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

Abstract

Antibody-drug conjugates (ADCs) 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, a novel ADC platform based on the payload auristatin hydroxypropylamide (AF-HPA), 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 Dolasynthen 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 patient-derived xenografts (PDX), XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recently entered clinical development in a Phase 1 study (NCT05377996) in cancer patients.

Nucleic acid‐based small molecules as targeted transcription therapeutics for immunoregulation

“…Toader et al. (2022) 40 later synthesized several peptide‐linked derivatives of the lead compound and conjugated them to trastuzumab, yielding ADCs with drug‐to‐antibody ratios between 3 and 5. This study provided the first evidence that PBD polyamide hybrids have the potential to serve as efficient ADC payloads.…”