Xmt-1660, A B7-H4-Targeted Dolasynthen Antibody-Drug Conjugate For The Treatment Of Breast Cancer.

Abstract XMT-1660 is a novel Dolasynthen-based antibody drug conjugate carrying a DolaLock payload with controlled bystander effect and targeting B7-H4, a tumor antigen that is broadly expressed on the cell surface in breast, ovarian and endometrial cancers. B7-H4 (VTCN1) exerts immunosuppressive effects by suppression of T cell proliferation and is expressed on tumor-associated macrophages (TAMs) as well as epithelial tumor cells. XMT-1660 is comprised of an anti-B7-H4 antibody site-specifically conjugated to Dolasynthen, with a total of 6 DolaLock Auristatin F-HPA (AF-HPA) anti-tubulin payloads per antibody (DAR-6). To select the optimal ADC, three ADCs using the same antibody and DolaLock payload were compared: site-specific Dolasynthen-based DAR-2 and DAR-6 ADCs, and a stochastically conjugated Dolaflexin-based DAR-12 ADC. In vitro, no significant differences were observed among the 3 ADCs: all exhibited specific recognition of B7-H4 and elicited potent cytotoxicity against B7-H4-expressing cancer cells. In vivo, XMT-1660 consistently exhibited more anti-tumor activity than the other ADCs in TNBC models and ER+/HER2- models after single, equivalent doses based on payload. XMT-1660 demonstrated dose-dependent anti-tumor activity and induced sustained tumor regressions after a single administration. XMT-1660 and the Dolasynthen DAR-2 ADC both exhibited improved pharmacokinetics in mouse relative to the Dolaflexin DAR 12 ADC. These data indicate that XMT-1660 exhibited a superior preclinical profile to the other ADCs and more generally demonstrate the importance of DAR-ranging studies to identify the optimal antibody-drug conjugate for a given target. These results, as well as results from exploratory toxicology studies in non-human primates, strongly support the clinical development of XMT-1660. Citation Format: Shawn P. Fessler, Jason Wang, Scott D. Collins, LiuLiang Qin, Kenneth Avocetien, Ling Xu, Ronald Eydelloth, Steven Vonderfecht, Chen-Ni Chin, Steven Bradley, Susan Clardy, Anouk Dirksen, Elizabeth Ditty, Bingfan Du, Dokyong Kim, Rebecca Mosher, Elena Ter-Ovanesyen, Kelly Slocum, Alex Uttard, Phonphimon Wongthida, Jeffrey Zurita, Dorin Toader, Marc Damelin, Timothy B. Lowinger. XMT-1660, a B7-H4-targeted Dolasynthen antibody-drug conjugate for the treatment of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 907.