Kovtun Yelena V, Audette Charlene A, Ye Yumei, Xie Hongsheng, Ruberti Mary F, Phinney Sara J, Leece Barbara A, Chittenden Thomas, Blättler Walter A, Goldmacher Victor S
ImmunoGen, Inc., Cambridge, Massachusetts 02139, USA.
Cancer Res. 2006 Mar 15;66(6):3214-21. doi: 10.1158/0008-5472.CAN-05-3973.
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.
已对抗CanAg人源化单克隆抗体huC242与微管形成抑制剂DM1（一种美登素类）或与DNA烷化剂DC1（一种CC1065类似物）的缀合物在培养物中和小鼠异种移植肿瘤中清除由CanAg阳性和CanAg阴性细胞形成的混合细胞群体的能力进行了评估。我们发现在培养物中，这两种药物的缀合物不仅杀死了靶抗原阳性细胞，还杀死了相邻的抗原阴性细胞。此外，我们表明，在体内，这些缀合物在根除同时含有抗原阳性和抗原阴性细胞的肿瘤方面是有效的。旁观者细胞的这种杀伤需要抗原阳性细胞的存在。这种靶细胞激活的旁观者细胞杀伤取决于抗体与药物之间连接子的性质。通过可还原二硫键连接的缀合物能够发挥旁观者效应，而通过不可还原硫醚键连接的同等效力的缀合物则不能。我们的数据为开发用于治疗以同质或异质方式表达靶抗原的肿瘤的最佳构建的抗体-药物缀合物提供了理论依据。
