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[Cancer Research 66, 3214-3221, March 15, 2006]
© 2006 American Association for Cancer Research

Experimental Therapeutics, Molecular Targets, and Chemical Biology

Antibody-Drug Conjugates Designed to Eradicate Tumors with Homogeneous and Heterogeneous Expression of the Target Antigen

Yelena V. Kovtun, Charlene A. Audette, Yumei Ye, Hongsheng Xie, Mary F. Ruberti, Sara J. Phinney, Barbara A. Leece, Thomas Chittenden, Walter A. Blättler and Victor S. Goldmacher

ImmunoGen, Inc., Cambridge, Massachusetts

Requests for reprints: Yelena V. Kovtun, ImmunoGen, Inc., 128 Sidney Street, Cambridge, MA 02139. Phone: 617-995-4917; Fax: 617-995-2510; E-mail: yelena.kovtun{at}immunogen.com.

Conjugates of the anti-CanAg humanized monoclonal antibody huC242 with the microtubule-formation inhibitor DM1 (a maytansinoid), or with the DNA alkylator DC1 (a CC1065 analogue), have been evaluated for their ability to eradicate mixed cell populations formed from CanAg-positive and CanAg-negative cells in culture and in xenograft tumors in mice. We found that in culture, conjugates of either drug killed not only the target antigen-positive cells but also the neighboring antigen-negative cells. Furthermore, we showed that, in vivo, these conjugates were effective in eradicating tumors containing both antigen-positive and antigen-negative cells. The presence of antigen-positive cells was required for this killing of bystander cells. This target cell–activated killing of bystander cells was dependent on the nature of the linker between the antibody and the drug. Conjugates linked via a reducible disulfide bond were capable of exerting the bystander effect whereas equally potent conjugates linked via a nonreducible thioether bond were not. Our data offer a rationale for developing optimally constructed antibody-drug conjugates for treating tumors that express the target antigen either in a homogeneous or heterogeneous manner. (Cancer Res 2006; 66(6): 3214-21)




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