A genotoxic antibody drug conjugate targeting CD276/B7H3 demonstrates efficacy across multiple biomarker defined classes of treatment refractory metastatic prostate cancer

ABSTRACT

B7H3, a cell surface protein often associated with higher grade solid tumors of various origins, is an attractive therapeutic target due to its frequent upregulated expression relative to normal tissue. In a large cohort of treatment-resistant, metastatic castrate resistant prostate cancer (mPC) patient derived xenografts and organoids, we present a comprehensive therapeutic and biomarker analysis. The 26 models tested encompass the heterogeneous genomic and histological categories of clinical mPC. In vitro and in vivo treatment with an anti-B7H3 targeted antibody conjugated to a pyrrolobenzodiazepine (PBD) cytotoxic agent were efficacious in 70% of models. All models expressed some B7H3 protein, the levels of which did not correlate with responses. Underlying susceptibilities to B7H3-PBD-ADC exposure were observed as multiple imperfectly overlapping classes of biomarkers, unrelated to androgen receptor dependence and substantially expanded beyond current homologous repair deficiencies. RB1 deficiency and/or replication stress, particularly prominent in small cell neuroendocrine prostate cancer (SCNPC), predicted responsiveness. The presence of SLFN11 in SCNPC and adenocarcinoma models correlated perfectly with vulnerability, although an absence of SLFN11 was not predictive. Of particular interest, an elevated interferon signature in adenocarcinomas, associated with alteration of wild type TP53, was quantitatively correlated with responsiveness. Finally, we also observed that susceptible models uniquely associated with the loss of select downstream DNA repair proteins. The above biomarkers are expressed in toto in about 70% of mPC clinical samples, suggesting broad potential for mechanistically complementary treatment of tumors escaping current regimens.