αv Integrin-Targeted Immunoconjugates Regress Established Human Tumors in Xenograft Models

Abstract

Purpose: 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 a v integrins with antibody-maytansinoid conjugates and to test the relative in vivo activities of several linkermaytansinoid chemistries. Experimental Design: CNTO 364, CNTO 365, and CNTO 366 are targeted cytotoxic agents created by conjugating the CNTO 95 anti-a v integrin antibody with three distinct maytansinoidlinker 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. Conclusion: CNTO 95^maytansinoid immunoconjugates are potent antitumor agents against a v integrin^expressing human carcinomas. These studies show for the first time the feasibility of targeting a 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.The a v integrin subfamily consists of at least five members, including a v h 1 , a v h 3 , a v h 5 , a v h 6 , and a v h 8 (1). a v Integrins a v h 3 , a v h 5 , and a v h 6 have been implicated in angiogenesis and tumor progression (2 -5). Up-regulation of a v integrins has been observed in various types of human cancer, including melanoma (6), renal (7), ovarian (8), gastric (9), breast (10), and colorectal carcinoma (11). The frequent overexpression of a v integrins by tumors, their more limited expression by healthy tissues, and their importance in tumor growth and progression make them attractive targets for cancer therapies. CNTO 95, a fully human monoclonal antibody, inhibits a v integrins and has in vivo antitumor and antiangiogenic activity (12). It is one of several a v integrin inhibitors, including both monoclonal antibodies and small molecules, that have been tested both preclinically and clinically for the treatment of solid tumors (4).Immunoconjugates are bifunctional molecules that combine the specificity of monoclonal antibodies to tumor antigens with the potency of cytotoxic agents (13 -15). To take advantage of the a v integrin specificity of CNTO 95, we generated the antibody-drug conjugates CNTO 364, CNTO 365, and CNTO 366. These molecules are tumor-activated prodrugs in which derivativ...

The Effect of Different Linkers on Target Cell Catabolism and Pharmacokinetics/Pharmacodynamics of Trastuzumab Maytansinoid Conjugates

“…T-DM1 was found to be slightly more active in mouse models than T-SPP-DM1 and several other disulfide-linked ADCs (6). This contrasts with similar studies of other ADCs that led to the selection of disulfide-based linkers for clinical development (7)(8)(9).…”

Antibody Conjugate Therapeutics: Challenges and Potential

“…Prostate-specific membrane antigen (PSMA) is a membrane glycoprotein that is expressed in prostate tumors (84). Finally, av integrin is found on several types of solid tumors, including lung, breast, and prostate cancers (85). It is also found on vascular cells in the process of forming new blood vessels, a process that needs to occur for any solid tumor to grow.…”

Anti–αv Integrin Monoclonal Antibody Intetumumab Enhances the Efficacy of Radiation Therapy and Reduces Metastasis of Human Cancer Xenografts in Nude Rats

“…One tumor per rat was inoculated. When tumors reached an average size of 200 mm 3 (150-250 mm 3 ), rats were randomly assigned to the different treatment groups. Intetumumab was injected i.p.…”

“…When tumors reached an average size of 200 mm 3 , rats were randomly assigned to one of four treatment groups and treated as described above in the Rat tumor model and therapy section. After 60 days, rats were euthanized and the lungs were immediately removed and fixed in either Bouin's solution or 10% buffered formalin for counting of pulmonary metastatic nodules.…”

“…1). Preclinical studies have shown that intetumumab exhibits antiangiogenic and antitumor activity in human cancer xenograft models in nude mice (1)(2)(3). Intetumumab has been reported to inhibit cell adhesion, migration, invasion, and proliferation of endothelial cells and tumor cells in vitro and tumor metastasis in vivo in nude mice with human breast cancer xenografts by inactivating the focal adhesion kinase (FAK) and the docking protein paxillin (1,4).…”