Abstract B098: An integrated fragment approach yields ABBV-973, a potent, pan-allele small molecule STING agonist for intravenous administration
Authors: Bromberg Kenneth D , Kline Douglas E , Samanta Tanushree , Ji Zhiqin , Cheng Min , Malchow Sven , Gruber Jennifer , Ferguson Debra , Smith Heath , Sun Chaohong , Lai Albert , Judd Andrew 
Published: February 2025

Abstract
Immunotherapy has revolutionized cancer therapy by activating the host immune system to attack the cancer. While immune checkpoint inhibitors that predominantly target T-cells have induced durable clinical responses across multiple tumor types, a large majority of patients do not respond, and resistance/relapse is frequently observed. The innate immune system also holds promise to trigger an anti-tumor immune response. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a critical innate immune sensor of cytoplasmic double-stranded DNA. Activation induces production of inflammatory cytokines and a robust type I interferon (IFN) response. Type I IFN enhances dendritic cell mediated cross-priming of CD8 T-cells, leading to their activation and subsequent killing of tumor cells. In preclinical models, activating STING directly via cyclic dinucleotide (CDN) analogs or small molecules results in robust anti-tumor immune responses and tumor eradication. As a result, there have been intense efforts to develop STING agonists for cancer immunotherapy. However, toxicity from cytokine release syndrome (CRS)-like effects and the observation that prolonged STING agonism can result in T-cell death have hampered the clinical potential of STING agonists. Here, we detail the discovery of ABBV-973, a potent pan-allele STING agonist. We implemented a fragment-based screening approach using SPR, TSA, 2D-NMR, and ITC to identify an efficient non-acid containing and non-nucleotide fragment that binds as two copies in the CDN binding site of the dimeric STING molecule. We then leveraged robust X-ray co-crystal structures to design a fragment linking strategy that led to the discovery of ABBV-973, a potent STING agonist that binds as a single copy in dimeric STING. ABBV-973 promotes robust STING activation and anti-tumor immunity in vivo as a single agent and in combination with anti-PD-1 antibody therapy in the anti-PD-1 refractory Pan02 tumor model. ABBV-973 has low projected human dose and favorable properties for intravenous dosing. This, together with its high clearance and a short half-life profile, enables robust anti-tumor activity while mitigating T-cell toxicity. Lastly, we have developed multiple strategies to further minimize cytokine release syndrome-like toxicity, which is a key challenge for translating STING agonists clinically. These results can aid the development of STING agonists to mitigate potential toxicity and thus further harness the clinical potential of STING agonists. AbbVie Disclosure Statement: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.
Citation Format: Kenneth D Bromberg, Douglas E Kline, Tanushree Samanta, Zhiqin Ji, Min Cheng, Sven Malchow, Jennifer Gruber, Debra Ferguson, Heath Smith, Chaohong Sun, Albert Lai, Andrew Judd. An integrated fragment approach yields ABBV-973, a potent, pan-allele small molecule STING agonist for intravenous administration [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B098.