Chimeric toxins for targeted therapy 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
US2002028914 A1 2002-03-07 [US20020028914]US6933271 B2 2005-08-23 [US6933271] / 2002-03-072005-08-23
申请号/申请日
1997US-09147346 / 1997-06-04
发明人
YARKONI SHAI;NECHUSHTAN AMOTZ;LORBERBOUM-GALSKI HAYA;MARIANOVSKY IRINA;
申请人
YISSUM RESEARCH DEVELOPMENT;
主分类号
IPC分类号
A01N-037/18A61K-031/00A61K-038/00A61K-038/22A61K-038/24A61K-039/395A61K-039/40A61K-039/42A61K-039/44A61K-047/48A61P-035/00C07H-021/02C07H-021/04C07KC07K-001/00C07K-002/00C07K-004/00C07K-005/00C07K-007/00C07K-014/00C07K-014/21C07K-014/575C07K-016/00C07K-017/00C07K-019/00C12N-005/10C12N-015/09C12P-021/02C12P-021/04
摘要
(US6933271) The present invention relates particularly to neoplastic cells targeted chimeric toxins comprising of cell targeting moieties and cell killing moieties for recognizing and for destroying the neoplastic cells, wherein the cell targeting moieties consist of gonadotropin releasing hormone homologues and the cell killing moieties consist of Pseudomonas Exotoxin A.  The present invention further relates to pharmaceutical compositions containing as an active ingredient these neoplastic cells targeted chimeric toxins and to a method for the production of these chimeric toxins.  The said invention also relates to a method for cancer therapy, treating malignant carcinoma cells and benign hyperplasia including uterine lyomyoma cells, extra uterian endometrial island cells, benign hyperplasia of prostate and breast and pituitary tumor adenoma cells, by the use of the above-mentioned chimeric toxins.
机翻摘要
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地址
代理人
代理机构
;
优先权号
1996IL-0118570 1996-06-04 1997WO-IL00180 1997-06-04
主权利要求
(US6933271) 1. A method for the treatment of adenocarcinoma or hepatocarcinoma in a mammal, comprising administering to the body of a mammal in need of such therapy an effective amount, sufficient to at least reduce the growth of said adenocarcinoma or hepatocarcinoma, of at least one fused chimeric protein comprising a linear genetically engineered molecule consisting essentially of peptide bonds, produced by fusing, at the level of cDNA: A. DNA encoding at least one cell targeting moiety consisting essentially of Met-GnRH or a Met-GnRH analog that specifically binds to GnRH binding sites on Caco2 adenocarcinoma cells;  and B. DNA encoding at least one cell killing moiety. 2. A method according to claim 1, wherein said fused chimeric protein is produced by fusing at the cDNA level an oligonucleotide encoding gonadotropin releasing hormone (GnRH) or a GnRH analog, preceded by a Met, to a mutated DNA fragment of the full length Pseudomonas exotoxin (PE), encoding the protein Met-GnRH-PE66. 3. A method according to claim 1, wherein said fused chimeric protein produced by fusing at the cDNA level an oligonucleotide encoding gonadotropin releasing hormone (GnRH) or a GnRH analog, preceded by a Met, to a DNA fragment comprising domains II and III of the Pseudomonas exotoxin (PE), encoding the protein Met-GnRH-PE40. 4. A method for adenocarcinoma or hepatocarcinoma therapy according to claim 1, wherein said administering step is by systemic administration of said chimeric protein. 5. A method of treating a mammal having at least one adenocarcinoma or hepatocarcinoma, comprising administering to said mammal in need thereof, an amount sufficient to ameliorate the effects of said adenocarcinoma or hepatocarcinoma, of a pharmaceutical composition, comprising a fused chimeric protein comprising a linear genetically engineered molecule consisting essentially of peptide bonds, produced by fusing, at the level of cDNA: A. DNA encoding at least one cell targeting moiety consisting essentially of Met-GnRH or a Met-GnRH analog that specifically binds to GnRH binding sites on Caco2 adenocarcinoma cells;  and B. DNA encoding at least one cell killing moiety. 