Compositions and methods for treatment of cancer
The present invention contemplates therapeutic constructs comprising superantigen homologues devoid of neutralizing antibodies in human sera conjugated recombinantly to costimulatory and tumor targeting molecules for treatment of cancer
1 . A method of treating a subject with a carcinoma comprising administering to said subject parenterally by infusion or injection a tumoricidally effective amount of a composition consisting of:
(i) native staphylococcal enterotoxin G which native protein:
(a) has the biological activity of stimulating T cell mitogensis via a T cell receptor vβregion; or
(ii) a biologically active homologue or fragment of a native staphylococcal enterotoxin or streptococcal pyrogenic exotoxin, which homologue or fragment:
(a) has the biological activity of stimulating T cell mitogenesis via a T cell receptor vβregion and
(b) has sequence homology characterized as a z value exceeding 13
when the sequence of the homologue or said fragment is compared to the sequence of a native staphylococcal enterotoxin or a native streptococcal pyrogenic exotoxin, determined by FASTA analysis using gap penalties of −12 and −2, Blosum 50 matrix and Swiss-PROT or PIR database; or
(iii) a biologically active fusion protein having said biological activity and said sequence homology, comprising
(A) said homologue,
(B) a native staphylococcal enterotoxin,
(C) a native streptococcal pyrogenic exotoxin, or
(D) a biologically active fragment of said homologue, said native enterotoxin or said native exotoxin,
fused to a peptide or polypeptide fusion partner.
2 . A fusion protein according to claim 1 wherein said fusion partner is selected from a group comprising an antibody or antibody fragment specific for tumor cells, tumor vasculature or tumor stroma expressing erb/neu, MUC1, 5T4, endoglin, TGFβ. receptor, E-selectin, P-selectin, VCAM-1, ICAM-1, PSMA, a VEGF/VPF receptor, a FGF receptor, a TIE, α v β 3 integrin, a pleiotropin, an endosialin, cytokine-inducible or coagulant-inducible products of intratumoral blood vessels, aminophospholipids, phosphatidylserine or phosphatidylethanolamine.
3 . A fusion protein according to claim 1 wherein said fusion partner is selected from a group comprising polypeptides consisting of costimulatory molecules OX-40L or 4-1BBL alone or fused to a tumor specific antibody fragment.