Tumor-derived biomarkers predict efficacy of B7H3 antibody-drug conjugate treatment in metastatic prostate cancer models
Supreet Agarwal, … , Elaine M. Hurt, Kathleen Kelly
Supreet Agarwal, … , Elaine M. Hurt, Kathleen Kelly
Published September 19, 2023
Citation Information: J Clin Invest. 2023;133(22):e162148. https://doi.org/10.1172/JCI162148.
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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 3

RB1 loss predicts B7H3-PBD-ADC response.

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RB1 loss predicts B7H3-PBD-ADC response. (A) B7H3-PBD-ADC response categ...
(A) B7H3-PBD-ADC response categorized by RB1 genomic status. Red line indicates the median nAUC for each group. TP53 genotypes are shown as different shapes. Color indicates RB1 signature score on z-transformed scale. Wilcoxon test with P value adjusted using the Holm method, P < 0.05 was considered significant. (B) Immunoblot analysis of organoid models and prostate cancer cell lines for the indicated markers. Heatmap (bottom) showing RB1 and TP53 genomic status and B7H3-PBD-ADC response. For RB1, red color indicates biallelic copy loss and blue indicates WT or single copy loss. TP53 status in red refers to alterations by biallelic inactivation or gain of function mutation and in blue indicates WT or monoallelic loss. For B7H3-PBD-ADC response; R, responsive; NR, nonresponse; NA, data not available. Bar plots for RB1 score is shown for the organoid models. (C) Correlation of B7H3-PBD-ADC response (nAUC) and RB1 signature score. Pearson’s correlation coefficient r = –0.64, P = 0.00081. (D) IF images confirming DOX-inducible knockdown of RB1 in LuCaP167 organoid model. (E) B7H3-PBD-ADC dose response curves in LuCaP167 (RB1+) organoid model expressing DOX-inducible RB1 shRNA. Error bars indicate the SEM. *P < 0.05, Wilcoxon test.