Mimicking peptides in cancer therapy

Details Mimicking peptides in cancer therapy Mimicking peptides in cancer therapy

1998-06-23

2002-02-05

Huff, Sheela (Department: 1642)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Cancer cell or component thereof

C514S012200, C424S184100, C424S185100

Reexamination Certificate

active

06344203

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to anti-Gal&agr;(1,3)Gal antibody binding peptides and to the use of such peptides in cancer therapy.
BACKGROUND OF THE INVENTION
A successful vaccine for cancer immunotherapy requires the identification of a suitable target antigen and the production of a cytotoxic T cell response (25). Cancer mucins, particularly MUC1 (2), provide a suitable target in cancer as there is a 10-fold increase in mucin expression, a ubiquitous (rather than polar) distribution on the cell surface, and altered glycosylation which reveals normally hidden peptide sequences (particularly an anti-MUC1 antibody detected epitope: the amino acids APDTR from the variable number of tandem repeat region (VNTR) (27). These changes apparently absent in normal mucin generate new targets for immunotherapy (28). The APDTR sequence is immunogenic in mice leading to antibody formation whether the antigen is administered as purified mucin (MHFG) or peptides (29). Such studies of immunogenicity in mice would be of little relevance to humans, were it not for the findings that tumour specific CTLp exist in the lymph nodes of patients with cancers of either breast, ovary or pancreas (30). Thus, theoretically, patients could be immunised with MUC1 peptide sequences to convert their CTLp into functional CTLs which should have a therapeutic anti-cancer effect.
The applicants have previously shown in a murine MUC1
+
tumour model, that a 20 mer MUC1 VNTR peptide sequence (made as a GST fusion protein (FP)) when coupled to oxidised mannan (M-FP-oxidised) generates H-2 restricted CTLs which protects from challenge with MUC1
+
mouse tumours, and in addition leads to the rapid reversal of the growth of established MUC1
+
tumours (stimulation of T
1
T cells) (International Patent Application No. PCT/AU9400789) (31,32). Based on the foregoing, adenocarcinoma patients have been immunised with M-FP and antibody and cellular responses generated. Nonetheless it is of interest that patients could be immunised, albeit weakly, against a self peptide, and both T and B cell tolerance appears to be broken. Despite the immune responses noted, MUC1 is a self peptide occurring in normal mucin in tissues such as breast, kidney, lung, ovary. As it is ubiquitous, anti-mucin responses have the potential for inducing autoimmune diseases against any of the normal tissues.
Surprisingly, when conducting investigations with peptides developed to bind with anti-Gal&agr;(1,3)Gal antibodies in relation to the problem of hyperacute xenograft rejection, it was found by the present inventors that the human mucin peptides (arising from muc1-muc4 genes, listed as muc pep 1-11 in table 1) also bound to the anti-Gal&agr;(1,3)Gal antibody (see co-pending international patent application filed on Sep. 27, 1996, also based on Australian Patent Application No. PN 5680/95). Given that the peptides developed to bind to anti-Gal&agr;(1,3)Gal antibodies exhibit similar antibody binding characteristics to the human mucin peptides, it was postulated that such peptides could be useful in generating an immune response against tumour antigens. Being non-self peptides this immune response has the potential to be greater than that generated by self peptides such as MUC1.
Accordingly therefore, it is an object of the present invention to develop novel cancer immunotherapy vaccines and methods of cancer therapy. Other objects of the present invention will become apparent from the following description thereof.
SUMMARY OF THE INVENTION
According to one embodiment of the present invention there is provided a cancer vaccine comprising a peptide which mimicks MUC1 or other cancer peptides and one or more pharmaceutically acceptable carrier or diluent, optionally in association with an appropriate carrier peptide or another therapeutic agent.
According to another embodiment of the present invention there is provided a method of treatment of a human patient suffering from or prone to suffer from cancer, which comprises administering to said patient an effective amount of a cancer vaccine comprising a peptide which mimicks MUC1 or other cancer peptides, and optionally one or more pharmaceutically acceptable carrier or diluent, optionally also in association with one or more appropriate carrier peptides or another therapeutic agents.
DETAILED DESCRIPTION OF THE INVENTION
It is to be recognised that throughout this specification, unless the context requires otherwise, the word “comprise”, or variations thereof such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element or integer or a group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.
It was recognised by the inventors of the present application that &agr;-galactosyl sugars such as d-galactose, melibiose, stachyose, methyl-&agr;-d-galactopyranoside, D-galactosamine and derivatives thereof bind to anti-Gal&agr;(1,3)Gal antibodies. It was also noted by the present inventors that the Gal&agr;(1,3)Gal epitope is present on the surface of endothelial cells of animals other than higher primates (humans and old world monkeys). Higher primates do not make Gal&agr;(1,3)Gal as they lack a functional &agr;(1,3) galactosyl transferase due to the presence of multiple in-phase stop codons and multiple insertions and deletions leading to frame shifts within the &agr;(1,3)galactosyl transferase genes, which result in non-functional pseudo-genes (8,7). All humans however, have natural antibodies to Gal&agr;(1,3)Gal(15,18), which is probably due to immiunisation with bacteria which carry &agr;-linked Gal as part of the lipopolysaccharide.
It is also known that the IB4 lectin which is a plant glycoprotein from the species
Griffonia simplicifolia
, is capable of binding to the Gal&agr;(1,3)Gal epitope. On this basis therefore, the present inventors proposed to locate peptides capable of binding to the anti-Gal&agr;(1,3)Gal antibody by screening peptides for binding with the IB4 lectin. A multitude of random amino acid sequence octapeptides was synthesised and displayed in a phage display library and screened for binding activity against the IB4 lectin, the surprising result of which was that a number of synthesised peptides demonstrated binding with the IB4 lectin. Similarly, other known peptides were also screened for binding against the IB4 lectin and it was surprisingly also found that the IB4 lectin bound to the protein core of the human mucin peptides (MUC 1-7) which are highly expressed on the surface of tumour cells (2,19) and which in this situation have an altered pattern of glycosylation which leads to exposure of the protein core (3). It has since been demonstrated by the present inventors that the IB4 binding synthetic peptides (Gal pep 1 to Gal pep 7) obtained from the random peptide library and the mucin peptides both bind to the anti-Gal&agr;(1,3)Gal antibody, and can be utilised in cancer therapy protocols.
The phrase within the specification peptides “mimicks MUC1 or other cancer peptides” encompasses all peptides which demonstrate analogous binding in the groove of class I MHC molecules. An indicator of mimicking MUC1 is binding to IB4 or anti-Gal&agr;(1,3)Gal antibodies. Relative affinities of peptides for the anti-Gal&agr;(1,3)Gal antibody or for IB4 can be calculated by comparing the molar concentration required to obtain 50% inhibition of the binding of antibody by lectin or sugars, using an ELISA (enzyrme-linked immunosorbent assay). The details of this technique will be described more fully in the examples under the heading “materials and methods”. The peptides of the invention include peptides having only as few as 3 amino acids up to polypeptides including up to or exceeding 200 amino acids. Although, as will be discussed in further detail, preferred peptides of the invention include the consensus is sequence ArXXArZ (as defined below) and the peptides Gal pep 1 to Gal pep 7 (SEQ ID Nos. 1-7, respectably), this is in no way to be considered limiting upon

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