Abstract 5644: DA-3501 (AT-211): Evaluation of immune-mediated antitumor activity and combination immunotherapy potential of a site-specific CLDN18.2-targeting antibody-drug conjugate (ADC).

Abstract Background: Claudin 18.2 (CLDN18.2) is a clinically validated therapeutic target in gastric and pancreatic cancers. However, acquired resistance to CLDN18.2-directed antibodies such as zolbetuximab and trastuzumab highlights the need for next-generation therapeutics with distinct mechanisms of action. DA-3501 (AT-211) is a CLDN18.2-targeting antibody-drug conjugate (ADC) developed using the AbClick® site-selective conjugation platform. The antibody component exhibits enhanced binding affinity, internalization efficiency, and molecular stability. This study aimed to evaluate the immune-mediated antitumor activity of DA-3501 and explore its potential for combination immunotherapy. Methods: To assess efficacy in resistant disease contexts, immune organoids derived from gastric cancer patients with acquired resistance to trastuzumab and zolbetuximab were used to evaluate DA-3501 activity. Antitumor effects were analyzed in immune cell co-culture systems to assess cytotoxicity, CLDN18.2-dependent responses, and immune activation markers. Furthermore, in vivo efficacy studies incorporating immune checkpoint inhibitor (ICI) combination groups were conducted under immunocompetent conditions to investigate immune-mediated mechanisms and the combinatorial potential of DA-3501. Results: DA-3501 demonstrated potent and selective cytotoxicity toward CLDN18.2-positive tumor cells and induced immune cell activation consistent with IgG1-mediated antibody-dependent cellular cytotoxicity (ADCC). In vivo, DA-3501 exhibited robust immune-mediated antitumor activity both as a monotherapy and in combination with ICIs, indicating complementary interactions between the ADC’s direct cytotoxic payload and immune-modulatory mechanisms. Conclusions: DA-3501 (AT-211) is a site-selectively conjugated CLDN18.2-targeting ADC that exerts strong immune-mediated antitumor effects, even in models derived from patients resistant to existing antibody therapies. These results highlight the dual mechanism of action of DA-3501—combining direct cytotoxicity and Fc-driven immune activation—and support the development of rational ADC-immunotherapy combinations as a promising strategy in the evolving landscape of ADC-based cancer treatment. Citation Format: Kyoung-Ho Pyo, Seong-Hyun Park, Dongsop Lee, Haneol Kim, Younggyu Kong, Younggeun Lee, Hojin Yeom, Sowon Aum, Sun Hee Park, Huijo Oh, Cheyeon Kim, Hyeonseok Jin, Hyeonseok Jin, Aera Lee, Hojeong Hong, Ju Hwan Kim, Hyungseok Choi, Mi-Kyung Kim, Taedong Han. DA-3501 (AT-211): Evaluation of immune-mediated antitumor activity and combination immunotherapy potential of a site-specific CLDN18.2-targeting antibody-drug conjugate (ADC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5644.