6. A method of treating a mammal having endometriosis, comprising administering to said mammal in need thereof, an amount sufficient to ameliorate the effects of said endometriosis, of a pharmaceutical composition, comprising a fused chimeric protein comprising a linear genetically engineered molecule consisting essentially of peptide bonds, produced by fusing, at the level of cDNA: A. DNA encoding at least one cell targeting moiety consisting essentially of Met-GnRH or a Met-GnRH analog that specifically binds to GnRH binding sites on Caco2 adenocarcinoma cells;  and B. DNA encoding at least one cell killing moiety. 7. A method for endometrioma therapy according to claim 6, further comprising trans-cervical washing of the mammal's endometrial cavity. 8. A method of treating a mammal having a uterine myoma, comprising administering to said mammal in need thereof, an amount sufficient to ameliorate the effects of said uterine myoma, of a pharmaceutical composition, comprising a fused chimeric protein comprising a linear genetically engineered molecule consisting essentially of peptide bonds, produced by fusing, at the level of cDNA: A. DNA encoding at least one cell targeting moiety consisting essentially of Met-GnRH or a Met-GnRH analog that specifically binds to GnRH binding sites on Caco2 adenocarcinoma cells;  and B. DNA encoding at least one cell killing moiety. 9. A method of treating a mammal having a pituitary adenoma, comprising administering to said mammal in need thereof, an amount sufficient to ameliorate the effects of said pituitary adenoma, of a pharmaceutical composition, comprising a fused chimeric protein comprising a linear genetically engineered molecule consisting essentially of peptide bonds, produced by fusing, at the level of cDNA: A. DNA encoding at least one cell targeting moiety consisting essentially of Met-GnRH or a Met-GnRH analog that specifically binds to GnRH binding sites on Caco2 adenocarcinoma cells;  and B. DNA encoding at least one cell killing moiety. 10. A method of treating a mammal having BPH, comprising administering to said mammal in need thereof, an amount sufficient to ameliorate the effects of said BPH, of a pharmaceutical composition, comprising a fused chimeric protein comprising a linear genetically engineered molecule consisting essentially of peptide bonds, produced by fusing, at the level of CDNA: A. DNA encoding at least one cell targeting moiety consisting essentially of Met-GnRH or a Met-GnRH analog that specifically binds to GnRH binding sites on Caco2 adenocarcinoma cells;  and B. DNA encoding at least one cell killing moiety. 11. A method of treating a mammal having polycystic breast disease, comprising administering to said mammal in need thereof, an amount sufficient to ameliorate the effects of said polycystic breast disease, of a pharmaceutical composition comprising a fused chimeric protein comprising a linear genetically engineered molecule consisting essentially of peptide bonds, produced by fusing, at the level of cDNA: A. DNA encoding at least one cell targeting moiety consisting essentially of Met-GnRH or a Met-GnRH analog that specifically binds to GnRH binding sites on Caco2 adenocarcinoma cells;  and B. DNA encoding at least one cell killing moiety. 12. A method according to claim 5, wherein said fused chimeric protein is produced by fusing at the cDNA level an oligonucleotide encoding gonadotropin releasing hormone (GnRH) or a GnRH analog, preceded by a Met, to a mutated DNA fragment of the full length Pseudomonas exotoxin (PE), encoding the protein Met-GnRH-PE66. 13. A method according to claim 5, wherein said fused chimeric protein is produced by fusing at the cDNA level an oligonucleotide encoding gonadotropin releasing hormone (GnRH) or a GnRH analog, preceded by a Met, to a DNA fragment comprising domains II and III of the Pseudomonas exotoxin (PE), encoding the protein Met-GnRH-PE40. 14. A method according to claim 6, wherein said fused chimeric protein is produced by fusing at the cDNA level an oligonucleotide encoding gonadotropin releasing hormone (GnRH) or a GnRH analog, preceded by a Met, to a mutated DNA fragment of the full length Pseudomonas exotoxin (PE), encoding the protein Met-GnRH-PE66. 