Intrathecal and intratumoral superantigens to treat malignant disease
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-039/085
A61K-039/09
A61K-039/395
A61K-035/00
출원번호
US-0759527
(2010-04-13)
등록번호
US-8128931
(2012-03-06)
발명자
/ 주소
Terman, David S
출원인 / 주소
Terman, David S
대리인 / 주소
Central Coast Patent Agency
인용정보
피인용 횟수 :
0인용 특허 :
2
초록▼
The presence of tumor nodules in organs often results in serious clinical manifestations and the permeation by cancer cells of sheaths surrounding organs often produces clinical manifestations of pleural effusion, ascites or cerebral edema. The present invention addresses this problem by providing a
The presence of tumor nodules in organs often results in serious clinical manifestations and the permeation by cancer cells of sheaths surrounding organs often produces clinical manifestations of pleural effusion, ascites or cerebral edema. The present invention addresses this problem by providing a method for treating minors comprising (a) intratumoral administration of a superantigen and/or (b) intrathecal or intracavitary administration of a superantigen directly into the sheath. Intratumoral superantigen results in significant and sustained reduction of the tumor size. Intrathecal administration produces significant sustained reduction of the fluid accumulation associated with clinical improvement and prolonged survival. Useful superantigen compositions for intrathecal and intratumoral injection include tumoricidally effective homologues, fragments and fusion proteins of native superantigens. Also disclosed is combined therapy that includes intratumoral or intrathecal superantigen compositions in combination with (i) intratumoral low, non-toxic doses of one or more chemotherapeutic drugs or (ii) systemic chemotherapy at reduced and non-toxic doses of chemotherapeutic drugs.
대표청구항▼
1. A method of treating a subject with a primary or metastatic carcinoma of the lung or pleura with or without pleural effusion comprising administering to said subject in need thereof parenterally by infusion or injection a tumoricidally effective amount of a composition consisting of: (i) a native
1. A method of treating a subject with a primary or metastatic carcinoma of the lung or pleura with or without pleural effusion comprising administering to said subject in need thereof parenterally by infusion or injection a tumoricidally effective amount of a composition consisting of: (i) a native staphylococcal enterotoxin or streptococcal pyrogenic exotoxin protein which native protein: (a) has the biological activity of stimulating T cell mitogenesis via a T cell receptor νβ region; 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 νβ region 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, wherein a chemotherapeutic drug or drugs is/are adminstered parenterally by infusion or injection before, together with or after administration of said enterotoxin or exotoxin composition. 2. A method of treating a subject with a primary or metastatic carcinoma of the lung or pleura with or without pleural effusion comprising administering to said subject in need thereof parenterally by infusion or injection a tumoricidally effective amount of a composition consisting of: (i) a native staphylococcal enterotoxin or streptococcal pyrogenic exotoxin protein which native protein: (a) has the biological activity of stimulating T cell mitogenesis via a T cell receptor νβ region; 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 νβ region 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, wherein a therapeutic dose of x-irradiation is administered before, together with or after administration of said enterotoxin or exotoxin composition. 3. The method according to claims claims 1 or 2 wherein said fusion partner is selected from a group comprising or a ligand specific for receptors selectively or preferentially expressed on tumor cells or an antibody or antibody fragment specific for tumor cells, tumor vasculature or tumor stroma. 4. The method according to claims 1 or 2 or wherein the native staphylococcal enterotoxin and streptococcal pyrogenic exotoxin is selected from a group comprising staphylococcal enterotoxin A, staphylococcal enterotoxin A, staphylococcal enterotoxin A, staphylococcal enterotoxin B, staphylococcal enterotoxin C1, staphylococcal enterotoxin C2, staphylococcal enterotoxin C3, staphylococcal enterotoxin D, staphylococcal enterotoxin E, Toxic Shock Syndrome Toxin−1, staphylococcal enterotoxin G, staphylococcal enterotoxin H, staphylococcal enterotoxin L staphylococcal enterotoxin J, staphylococcal enterotoxin K, staphylococcal enterotoxin L, staphylococcal enterotoxin M, streptococcal pyrgogenic exotoxin A, streptococcal pyrgogenic exotoxin B, streptococcal pyrgogenic exotoxin C, staphylococcal superantigen A, streptococcal pyrgogenic exotoxin G, streptococcal pyrgogenic exotoxin H, streptococcal mitogenic exotoxin z. 5. The method according to claims 1 or 2 wherein the tumoricidally effective amount of the said staphylococcal entertoxin and streptococcal pyrogenic exotoxin compositions comprise administering said tumoricidal amount of said compositions to said subjects (i) intravenously, (ii) intramuscularly, (iii) subcutaneously, (iv) intradermally or (v) by any two or more of routes (i)-(iv). 6. The method according to claim 1 wherein the chemotherapeutic drug or drugs in are selected from a group comprising docetaxel, paclitaxel, taxol, taxotere, cisplatin, doxorubicin, vinorelbine, gemcitabine, camptothecin dactinomycin, mitomycin, carminomycin, daunomycin, tamoxifen, vincristine, vinblastine, etoposide, 5-fluorouracil, cytosine arabinoside, cyclophosphamide, thiotepa, methotrexate, actinomycin-D, mitomycin C, aminopterin, combretastatin(s) and derivatives and prodrugs thereof. 7. The method according to claim 2 in which x-irradiation is administered in doses of 60-65Gy beginning up to 30 days before, at the same time or 30 days after the start of administration of staphylococcal enterotoxin or streptococcal pyrogenic exotoxin compositions. 8. The method according to claim 1 or 2 wherein said fusion partner is a polypeptide that binds to a coagulation factor. 9. The method according to claim 8 in which said coagulation factor is a truncated tissue factor polypeptide deficient in phospholipid membrane binding capacity such that said truncated tissue factor does not convert Factor VII to Factor VIIa. 10. The method according to claim 3 wherein the antibody or antibody fragment is specific for tumor cells, tumor vasculature or tumor stroma expressing erb/neu, MUC 1, 5T4, endoglin, TGFβ. receptor, E-selectin, P-selectin,VCAM-1, ICAM-1, PSMA, a VEGF/VPF receptor, a FGF receptor, a TIE, ανβ3 integrin, a pleiotropin, an endosialin, cytokine-inducible or coagulant-inducible products of intratumoral blood vessels, aminophospholipids, phosphatidylserine or phosphatidylethanolamine. 11. The method according to claim 1 or 2 wherein the fusion partner is a peptide or polypeptide costimulatory molecule. 12. The method according to claim 11 in which said peptide or polypeptide costimulatory molecule is OX-40 ligand, 4-1BB ligand or CD-38. 13. The method according to claim 11 or 12 wherein said fusion protein is further fused to a tumor specific tartgeting structure selected from a group comprising a tumor specific antibody or fragment or a ligand specific for receptors selectively or preferentially expressed on tumor cells.
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이 특허에 인용된 특허 (2)
Terman, David S., Intrathecal and intratumoral superantigens to treat malignant disease.
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