Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-07-28
1998-11-17
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 16, 514 18, 530329, 530330, 530331, A61K 3803, C07K 400
Patent
active
058376860
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention is in the field of rheumatoid arthritis (RA) treatment.
DESCRIPTION OF THE PRIOR ART
Rheumatoid arthritis, (RA), has been described as an unresolved systemic inflammation in which immune dysfunction and genetic susceptibility play roles. There is increasing evidence that the major immunopathological factor in RA is the covalently linked complex between serum IgA and .alpha..sub.1 -antitrypsin (.alpha..sub.1 AT), a major anti-protease. This disulphide-bridged complex is found to be present at abnormally high levels in the sera and joint fluids of RA patients. In vitro studies have revealed that the complex is capable of inducing the release of tissue-degradative enzymes from mouse macrophages, whilst injection of the complex itself into the knee joints of rabbits or mice causes the onset of RA like arthritis.
It has been shown that a fall in the circulating level of the complex is observed in those rheumatoid patients who respond favourably to treatment with so-called "second-line" anti-rheumatic drugs such as D-penicillamine (dimethyl cysteine) and myocrisin (sodium aurothiomalate). This can be explained by these thiol compounds forming mixed disulphides with the thiol-active IgA produced in large amounts by rheumatoid patients, thereby preventing its reaction with .alpha..sub.1 -antitrypsin to form the undesired IgA-.alpha..sub.1 AT complex (Stanworth, D. R.--Immunology Today 1985, 6, 43).
There is a problem with the currently available thiol-based anti-rheumatic drugs such as D-penicillamine in that they are relatively toxic, causing many rheumatoid patients to end their treatment prematurely.
It is therefore desirable to find alternative means of combatting rheumatoid arthritis.
SUMMARY OF THE INVENTION
RA patients are known to produce grossly elevated levels of thiol-reactive IgA which is thought to be covalently bonded to .alpha..sub.1 AT to form the IgA-.alpha..sub.1 AT complex. It has now been found that certain peptides, fulfilling certain specified requirements as to their charged amino acid groups and capable of interacting with thiol-reactive IgA at a thiol-reactive cysteine residue, are capable of dissociating IgA-.alpha..sub.1 AT complex or preventing IgA-.alpha..sub.1 AT complex formation. Dissociation of complex or prevention of complex formation might be expected to have a favourable effect against clinical RA and is therefore of therapeutic potential. Monoclonal antibodies raised against IgA-.alpha..sub.1 AT complex are also capable of alleviating the effects of IgA-.alpha..sub.1 AT complex in RA patients.
Accordingly, the invention provides a synthetic peptide of not more than 20 amino acid residues or an analogue thereof wherein the analogue is at least partly non-peptide in nature comprising a thiol-active cysteine residue and at least two positively charged amino acid residues situated on (but not necessarily adjacent to) the N-terminal side, or on (but not necessarily adjacent to) the C-terminal side or on (but not necessarily adjacent to) both the N- and C-terminal sides of the thiol-active cysteine residue for use in therapy. The term "comprising" here and throughout the text, means "consisting of or including" and likewise for other parts of the verb. Thus the total peptide can extend beyond the peptide defined above, having additional peptide sequences or non-peptide sequences at one or both ends of the peptide. The peptide will normally have from 3 to 20 amino acid residues, more typically from 4 to 10 amino acid residues. Terminal functions of the peptide can be blocked, e.g. by N-acylation or C-amidation, or the peptides can be derivatised in any conventional manner.
The invention also provides a ligand comprising an antibody domain specific for an antigenic determinant of a complex of human IgA and .alpha..sub.1 -antitrypsin, said antibody domain being substantially non-reactive with free human IgA and free human .alpha..sub.1 -antitrypsin, for use in therapy.
This definition covers monoclonal and polyclonal antibodies, antigen bind
REFERENCES:
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Kirby Julian
Lewin Ian V.
Maman Sarita
Stanworth Denis R.
Gupta Anish
Peptide Therapeutics Limited
Tsang Cecilia J.
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