15. A method according to claim 6, wherein said fused chimeric protein is produced by fusing at the cDNA level an oligonucleotide encoding gonadotropin releasing hormone (GnRH) or a GnRH analog, preceded by a Met, to a DNA fragment comprising domains II and III of the Pseudomonas exotoxin (PE), encoding the protein Met-GnRH-PE40. 16. A method according to claim 8, wherein said fused chimeric protein is produced by fusing at the cDNA level an oligonucleotide encoding gonadotropin releasing hormone (GnRH) or a GnRH analog, preceded by a Met, to a mutated DNA fragment of the full length Pseudomonas exotoxin (PE), encoding the protein Met-GnRH-PE66. 17. A method according to claim 8, wherein said fused chimeric protein is produced by fusing at the cDNA level an oligonucleotide encoding gonadotropin releasing hormone (GnRH) or a GnRH analog, preceded by a Met, to a DNA fragment comprising domains II and III of the Pseudomonas exotoxin (PE), encoding the protein Met-GnRH-PE40. 18. A method according to claim 9, wherein said fused chimeric protein is produced by fusing at the cDNA level an oligonucleotide encoding gonadotropin releasing hormone (GnRH) or a GnRH analog, preceded by a Met, to a mutated DNA fragment of the full length Pseudomonas exotoxin (PE), encoding the protein Met-GnRH-PE66. 19. A method according to claim 9, wherein said fused chimeric protein is produced by fusing at the cDNA level an oligonucleotide encoding gonadotropin releasing hormone (GnRH) or a GnRH analog, preceded by a Met, to a DNA fragment comprising domains II and III of the Pseudomonas exotoxin (PE), encoding the protein Met-GnRH-PE40. 20. A method according to claim 10, wherein said fused chimeric protein is produced by fusing at the cDNA level an oligonucleotide encoding gonadotropin releasing hormone (GnRH) or a GnRH analog, preceded by a Met, to a mutated DNA fragment of the full length Pseudomonas exotoxin (PE), encoding the protein Met-GnRH-PE66. 21. A method according to claim 10, wherein said fused chimeric protein is produced by fusing at the cDNA level an oligonucleotide encoding gonadotropin releasing hormone (GnRH) or a GnRH analog, preceded by a Met, to a DNA fragment comprising domains II and III of the Pseudomonas exotoxin (PE), encoding the protein Met-GnRH-PE40. 22. A method according to claim 11, wherein said fused chimeric protein is produced by fusing at the CDNA level an oligonucleotide encoding gonadotropin releasing hormone (GnRH) or a GnRH analog, preceded by a Met, to a mutated DNA fragment of the full length Pseudomonas exotoxin (PE), encoding the protein Met-GnRH-PE66. 23. A method according to claim 11, wherein said fused chimeric protein is produced by fusing at the cDNA level an oligonucleotide encoding gonadotropin releasing hormone (GnRH) or a GNRH analog, preceded by a Met, to a DNA fragment comprising domains II and III of the Pseudomonas exotoxins (PE), encoding the protein Met-GnRH-PE40.
法律状态
(US6933271) LEGAL DETAILS FOR US2002028914  Actual or expected expiration date=2013-09-23    Legal state=DEAD    Status=LAPSED     Event publication date=1999-03-01  Event code=US/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=US US09147346  Application date=1999-03-01  Standardized application number=1997US-09147346     Event publication date=1998-12-04  Event code=US/R371  Event type=Administrative notifications  Event type=OAI  Receipt of 371 Request    Event publication date=1999-01-28  Event code=US/M905  Event type=Examination events  Event type=OAO  Notice of DO/EO Missing Requirements Mailed    Event publication date=1999-03-01  Event code=US/EXMR  Event type=Administrative notifications  USPTO Examiner Name Primary Examiner: HELMS, LARRY RONALD    Event publication date=1999-03-01  Event code=US/ART  Event type=Administrative notifications  USPTO Art Group  ART=1642     Event publication date=1999-03-01  Event code=US/SMALL  Event type=Administrative notifications  Appl Has Filed a Verified Statement of Micro to Small Entity Status Business Entity Status: SMALL    Event publication date=1999-03-01  Event code=US/AIA  Event type=Administrative notifications  First Inventor File Indicated:  