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

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

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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