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Updated: Jul 14, 2026
A Human Peripheral Blood Mononuclear Cell (PBMC) Engrafted Humanized Xenograft Model for Translational Immuno-oncology (I-O) Research
Published on: August 15, 2019
Alphav integrin-targeted immunoconjugates regress established human tumors in xenograft models
Qiming Chen1, Hillary J Millar, Francis L McCabe
1Oncology Research, Centocor R&D, Inc., Malvern, Pennsylvania 19087, USA. qchen2@cntus.jnj.com
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 alpha(v) integrins with antibody-maytansinoid conjugates and to test the relative in vivo activities of several linker-maytansinoid chemistries.
Experimental Design:
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.
Conclusion:
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.
Insights
Targeting alpha(v) integrins on solid tumors with antibody-maytansinoid conjugates shows promise for cancer treatment. CNTO 365 demonstrated superior in vivo antitumor activity compared to other linker-maytansinoid chemistries tested.
Area of Science:
- Oncology
- Immunotherapy
- Drug Development
Background:
- Targeted delivery of cytotoxic agents to solid tumors via cell surface antigens can minimize systemic toxicity and enhance drug efficacy.
- Alpha(v) integrins are cell surface antigens overexpressed on various solid tumors, making them attractive targets for cancer therapy.
Purpose of the Study:
- To demonstrate the feasibility of treating solid tumors by targeting alpha(v) integrins using antibody-maytansinoid conjugates.
- To evaluate and compare the in vivo antitumor activities of different linker-maytansinoid chemistries within these conjugates.
Main Methods:
- Three antibody-maytansinoid conjugates (CNTO 364, CNTO 365, CNTO 366) were synthesized by linking a CNTO 95 anti-alpha(v) integrin antibody to distinct maytansinoid-linker structures.
- Linker structures varied in chemical substitution around the disulfide bond, influencing stability and drug release.
- A model conjugate confirmed specific cytotoxicity in vitro and significant activity against human tumor xenografts in rats.
Main Results:
- CNTO 365, featuring a linker with intermediate stability, exhibited substantially greater antitumor activity than conjugates with less or more substitution around the disulfide linkage.
- In vivo studies in rat xenograft models confirmed the differential efficacy of the tested conjugates.
Conclusions:
- CNTO 95-maytansinoid immunoconjugates are effective antitumor agents against alpha(v) integrin-expressing human carcinomas.
- These findings establish the feasibility of targeting alpha(v) integrins on solid tumors using tumor-activated prodrugs.
- The DM4 linker-maytansinoid configuration in CNTO 365 proved significantly more potent than alternative configurations in the tested models.
