Abstract 2947: Preclinical evaluation of a novel B7-H4 targeted antibody-drug conjugate AZD8205 as a single agent and in combination with novel PARP inhibitor and checkpoint blockade
Authors: Cazes Alex , Kinneer Krista , Omar Bilal , Chesebrough Jon , Anderton Judith , Wang Jixin , Staniszewska Anna D. , Arbitman Steven , Daita Kalyani , Desai Himanshi , Johnson Yoshimi , Rothstein Raymond , Gymnopoulos Marco , Fabbri Giulia , Cooper Zachary A. , Albertella Mark , Hammond Scott A. , Cosulich Sabina , Luheshi Nadia , Sapra Puja 
Published: April 2023

Abstract
B7-H4 is a cell-surface protein overexpressed in several tumor types and is most prevalent in triple-negative breast (TNBC) cancer (74%), ovarian carcinoma (77%), endometrial carcinoma (94%), and cholangiocarcinoma (89%). In contrast, it has a limited expression in normal tissue, making it an attractive target for an antibody-drug conjugate (ADC). Here we report and characterize the preclinical efficacy of AZD8205, a novel B7-H4 targeted ADC carrying a topoisomerase 1 inhibitor (TOP1i) linker-warhead, AZ’0133 at a drug:antibody ratio (DAR) of 8. The primary mechanism of action of AZD8205 is intracellular delivery of the TOP1i warhead to B7-H4 positive cells, leading to DNA damage and apoptotic cell death. A single IV administration of AZD8205 at 3.5 mg/kg provided robust antitumor activity in patient-derived xenografts from TNBC, ovarian and cholangiocarcinoma tumors, with overall response rates in B7H4-expressing samples of 75%, 64% and 21% respectively. Tumor response was found to be correlated to cell surface target expression and homologous recombination repair deficiency status. To further exploit the DNA damage elicited by the specific delivery of the TOP1i warhead, the combination of AZD8205 with a novel poly-ADP ribose polymerase 1 (PARP1) selective inhibitor, AZD5305, was investigated. Combination of AZD8205 and AZD5305 provided higher antitumor activity than monotherapy, even in PARP inhibition-resistant or low B7-H4 expressing PDX tumors. Finally, cancer cell lines were found to express markers of immunogenic cell death and antigenicity post-AZD8205 treatment in vitro. Therapeutic benefit of combining AZD8205 with checkpoint immunotherapies was then evaluated in syngeneic models, demonstrating enhanced antitumor efficacy of AZD8205 when combined with an anti-PD-L1 antibody. These data demonstrate that AZD8205 is a promising therapeutic candidate for the treatment of B7-H4 positive solid tumors. A first in human phase I/IIa study in patients with advanced solid tumors is currently ongoing (NCT05123482).
Citation Format: Alex Cazes, Krista Kinneer, Bilal Omar, Jon Chesebrough, Judith Anderton, Jixin Wang, Anna D. Staniszewska, Steven Arbitman, Kalyani Daita, Himanshi Desai, Yoshimi Johnson, Raymond Rothstein, Marco Gymnopoulos, Giulia Fabbri, Zachary A. Cooper, Mark Albertella, Scott A. Hammond, Sabina Cosulich, Nadia Luheshi, Puja Sapra. Preclinical evaluation of a novel B7-H4 targeted antibody-drug conjugate AZD8205 as a single agent and in combination with novel PARP inhibitor and checkpoint blockade [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 2947.