Article
作者: Toader, Dorin ; Kozytska, Mariya V ; Bradley, Stephen P ; Ditty, Elizabeth ; Xu, Ling ; Dirksen, Anouk ; Wang, Jason ; Fessler, Shawn P ; Wongthida, Phonphimon ; Mosher, Rebecca ; Damelin, Marc ; Conlon, Patrick R ; Collins, Scott D ; Catcott, Kalli C ; Duvall, Jeremy R ; Stevenson, Cheri A ; Routhier, Caitlin ; Li, Fu ; Du, Bingfan ; Qin, Liuliang ; Higgins, Stacy ; Faircloth, Chelsey ; Ter-Ovanesyan, Elena ; Shaw, Pamela ; Lee, David ; Lowinger, Timothy B ; Chin, Chen-Ni ; Yurkovetskiy, Alexandr V ; Bellovoda, Kamela ; Bollu, Reddy ; Yin, Mao
Antibody-drug conjugates (ADC) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The activity and safety profile of an ADC depends on its construction: antibody, payload, linker, and conjugation method, as well as the number of payload drugs per antibody [drug-to-antibody ratio (DAR)]. To allow for ADC optimization for a given target antigen, we developed Dolasynthen (DS), a novel ADC platform based on the payload auristatin hydroxypropylamide, that enables precise DAR-ranging and site-specific conjugation. We used the new platform to optimize an ADC that targets B7-H4 (VTCN1), an immune-suppressive protein that is overexpressed in breast, ovarian, and endometrial cancers. XMT-1660 is a site-specific DS DAR 6 ADC that induced complete tumor regressions in xenograft models of breast and ovarian cancer as well as in a syngeneic breast cancer model that is refractory to PD-1 immune checkpoint inhibition. In a panel of 28 breast cancer PDXs, XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recently entered clinical development in a phase I study (NCT05377996) in patients with cancer.