Abstract
The selective targeting of pathogenic T cells is a holy grail in the development of new therapeutics for T cell–mediated disorders, including many autoimmune diseases and graft versus host disease. We describe the development of a CD6-targeted antibody-drug conjugate (CD6-ADC) by conjugating an inactive form of monomethyl auristatin E (MMAE), a potent mitotic toxin, onto a mAb against CD6, an established T cell surface marker. Even though CD6 is present on all T cells, only the activated (pathogenic) T cells vigorously divide and thus are susceptible to the antimitotic MMAE-mediated killing via the CD6-ADC. We found CD6-ADC selectively killed activated proliferating human T cells and antigen-specific mouse T cells in vitro. Furthermore, in vivo, whereas the CD6-ADC had no significant detrimental effect on normal T cells in naive CD6-humanized mice, the same dose of CD6-ADC, but not the controls, efficiently treated 2 preclinical models of autoimmune uveitis and a model of graft versus host disease. These results provide evidence suggesting that CD6-ADC could be further developed as a potential therapeutic agent for the selective elimination of pathogenic T cells and treatment of many T cell–mediated disorders.
Authors
Lingjun Zhang, Liping Luo, Jin Y. Chen, Rupesh Singh, William M. Baldwin III, David A. Fox, Daniel J. Lindner, Daniel F. Martin, Rachel R. Caspi, Feng Lin
Figure 5
CD6-ADC treatments potently eliminate the pathogenic T cells in a preclinical model of GVHD.
