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

Autor:	Toader D; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Fessler SP; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Collins SD; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Conlon PR; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Bollu R; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Catcott KC; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Chin CN; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Dirksen A; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Du B; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Duvall JR; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Higgins S; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Kozytska MV; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Bellovoda K; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Faircloth C; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Lee D; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Li F; Pheon Therapeutics, Cambridge MA 02139., Qin L; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Routhier C; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Shaw P; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Stevenson CA; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Wang J; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Wongthida P; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Ter-Ovanesyan E; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Ditty E; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Bradley SP; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Xu L; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Yin M; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Yurkovetskiy AV; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Mosher R; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Damelin M; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts., Lowinger TB; Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2023 Sep 05; Vol. 22 (9), pp. 999-1012.
DOI:	10.1158/1535-7163.MCT-22-0786
Abstrakt:	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.)
Databáze:	MEDLINE
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