AIA=No     Event publication date=1999-03-01  Event code=US/DK  Event type=Examination events  Attorney Docket Number Docket Nbr: RCP-PT007    Event publication date=1999-03-01  Event code=US/CUST  Event type=Examination events  Attorney/Agent Customer Number Customer Nbr: 3624    Event publication date=1999-03-01  Event code=US/AS  Event type=Change of name or address  Event type=Reassignment  Assignment Owner: YISSUM RESEARCH DEVELOPMENT COMPANY OF THE HEBREW ASSIGNMENT OF ASSIGNORS INTEREST ASSIGNORS:YARKONI, SHAI NECHUSHTAN, AMOTZ LORBEROUM--GALSKI, HAVA AND OTHERS REEL/FRAME:009786/0593 SIGNING DATES FROM 19990125 TO 19990210     Event publication date=1999-03-01  Event code=US/IDS  Event type=Examination events  Event type=OAI  Information Disclosure Statement Filed    Event publication date=1999-03-01  Event code=US/APE  Event type=Corrections  Preliminary amendments    Event publication date=1999-03-01  Event code=US/A371  Event type=Administrative notifications  Event type=OAI  Receipt of Applicant 371 Request    Event publication date=1999-03-12  Event code=US/M903  Event indicator=Pos  Event type=Examination events  Event type=OAO  Notice of DO/EO Acceptance Mailed    Event publication date=1999-04-15  Event code=US/DOCK  Event indicator=Pos  Event type=Examination events  Case Docketed to Examiner    Event publication date=1999-09-14  Event code=US/DOCK  Event indicator=Pos  Event type=Examination events  Case Docketed to Examiner    Event publication date=2000-01-24  Event code=US/AS  Event type=Change of name or address  Event type=Reassignment  Assignment Owner: YISSUM RESEARCH DEVELOPMENT COMPANY OF THE HEBREW (ASSIGNMENT OF ASSIGNOR'S INTEREST) RECORD TO CORRECT THE ASSIGNOR'S NAME ON A DOCUMENT PREVIOUSLY RECORDED AT REEL/9786, FRAME/0593 ASSIGNORS:YARKONI, SHAI NECHUSHTAN, AMOTZ LORBERBOUM-GALSKI, HAYA AND OTHERS REEL/FRAME:010551/0095 SIGNING DATES FROM 19990125 TO 19990210     Event publication date=2000-01-28  Event code=US/RESTREQ  Event type=Examination events  Event type=Corrections  Event type=OAO  Restriction/Election Requirement    Event publication date=2000-03-01  Event code=US/SUPRSP  Event type=OAI  Supplemental Response    Event publication date=2000-03-01  Event code=US/ELC  Event type=Examination events  Event type=OAI  Response to Election / Restriction Filed    Event publication date=2000-04-17  Event code=US/CTNF  Event type=Examination events  Event type=OA  Event type=OAO  Non-Final Rejection    Event publication date=2000-09-13  Event code=US/AINEA  Event type=OAI  Event type=Examination events  Informal or Non-Responsive Amendment after Examiner Action    Event publication date=2000-09-13  Event code=US/136G  Event type=OAO  Request for Extension of Time - Granted    Event publication date=2001-01-18  Event code=US/AINEA  Event type=OAI  Event type=Examination events  Informal or Non-Responsive Amendment after Examiner Action    Event publication date=2001-01-18  Event code=US/CTNFR  Event type=Examination events  Event type=OAI  Response after Non-Final Action    Event publication date=2001-03-12  Event code=US/CTFR  Event type=Examination events  Event type=OA  Event type=OAO  Final Rejection    Event publication date=2001-07-13  Event code=US/CTFAR  Event type=Examination events  Event type=OAI  Response after Final Action    Event publication date=2001-07-13  Event code=US/136G  Event type=OAO  Request for Extension of Time - Granted    Event publication date=2001-07-27  Event code=US/CTAV  Event type=OAO  Advisory Action (PTOL-303)    Event publication date=2001-08-03  Event code=US/IDS  Event type=Examination events  Event type=OAI  Information Disclosure Statement Filed    Event publication date=2001-09-13  Event code=US/ABNEA  Event indicator=Neg  Event type=Event indicating Not In Force  Event type=OAI  Expressly Abandoned -- During Examination    Event publication date=2001-09-13  Event code=US/ACPA  Event type=Examination events  Event type=CPA  Continued Prosecution Application - Continuation (ACPA)    Event publication date=2001-09-13  Event code=US/136G  Event type=OAO  Request for