Compositions and methods for treatment of neoplastic disease

Abstract

Compositions and methods for treating a tumor, neoplastic disease or infectious disease in a subject are based on superantigens in the form of polypeptides including fusion polypeptides or conjugates, homologues, and fragments, all of which induce a tumoricidal response when administered directly into tumor or an organ sheath or body cavity affected by the tumor. Nucleic acid constructs encoding the foregoing polypeptides are also used in antitumor therapy. The above agents may be administered in sustained release or controlled release vehicles at or near sites of tumors in a tumor-bearing subject.

What is claimed is:  
     
         1 . A method of treating a subject having a tumor or malignant mass comprising administering intratumorally to said subject a tumoricidally effective amount of a superantigen composition comprising a superantigen or a superantigen-like exotoxin.  
     
     
         2 . The method of  claim 1  wherein the superantigen or exotoxin is selected from the group consisting of a  Staphylococcal  enterotoxin, a  Streptococcal pyrogenic  exotoxin,  Yersinia pseudotuberculosis  superantigen,  Mycoplasma arthritides  superantigen, and  Clostridium perfringens  superantigen-like exotoxin.  
     
     
         3 . A method of treating a subject having a tumor comprising administering intratumorally to said subject a tumoricidally effective amount of a superantigen composition which comprises: 
 (a) a biologically active fragment of a full-length  Staphylococcal  enterotoxin, a  Streptococcal pyrogenic  exotoxin,  Yersinia pseudotuberculosis  superantigen,  Mycoplasma arthritides  superantigen, and  Clostridium perfringens  superantigen-like exotoxin;    (b) a biologically active homologue of a  Staphylococcal  enterotoxin, a  Streptococcal pyrogenic  exotoxin,  Yersinia pseudotuberculosis  superantigen,  Mycoplasma arthritides  superantigen, and  Clostridium perfringens  superantigen-like exotoxin,    (c) a biologically active fusion polypeptide comprising a superantigen sequence of (1) said full length superantigen or exotoxin, (2) said fragment or (3) said homologue which is fused to a fusion partner polypeptide sequence;    wherein:    (i) the fragment, homologue or fusion polypeptide has the biological activity of (A) stimulating T cells or (B) stimulating T cells via a T cell receptor Vβ region; and    (ii) the homologue has the following sequence homology or identity compared to the native superantigen or exotoxin: 
 (A) at least 20% amino acid sequence identity as measured using a sequence comparison algorithm; or  
 (B) sequence homology characterized as a z value exceeding 10 using an algorithm and Monte Carlo analysis according to W. R. Pearson and D. J. Lipman in the  Proceedings of the National Academy of Science  U.S.A., 85:2444-2448, 1988, when the sequence of the homologue is compared to the sequence of a native  Staphylococcal  enterotoxin, a  Streptococcal pyrogenic  exotoxin,  Yersinia pseudotuberculosis  superantigen,  Mycoplasma arthritides  superantigen, and  Clostridium perfringens  superantigen-like exotoxin; or  
 (C) has sequence homology characterized as a z value exceeding 10 using the FASTA/FASTP programs and Monte Carlo of Pearson and Lipman when compared to a native  Staphylococcal  enterotoxin, a  Streptococcal pyrogenic  exotoxin,  Yersinia pseudotuberculosis  superantigen,  Mycoplasma arthritides  superantigen, and  Clostridium perfringens  superantigen-like exotoxin  
   
     
     
         4 . The method of claim of any of claims  1 - 3  wherein the superantigen composition is administered in a sustained release vehicle.  
     
     
         5 . The method of  claim 4  wherein the sustained release vehicle is selected from a group consisting of poly (D-, L- or DL-lactic acid/polyglycolide) polymer, ethylene-vinyl acetate, a bioerodible polyanhydride, a polyimino carbonate, sodium alginate microspheres, a hydrogel, a biodegradable amphipathic copolymer, and a collagen-poly (hema) hydrogel matrix.  
     
     
         6 . The method of any of claims  1 - 3  further comprising administering one or more chemotherapeutic drugs or prodrugs together with or after administration of said superantigen composition, wherein the chemotherapeutic drug or prodrug is or are given in a dose which is lower than a therapeutically effective dose of said drug or prodrug, which therapeutically effective dose is based on administration of said drug or prodrug in monotherapy or in combination therapy but without said superantigen composition.  
     
     
         7 . The method of  claim 4  further comprising administering one or more chemotherapeutic drugs or prodrugs together with or after administration of said superantigen composition, wherein the chemotherapeutic drug or prodrug is or are given in a dose which is lower than a therapeutically effective dose of said drug or prodrug, which therapeutically effective dose is based on administration of said drug or prodrug in monotherapy or in combination therapy but without said superantigen composition.  
     
     
         8 . The method  claim 6  wherein the chemotherapeutic drug is administered in a dose that is 10-95% below said therapeutically effective dose.  
     
     
         9 . The method  claim 7  wherein the chemotherapeutic drug is administered in a dose that is 10-95% below said therapeutically effective dose.  
     
     
         10 . The method of  claim 6  wherein said drug bis given within the 36 hours after the intratumoral administration of the superantigen composition.  
     
     
         11 . The method of  claim 7  wherein said drug bis given within the 36 hours after the intratumoral administration of the superantigen composition.  
     
     
         12 . The method of  claim 8  wherein said drug is first administered after the superantigen composition has been administered for two to four doses.  
     
     
         13 . The method of  claim 9  wherein said drug is first administered after the superantigen composition has been administered for two to four doses.  
     
     
         14 . The method  claim 6  wherein the chemotherapeutic drug is selected from the group consisting of an antimetabolite, a pyrimidine analogue, a purine analogue, an anthracycline, a vinca alkaloid, an anti-tubulin drug, an antibiotic, an alkylating agent, an epipodophyllotoxin, and a platinum-based agent.  
     
     
         15 . The method  claim 7  wherein the chemotherapeutic drug is selected from the group consisting of an antimetabolite, a pyrimidine analogue, a purine analogue, an anthracycline, a vinca alkaloid, an anti-tubulin drug, an antibiotic, an alkylating agent, an epipodophyllotoxin, and a platinum-based agent.  
     
     
         16 . The method of any of claims  1 - 3  further comprising administering to the subject after the intratumoral administration of the superantigen composition, one or more additional cancer therapeutic agents selected from the group consisting of (a) a radiotherapeutic agent, (b) an antiangiogenic agent, (c) a cytotoxin, (d) an apoptosis-inducing agent, or (e) tumor-targeted form of any of (a)-(d).