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

  • Mol Cancer Ther. 2023 Sep 5;22(9):999-1012. doi: 10.1158/1535-7163.MCT-22-0786.
Dorin Toader  1 ,  Shawn P Fessler  1 ,  Scott D Collins  1 ,  Patrick R Conlon  1 ,  Reddy Bollu  1 ,  Kalli C Catcott  1 ,  Chen-Ni Chin  1 ,  Anouk Dirksen  1 ,  Bingfan Du  1 ,  Jeremy R Duvall  1 ,  Stacy Higgins  1 ,  Mariya V Kozytska  1 ,  Kamela Bellovoda  1 ,  Chelsey Faircloth  1 ,  David Lee  1 ,  Fu Li  2 ,  Liuliang Qin  1 ,  Caitlin Routhier  1 ,  Pamela Shaw  1 ,  Cheri A Stevenson  1 ,  Jason Wang  1 ,  Phonphimon Wongthida  1 ,  Elena Ter-Ovanesyan  1 ,  Elizabeth Ditty  1 ,  Stephen P Bradley  1 ,  Ling Xu  1 ,  Mao Yin  1 ,  Alexandr V Yurkovetskiy  1 ,  Rebecca Mosher  1 ,  Marc Damelin  1 ,  Timothy B Lowinger  1
Affiliations
  • 1. Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts.
  • 2. Pheon Therapeutics, Cambridge MA 02139.
PMID: 37294948 DOI: 10.1158/1535-7163.MCT-22-0786
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.

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