Alphav integrin-targeted immunoconjugates regress established human tumors in xenograft models.
OBJECTIVE
Targeted delivery of cytotoxic agents to solid tumors through cell surface antigens can potentially reduce systemic toxicity and increase the efficacy of the targeted compounds. The purpose of this study was to show the feasibility of treating solid tumors by targeting alpha(v) integrins with antibody-maytansinoid conjugates and to test the relative in vivo activities of several linker-maytansinoid chemistries.


METHODS
CNTO 364, CNTO 365, and CNTO 366 are targeted cytotoxic agents created by conjugating the CNTO 95 anti-alpha(v) integrin antibody with three distinct maytansinoid-linker structures. These structures were designed to have varying degrees of chemical substitution surrounding the disulfide bond linking the cytotoxic agent to the antibody. A model conjugate was shown to be specifically cytotoxic in vitro and highly active against established human tumor xenografts in immunocompromised rats. The in vivo antitumor activities of CNTO 364, CNTO 365, and CNTO 366 were compared in rat xenograft models.


RESULTS
CNTO 365, with a linker chemistry of expected intermediate stability, was shown to be substantially more active than the other two conjugates with lesser or greater substitution around the disulfide linkage.


CONCLUSIONS
CNTO 95-maytansinoid immunoconjugates are potent antitumor agents against alpha(v) integrin-expressing human carcinomas. These studies show for the first time the feasibility of targeting alpha(v) integrins on solid tumors with tumor-activated prodrugs. The DM4 linker-maytansinoid configuration of CNTO 365 was substantially more active in the models tested here when compared with alternative configurations with greater or lesser chemical substitution surrounding the linker.
Chen
Qiming
Q
Oncology Research, Centocor R&D, Inc., Malvern, Pennsylvania 19087, USA. qchen2@cntus.jnj.com
Millar
Hillary J
HJ
McCabe
Francis L
FL
Manning
Carol D
CD
Steeves
Rita
R
Lai
Kate
K
Kellogg
Brenda
B
Lutz
Robert J
RJ
Trikha
Mohit
M
Nakada
Marian T
MT
Anderson
G Mark
GM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000737:chemistry; D007167:Immunotherapy; D039482:Integrin alpha5 / Q000276:immunology*; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D051381:Rats; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D039482:Integrin alpha5; C486839:intetumumab