Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific...
Reexamination Certificate
1996-11-25
2001-05-08
Kaufman, Claire M. (Department: 1646)
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
C514S002600, C514S017400, C514S062000, C530S300000
Reexamination Certificate
active
06228373
ABSTRACT:
FIELD OF INVENTION
The present invention relates to non-antigen-specific immunomodulation, including both immunosuppression and immunostimulation.
BACKGROUND OF INVENTION
The immune system, when it is working properly, protects the individual from infection and from growth of cancers. In order to carry out these functions, it must be able to recognise and mount an attack against foreign antigens (including cancer-specific antigens), but not against self antigens present on normal cells throughout the body.
It is possible to stimulate the immune system in order to improve its level of protection. Vaccines, including single-protein antigens such as diptheria toxoid, are widely used to generate immunity against a specific antigen and thus a specific disease associated with that antigen. Where general stimulation of the immune system is desired, this can sometimes be achieved with nonspecific agents such as adjuvants, interleukins, interferons, and colony stimulating factors.
Occasionally, the immune system loses its critical ability to distinguish self from non-self. The resulting immunological assault on the individual's own tissues can take the form of autoimmune disease: for example, systemic lupus erythrematosis, Type 1 diabetes, or rheumatoid arthritis. In such a case, or alternatively where the individual is the recipient of a transplanted organ or tissue, suppression rather than stimulation of the immune response is desirable.
Non-specific down-regulation of the immune response is typically achieved by treatment with corticosteroids, azathioprine, cyclosporine, tacrolimus (FK506), rapamycin, or mycophenolate mofetil. Certain immunoglobulins, including the monoclonal antibody OKT3, have also been used for this purpose. Suppression of immunity against a specific antigen, called “tolerance induction”, may also be possible. Methods that have been used for inducing tolerance against a particular antigen include intravenous or repeated topical administration of the antigen in dilute form, treatment with a very high dose of the antigen, and oral administration of the antigen.
SUMMARY OF THE INVENTION
It has now been found that certain peptides have activity as immunomodulators. Some of these peptides have been found to be immunoinhibitory, while others are immunostimulatory in effect. Experiments in animal models indicate that these peptides will be therapeuticly useful for the treatment of certain diseases, such as cancer and arthritis. Furthermore, and even more surprisingly, it has been found that oral administration of the peptides is a highly effective way to induce the desired immunomodulatory effect, even in the absence of any transport agents such as delivery vehicles, e.g., vesicular delivery systems which are designed to improve delivery to the mucosal epithelial cell lining of the gut. In addition, it has also been found that the amount of peptide required to produce the therapeutic effect by oral delivery can be significantly lower than that required to produce a similar effect when the peptide is delivered otherwise, e.g., by parenteral injection.
According to the present invention there is provided a purified physiologically active peptide comprising at least two cysteine amino acid residues, said two residues being aligned contiguous one to the other or separated by no more than one amino acid, the peptides being absorbable by the epithelial cell lining in a mammal resulting in a modulated immune response and thereby a therapeutic effect against disease.
The peptides are made up of amino acid residues independently selected from amino acid residues having aliphatic side chains, aliphatic hydroxyl side chains, basic side chains, acidic side chains, secondary amino groups, amide side chains, and sulphur containing side chains. Peptides of the invention must be physiologically active in the sense that they must be capable of inducing a modulated immune response and thereby a therapeutic effect against disease. Suitable amino acids may be independently selected from the groups comprising naturally and non-naturally occurring amino acid residues. Examples of naturally occurring amino acid residues include isoleucine (Ile), leucine (Leu), alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), lysine (Lys), phenyl alanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), methionine (Met), valine (Val) and histidine (His). Thus, peptides of the invention can include additional cysteine residues either adjacent to or remote from the at least two cysteine amino acid residues mentioned hereinabove. Naturally, the skilled addressee will appreciate that naturally occurring amino acid residues means those amino acid residues which are found in peptides and/or proteins of living organisms. The skilled addressee will also appreciate that such naturally occurring amino acid residues may be present in peptides of the invention in chemically modified forms eg including added protecting groups such as ethyl, trityl (Trt), allyl, t-butyl and the like. Naturally, the skilled addressee will appreciate that any protecting group(s) which may be present on the peptides of the invention should be such so as not to substantially interfere with the immunomodulatory properties thereof and hence therapeutic effect thereof.
Purified peptides of the invention can be made synthetically, for example by chemical means, or through the use of recombinant DNA technology. Alternatively, peptides of the invention can be isolated from polypeptides or proteins and the like.
A peptide of the invention may take the form of a dimer consisting of two like or two dissimilar peptide monomers linked to each other by way of sulphur to sulphur bonds between at least one of the at least two cysteine amino acid residues of the first peptide monomer and at least one of the at least two cysteine amino acid residues of a second peptide monomer. In an aspect of the invention, the peptide monomers will be linked one to the other through sulphur to sulphur bonds between the at least two cysteine amino acid residues of the first peptide monomer and the at least two cysteine amino acid residues of the second peptide monomer. Dimers of the present invention may be in parallel form ie two peptide monomers aligned parallel one to the other such that both the peptide monomers are readable in one direction eg from the N-terminal to C-terminal direction. The peptide monomers making up the dimer may or may not be the same length. Preferably, the peptide monomers are the same length and the N- and C-terminal amino acid residues of one monomer are located adjacent to the N- and C-terminal amino acid residues of the second peptide monomer. Alternatively, a dimer of the present invention may be in anti-parallel form. That is to say, a first monomer read from the N-terminal amino acid residue to the C-terminal amino acid residue is aligned against a second monomer which is read from the C-terminal amino acid residue to the N-terminal amino acid residue ie in the opposite direction to that of the first peptide monomer; the two peptide monomers being linked through sulphur to sulphur bonds via the cysteine amino acid residues as described above for parallel or anti-parallel dimers of the invention. Where the two peptide monomers forming a peptide dimer of the invention are dissimilar one to the other, the dimer is referred to as an heterodimer. An heterodimer can be in parallel or anti-parallel form. Thus, a heterodimer can be composed of two peptide monomers of the same length, differing, for example, in the substitution of an amino acid residue having the L-form to an amino acid residue having the D-form. Alternatively, the lengths of the peptide monomers making up the dimer may be different. Preferably, the first and second peptide monomers making up a dimer of the present invention are the same.
Peptides of the invention also include monomers wherein the at least two contiguously aligned or spaced apart essenti
Bergstrand Håkan
Eriksson Tomas
Lindvall Magnus
Sarnstrand Bengt
Astra Aktiebolag
Fish & Richardson P.C.
Kaufman Claire M.
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