Tumor-derived biomarkers predict efficacy of B7H3 antibody-drug conjugate treatment in metastatic prostate cancer models
Supreet Agarwal, Lei Fang, Kerry McGowen, JuanJuan Yin, Joel Bowman, Anson T. Ku, Aian Neil Alilin, Eva Corey, Martine P. Roudier, Lawrence D. True, Ruth Dumpit, Ilsa Coleman, John K. Lee, Peter S. Nelson, Brian J. Capaldo, Aida Mariani, Clare Hoover, Ilya S. Senatorov, Michael Beshiri, Adam G. Sowalsky, Elaine M. Hurt, Kathleen Kelly
Supreet Agarwal, Lei Fang, Kerry McGowen, JuanJuan Yin, Joel Bowman, Anson T. Ku, Aian Neil Alilin, Eva Corey, Martine P. Roudier, Lawrence D. True, Ruth Dumpit, Ilsa Coleman, John K. Lee, Peter S. Nelson, Brian J. Capaldo, Aida Mariani, Clare Hoover, Ilya S. Senatorov, Michael Beshiri, Adam G. Sowalsky, Elaine M. Hurt, Kathleen Kelly
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Research Article Cell biology

Tumor-derived biomarkers predict efficacy of B7H3 antibody-drug conjugate treatment in metastatic prostate cancer models

Abstract

Antibody-drug conjugates (ADCs) are a promising targeted cancer therapy; however, patient selection based solely on target antigen expression without consideration for cytotoxic payload vulnerabilities has plateaued clinical benefits. Biomarkers to capture patients who might benefit from specific ADCs have not been systematically determined for any cancer. We present a comprehensive therapeutic and biomarker analysis of a B7H3-ADC with pyrrolobenzodiazepine(PBD) payload in 26 treatment-resistant, metastatic prostate cancer (mPC) models. B7H3 is a tumor-specific surface protein widely expressed in mPC, and PBD is a DNA cross–linking agent. B7H3 expression was necessary but not sufficient for B7H3-PBD-ADC responsiveness. RB1 deficiency and/or replication stress, characteristics of poor prognosis, and conferred sensitivity were associated with complete tumor regression in both neuroendocrine (NEPC) and androgen receptor positive (ARPC) prostate cancer models, even with low B7H3 levels. Non-ARPC models, which are currently lacking efficacious treatment, demonstrated the highest replication stress and were most sensitive to treatment. In RB1 WT ARPC tumors, SLFN11 expression or select DNA repair mutations in SLFN11 nonexpressors governed response. Importantly, WT TP53 predicted nonresponsiveness (7 of 8 models). Overall, biomarker-focused selection of models led to high efficacy of in vivo treatment. These data enable a paradigm shift to biomarker-driven trial designs for maximizing clinical benefit of ADC therapies.

Authors

Supreet Agarwal, Lei Fang, Kerry McGowen, JuanJuan Yin, Joel Bowman, Anson T. Ku, Aian Neil Alilin, Eva Corey, Martine P. Roudier, Lawrence D. True, Ruth Dumpit, Ilsa Coleman, John K. Lee, Peter S. Nelson, Brian J. Capaldo, Aida Mariani, Clare Hoover, Ilya S. Senatorov, Michael Beshiri, Adam G. Sowalsky, Elaine M. Hurt, Kathleen Kelly

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Figure 1

CD276/B7H3 expression in samples from patients with mPC and mPC PDX/organoid models.

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CD276/B7H3 expression in samples from patients with mPC and mPC PDX/orga...
(A) CD276/B7H3, FOLH1/PSMA, PSCA, TACSTD2/TROP2, STEAP1, and CEACAM5 transcript abundance determined by RNA-Seq analysis of 185 metastatic prostate tumors from 98 patients. Transcript levels are shown as Log2 FPKM. (B) Comparisons of CD276/B7H3 (green dots) and FOLH1/PSMA (blue dots) expression by phenotypes of metastatic tumors. Groups were compared using 2-sided Wilcoxon rank tests with Benjamini-Hochberg multiple-testing correction. (C) IHC assessments of B7H3 protein expression. Representative staining of tumors with low, medium, and high B7H3 expression in AR+/NE– and AR–/NE+ phenotypes. (D) Distribution of B7H3 protein expression in 181 metastatic tumors within and between 58 patients. (E) Distribution of B7H3 protein expression in mPCs categorized by phenotype (AR+/NE–; n = 146, AR+/NE+; n = 10, AR–/NE–; n = 3, AR–/NE+; n = 18, Cases not evaluated n = 4), **P ≤ 0.01, ***P ≤ 0.001. Wilcoxon test. (F) Western blot quantification of B7H3 protein expression in PDX tissue samples and 2 PDOs (NCI-PC44, NCI-PC155) by Simple Western. ARPC samples with high B7H3 expression are categorized separately in the B7H3HI group. Y-axis represents CD276/B7H3 protein quantification scaled by a factor of 10. For pairwise comparison between groups, Wilcoxon test was used with P value adjusted using the Holm method. P < 0.05 was considered significant. (G and H) Flow cytometry analysis for B7H3 cell–surface expression from organoids dissociated into single cells. P < 0.05; significant, Wilcoxon test. (G) Median Fluorescence Intensity (MFI) and (H) Percentage positive cells are shown for 9 analyzed models.