Discovery and Preclinical Characterization of XMT-1660, an Optimized B7-H4-Targeted Antibody–Drug Conjugate for the Treatment of Cancer

• Published in: Molecular cancer therapeutics Vol. 22; no. 9; pp. 999 - 1012
• Main Authors: Toader, Dorin, Fessler, Shawn P., Collins, Scott D., Conlon, Patrick R., Bollu, Reddy, Catcott, Kalli C., Chin, Chen-Ni, Dirksen, Anouk, Du, Bingfan, Duvall, Jeremy R., Higgins, Stacy, Kozytska, Mariya V., Bellovoda, Kamela, Faircloth, Chelsey, Lee, David, Li, Fu, Qin, Liuliang, Routhier, Caitlin, Shaw, Pamela, Stevenson, Cheri A., Wang, Jason, Wongthida, Phonphimon, Ter-Ovanesyan, Elena, Ditty, Elizabeth, Bradley, Stephen P., Xu, Ling, Yin, Mao, Yurkovetskiy, Alexandr V., Mosher, Rebecca, Damelin, Marc, Lowinger, Timothy B.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 09.06.2023
• Subjects: First Disclosures
• ISSN: 1535-7163; 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.MCT-22-0786

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.