Extension of Time - Granted    Event publication date=2002-03-07  Event code=US/A1  Event type=Examination events  Application published  Publication country=US  Publication number=US2002028914  Publication stage Code=A1  Publication date=2002-03-07  Standardized publication number=US20020028914     Event publication date=2002-12-17  Event code=US/CTNF  Event type=Examination events  Event type=OA  Event type=OAO  Non-Final Rejection    Event publication date=2003-06-16  Event code=US/AINEA  Event type=OAI  Event type=Examination events  Informal or Non-Responsive Amendment after Examiner Action    Event publication date=2003-06-16  Event code=US/CTNFR  Event type=Examination events  Event type=OAI  Response after Non-Final Action    Event publication date=2003-06-16  Event code=US/136G  Event type=OAO  Request for Extension of Time - Granted    Event publication date=2003-08-05  Event code=US/CTNFR  Event type=Examination events  Event type=OAI  Response after Non-Final Action    Event publication date=2003-10-28  Event code=US/CTNF  Event type=Examination events  Event type=OA  Event type=OAO  Non-Final Rejection    Event publication date=2004-04-30  Event code=US/AINEA  Event type=OAI  Event type=Examination events  Informal or Non-Responsive Amendment after Examiner Action    Event publication date=2004-04-30  Event code=US/CTNFR  Event type=Examination events  Event type=OAI  Response after Non-Final Action    Event publication date=2004-04-30  Event code=US/136G  Event type=OAO  Request for Extension of Time - Granted    Event publication date=2004-05-21  Event code=US/POAC  Event type=Change of name or address  Change in Power of Attorney (May Include Associate POA)    Event publication date=2004-06-29  Event code=US/CTNFR  Event type=Examination events  Event type=OAI  Response after Non-Final Action    Event publication date=2004-09-10  Event code=US/CTFR  Event type=Examination events  Event type=OA  Event type=OAO  Final Rejection    Event publication date=2004-12-13  Event code=US/CTFAR  Event type=Examination events  Event type=OAI  Response after Final Action    Event publication date=2004-12-27  Event code=US/CTAV  Event type=OAO  Advisory Action (PTOL-303)    Event publication date=2005-02-14  Event code=US/CTFAR  Event type=Examination events  Event type=OAI  Response after Final Action    Event publication date=2005-02-14  Event code=US/136G  Event type=OAO  Request for Extension of Time - Granted    Event publication date=2005-03-10  Event code=US/DOCK  Event indicator=Pos  Event type=Examination events  Case Docketed to Examiner    Event publication date=2005-03-11  Event code=US/NOAM  Event indicator=Pos  Event type=Examination events  Event type=OAO  Mail Notice of Allowance    Event publication date=2005-07-21  Event code=US/APRDY  Event indicator=Pos  Event type=Examination events  Application Is Considered Ready for Issue    Event publication date=2005-08-03  Event code=US/ISSM  Event indicator=Pos  Event type=Examination events  Event type=OAO  Event type=Restitution or restoration  Issue Notification Mailed    Event publication date=2005-08-23  Event code=US/B2  Event indicator=Pos  Event type=Event indicating In Force  Granted patent as second publication  Publication country=US  Publication number=US6933271  Publication stage Code=B2  Publication date=2005-08-23  Standardized publication number=US6933271     Event publication date=2005-08-23  Event code=US/354  Event indicator=Pos  Event type=Extension of term of duration of protection  Patent term extended under  35 U.S.C 154(b) until/for Delays (A,B,C): 344  Overlap Delays: 0  Non Overlap Delays: 344   PTO Office Delays: 0  Applicant Delays: 436  Adjustment total:  Number of days of extension=0    Event publication date=2006-08-11  Event code=US/POAC  Event type=Change of name or address  Change in Power of Attorney (May Include Associate POA)    Event publication date=2008-09-02  Event code=US/NMFP  Event type=Payment or non-payment notifications  Publication of First Notice of Maintenance Fees Payable. 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