER OF SEQUENCES: 3
(iv) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk
(B) COMPUTER: IBM PC compatible
(C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: Patentln Release #1.0, Version #1.30 (EPO)
(vi) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: GB 9416316.9
(B) FILING DATE: 12-AUG-1994
(2) INFORMATION FOR SEQ ID NO: 1:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5 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:1
(D) OTHER INFORMATION:/product= "Xaa 1"
/note= "residue of amino acid or of a sequence of two or more amino acids, which may be the same or different"
(ix) FEATURE:
(A) NAME/KEY: Modified-site
(B) LOCATIONS
(D) OTHER INFORMATION:/product= "Xaa 2"
/note= "residue of a - (ve) amino acid, preferably Glu"
(ix) FEATURE: (A) NAME/KEY: Modified-site
(B) LOCATIONS
(D) OTHER INFORMATION: /product= "Xaa 3"
/note= "spacing residue, preferably of a non-charged amino acid, preferably Pro, or of a non-charged dipeptide"
(ix) FEATURE:
(A) NAME/KEY: Modified-site
(B) LOCATIONS
(D) OTHER INFORMATION:/product= "Xaa 4"
/note= "residue of a - (ve) amino acid, preferably Glu"
(ix) FEATURE:
(A) NAME/KEY: Modified-site
(B) LOCATIONS
(D) OTHER INFORMATION: /product= "Xaa 5"
/note= "Residue of an amino acid or a sequence of two or more amino acids, which may be the same or different "
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1:
Xaa Xaa Xaa Xaa Xaa
1 5
(2) INFORMATION FOR SEQ ID NO: 2:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 6 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2:
Ala Ala Ala Glu Pro Glu 1 5
(2) INFORMATION FOR SEQ ID NO: 3:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 20 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3:
Ser His Ala lie Arg Ser lie Thr Glu Pro Glu Thr Ala Ala Met Phe 1 5 10 15 lie Tyr Asn Glu 20

Claims

Claims
1. Use of a compound comprising a first negatively charged atom or group and a second negatively charged atom or group, separated by a spacing group effective conformationally to position said negatively charged atoms or groups so that they will neutralise the lysine residues of the amino acid sequence Lys Thr Lys at positions 497-499 of the Ce4 constant domain of human IgE, in the manufacture of a medicament for the treatment of carcinomas, especially mammary adenocarcinomas.
2. Use of a peptide of the following formula I (in which the left-hand side represents the N-terminus and the right-hand side the C-terminus) :
R Xaa1 Sp Xaa2 R2 n (Formula I)
(SEQ ID NO:l) wherein:
R1 represents a residue of an amino acid or of a sequence of two or more amino acids, which may be the same or different; R2 represents a residue of an amino acid or of a sequence of two or more amino acids, which may be the same or different; (but preferably any amino acid residue of R1 or R2 adjacent to an Xaa residue is neither positively nor negatively charged) ; Xaa1 represents a residue of a negatively charged amino acid, preferably Glu;
Sp represents a spacing residue, preferably of a non-charged amino acid, preferably Pro, or of a non-charged dipeptide, which provides the spacing required for the negatively charged groups of the XAA residues to be sufficiently proximal to the lysine residues of the amino acid sequence Lys Thr Lys at positions 497-499 of the Ce4 constant domain of human IgE to neutralise them; Xaa2 represents a residue of a negatively charged amino acid, preferably Glu; and m and n denote the number of amino acids in R1 and 2R respectively and each of m and n independently is 0 or an integer of from 1 to 22, and the sum of m plus n is from 0 to
22; and their terminal functional derivatives, in the manufacture of a medicament for the treatment of carcinomas especially mammary adenocarcinomas.
3. Use of compounds according to Claim 1, wherein the negative charges are separated by a distance of at least 1.0 but less than 1.6 nm.
4. Use of peptides according to Claim 2, wherein the charges on the negatively charged amino acids Xaa1 and Xaa2 are separated by more than 1.0 and less than 1.6 nm.
5. Use of peptides according to Claim 2 or 4, wherein any amino acid residue of R1 or R adjacent to an Xaa residue is neither positively nor negatively charged.
6. Use of peptides according to Claim 2, 4 or 5, wherein each of Xaa1 and Xaa2 is Glu and Sp is a residue of a single, non-charged amino acid.
7. Use of peptides according to Claim 2, 4, 5, or 6, wherein Sp comprises a proline residue.
8. Use of peptides according to any one of Claims 2 or 4 to 7, wherein m and n are both 0.
9. Use of peptides according to any one of Claims 2 or 4 to 7, wherein the sum of m plus n is from 1 to 17.
10. Use according any preceding claim, of the tripeptide Glu Pro Glu and its terminal f nctional derivatives.
11. Use according to any preceding claim of a peptide having an N-acetyl or C-amide terminal functional group or both these groups.
12. Use according to any preceding claim of the tripeptide N-acetyl Glu Pro Glu and its C-terminal functional derivatives.
13. A method of treatment of carcinoma which consists of administering to a patient an effective amount of a compound as defined in Claim 1 or 3.
1 . A method of treatment of mammary adenocarcinoma which consists of administering to a patient an effective amount of a peptide as defined in Claim 2 or 4 to 12.
PCT/GB1995/001892 1994-08-12 1995-08-10 Compounds for use in treatment of carcinomas WO1996005220A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU32266/95A AU3226695A (en) 1994-08-12 1995-08-10 Compounds for use in treatment of carcinomas

Applications Claiming Priority (2)

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GB9416316A GB9416316D0 (en) 1994-08-12 1994-08-12 Compounds for use in treatment of carcinomas
GB9416316.9 1994-08-12

Publications (1)

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WO1996005220A1 true WO1996005220A1 (en) 1996-02-22

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GB (1) GB9416316D0 (en)
WO (1) WO1996005220A1 (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995010532A1 (en) * 1993-10-11 1995-04-20 Peptide Therapeutics Limited Compounds useful in anti-allergy treatment

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995010532A1 (en) * 1993-10-11 1995-04-20 Peptide Therapeutics Limited Compounds useful in anti-allergy treatment

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AU3226695A (en) 1996-03-07
GB9416316D0 (en) 1994-10-05

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