Abstract 6330: Countering antidrug antibodies to programmed cell death-1 blockade in mouse Pten-null prostate cancer
Authors: De Velasco Marco A. , Kura Yurie , Sako Noriko , Ando Naomi , Fujita Kazutoshi , Nishimoto Mitsuhisa , Sakai Kazuko , Yoshimura Kazuhiro , Nozawa Masahiro , Hammond Scott A. , Dovedi Simon J. , Davies Barry R. , Nishio Kazuto , Uemura Hirotsugu 
Published: June 2023

Abstract
Therapeutic biologics have the potential to elicit immune responses that results in the development anti-drug antibodies (ADAs). ADAs that develop after immune checkpoint blockade (ICB) limit their therapeutic efficacy and increase the risk of adverse events. Mitigating ADAs would improve the efficacy of antibody-based therapeutics and identifying reliable biomarkers would allow for rational, evidence-based criteria for tailoring treatments. However, detecting ADAs is challenging and data regarding their biology and means to counter this phenomenon are limited. Here, we examined the development of ADAs to anti-programmed cell death-1 (PD-L1) monoclonal antibodies in a mouse model Pten/Trp53-null (DKO) prostate cancer and countered their negative effect with systemic administration of a JAK1/2 inhibitor. Like human prostate cancer, adding PD-L1 ICB to androgen deprivation therapy has failed to produce a therapeutic effect in DKO cancer model. Our analysis showed that tumor-bearing DKO mice have increased levels of peripheral dendritic cells (pDC) of which &gt;80% exhibited high levels of PD-L1. Given this finding, we developed a system to monitor the development of ADAs against two murine anti-PD-L1 (aPD-L1) monoclonal antibodies clone 80 and 10F9.G2. Pharmacodynamic studies showed that a single-dose administration of the blocking antibodies effectively neutralized PD-L1 in pDC that lasted for four days. Chronic (twice/week) dosing of the aPD-L1 antibodies strongly neutralized PD-L1 in pDCs, but the efficacy waned after 22 days. Using crossover approach, consisting of clone 10F9.G2 dosing for two weeks followed by clone 80, extended PD-L1 blockade in pDCs to 36 days, but did not improve antitumor activity. Blocking STAT3 signaling with the JAK1/2 inhibitor AZD1480 restored PD-L1 blockade in pDCs and was associated with improved reduction of tumor burden. Further analysis showed improved neutralization of PD-L1 in cancer cells and tumor infiltrating immune cells in mice treated with AZD1480. These effects were associated with greater T and NK cell reactivity in tumors. Our study shows that the presence of ADAs is associated with lack of antitumor responses to ant-PD-L1 blockade in a preclinical model of prostate cancer and provides additional data that will improve our understanding of ADAs against immune checkpoint inhibitors. This study also offers an approach to monitor ADA development and a platform to investigate novel approaches to target ADAs.
Citation Format: Marco A. De Velasco, Yurie Kura, Noriko Sako, Naomi Ando, Kazutoshi Fujita, Mitsuhisa Nishimoto, Kazuko Sakai, Kazuhiro Yoshimura, Masahiro Nozawa, Scott A. Hammond, Simon J. Dovedi, Barry R. Davies, Kazuto Nishio, Hirotsugu Uemura. Countering antidrug antibodies to programmed cell death-1 blockade in mouse Pten-null prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6330.