1. Discovery and Preclinical Characterization of XMT-1660, an Optimized B7-H4-Targeted Antibody-Drug Conjugate for the Treatment of Cancer.
- Author
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Toader D, Fessler SP, Collins SD, Conlon PR, Bollu R, Catcott KC, Chin CN, Dirksen A, Du B, Duvall JR, Higgins S, Kozytska MV, Bellovoda K, Faircloth C, Lee D, Li F, Qin L, Routhier C, Shaw P, Stevenson CA, Wang J, Wongthida P, Ter-Ovanesyan E, Ditty E, Bradley SP, Xu L, Yin M, Yurkovetskiy AV, Mosher R, Damelin M, and Lowinger TB
- Subjects
- Humans, Female, Antibodies, Cell Line, Tumor, Xenograft Model Antitumor Assays, Immunoconjugates pharmacology, Immunoconjugates therapeutic use, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Breast Neoplasms
- Abstract
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., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
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