Abstract 1521: Unlocking the therapeutic index of highly potent site-specific ADCs in solid tumors

Abstract CD276 (B7-H3) is a transmembrane protein of the B7 family, which includes many prominent immune checkpoint targets, and is expected to play a role in T-cell stimulation, tumor-infiltration, as well as other tumorigenic functions with poor prognosis when upregulated. CD276 is highly expressed in solid tumors, cancer initiating stem cells, and tumor associated vasculature with minimal to no expression in healthy tissue. This promising expression profile has piqued interest for various targeted therapeutic modalities, such as antibody-drug conjugates (ADCs). Developing effective ADCs for solid tumors remains a challenge due to inefficient conjugation technologies which are either non-homogeneous, unstable, or do not position payloads at optimal sites. BrickADCs minimize hydrophobicity, optimize payload release kinetics, and tune biophysical properties to improve efficacy, safety, and bioavailability, resulting in improved therapeutic indexes. Potent payloads such as pyrrolobenzodiazepines have been underutilized due to toxicity, preventing their widespread use. BrickBio’s unique bioconjugation methodology enables precise (site-specific), flexible (unfettered site accessibility and chemistry), efficient, and scalable generation of ADCs which overcome these limitations. In this work, UAAs (unnatural amino acids) were incorporated into full-length anti-CD276 antibodies and conjugated with optimized pyrrolobenzodiazepine (PBD) payloads. BrickADCs leverage a proprietary Site-Select Panel to find optimal sites that shield the toxicity of highly potent, hydrophobic PBD payloads while maintaining their high activity to generate anti-CD276-UAA-PBD ADCs. The highest performing BrickADCs, developed by a rapid screen of PBD payloads conjugated to different sites in the antibody backbone, exhibit high therapeutic efficacy in a variety of CD276 positive solid tumor cell lines (eg. colon, ovarian, lung, sarcoma, etc) and in mouse xenograft models with a 3x differential in complete response. The tuned hydrophobicity and release kinetics have resulted in ADCs that have an increased therapeutic index, particularly due to their improved safety profile compared to cysteine conjugation.The BrickADC platform enables an increased therapeutic window for potent payloads across solid tumors, opening the floodgates for further development of ADCs which leverage payloads that have been plagued by poor therapeutic index. Continued work is underway for the CD276 pipeline candidates as they progress towards IND, as well as investigation into other targets and conjugate modalities. Citation Format: James S. Italia, Colby A. Souders, Sreedhar Reddy Suthe, Myer Hussain, Zhi Li, John Boyce, Audrey Warner, Abhishek Chatterjee. Unlocking the therapeutic index of highly potent site-specific ADCs in solid tumors [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 1521.