CNTO 95, a fully human monoclonal antibody that inhibits alphav integrins, has antitumor and antiangiogenic activity in vivo.
Integrins of the alphav family, such as alphavbeta3 and alphavbeta5, are implicated in tumor-induced angiogenesis; but their role in tumor growth has not been fully explored. CNTO 95 is a fully human antibody that recognizes the alphav family of integrins and is likely to be less immunogenic in humans compared to chimeric or humanized antibodies. CNTO 95 bound to purified alphavbeta3 and alphavbeta5 with a Kd of approximately 200 pM and to alphav integrin-expressing human cells with a Kd of 1-24 nM. In vitro, CNTO 95 inhibited human melanoma cell adhesion, migration and invasion at doses ranging 7-20 nM. In a rat aortic ring sprouting assay, CNTO 95 (approx. 70 nM) completely inhibited sprouting. Using a human melanoma xenograft model in nude mice wherein CNTO 95 recognized alphavbeta3 and alphavbeta5 on human tumor cells but not mouse angiogenic integrins, CNTO 95 (10 mg/kg, 3 times/week) inhibited growth of human melanoma tumors in nude mice by approximately 80% (p = 0.0005), suggesting that CNTO 95 inhibited human tumor growth independently of its antiangiogenic activity. In a nude rat human xenograft model where CNTO 95 binds and blocks both tumor and host integrins, this antibody (10 mg/kg once/week) reduced final tumor weight by >99% (p < 0.0001). Based on these preclinical data, a dose-escalating phase I clinical trial in cancer patients has been initiated. To our knowledge, CNTO 95 is the first fully human MAb to alphav integrins that has potent antitumor and antiangiogenic properties in in vivo preclinical models.
Trikha
Mohit
M
Centocor, Inc., Malvern, PA 19355, USA. mtrikha@cntus.jnj.com
Zhou
Zhao
Z
Nemeth
Jeffrey A
JA
Chen
Qiming
Q
Sharp
Celia
C
Emmell
Eva
E
Giles-Komar
Jill
J
Nakada
Marian T
MT
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000915:Antibody Affinity; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002417:Cattle; D002448:Cell Adhesion; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D039564:Integrin alphaV / Q000737:chemistry*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D007700:Kinetics; D007797:Laminin / Q000494:pharmacology; D008252:Macaca fascicularis; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010920:Placenta / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011509:Proteoglycans / Q000494:pharmacology; D051381:Rats; D011923:Rats, Nude; D019030:Receptors, Vitronectin / Q000378:metabolism; D013997:Time Factors
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004338:Drug Combinations; D039564:Integrin alphaV; D039302:Integrin alphaVbeta3; D016023:Integrins; D007797:Laminin; D011509:Proteoglycans; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D003094:Collagen; C486839:intetumumab