Abstract LB252: ABN202, a TROP2-targeted IFN-β mutein fusion protein, overcomes ADC resistance and elicits durable CD8⁺ T cell-dependent antitumor immunity

Abstract Background: TROP2-targeted antibody-drug conjugates (ADCs) have shown clinical benefit in advanced epithelial tumors; however, acquired resistance and limited durability of response remain major challenges. ABN202 is a next-generation antibody-cytokine fusion protein comprising a TROP2-targeting monoclonal antibody fused to an IFN-β mutein (ABN102). Here, we evaluated whether ABN202 could overcome ADC resistance and induce long-term immunological memory, addressing the critical need for effective therapies after ADC failure. Methods: Antitumor efficacy was assessed in TROP2⁺ breast cancer models with acquired resistance to ADCs. Antitumor immune responses were evaluated in human IFNAR1/2 knock-in (hIFNAR KI) mice bearing MB49-hTROP2 (bladder) and PyMT-hTROP2 (breast) tumors. We compared ABN202 monotherapy with TROP2-targeted ADCs alone and in combination with anti-PD-1. Mechanistic studies included tumor rechallenge, adoptive splenocyte transfer, in vivo immune cell depletion and immunophenotyping of tumor-draining lymph nodes (TDLNs) and the tumor microenvironment (TME). Safety and pharmacokinetics (PK) were characterized in cynomolgus monkeys. Results: ABN202 demonstrated potent antiproliferative activity in ADC-resistant models in which conventional ADCs showed limited efficacy. In the human TROP2-expressing PyMT (PyMT-hTROP2) model, ABN202 monotherapy produced superior tumor growth inhibition compared with the combination of a TROP2-targeted ADC and anti-PD-1. In the MB49-hTROP2 model, ABN202 induced frequent complete regressions (CRs) with long-term (100-day) survival. Cured mice rejected tumor rechallenge, and adoptive transfer of their splenocytes effectively inhibited established tumors in naïve recipients, confirming the induction of robust immunological memory. This efficacy was CD8⁺ T cell-dependent, as demonstrated by depletion studies. Consistent with these findings, immunophenotyping revealed expansion of tumor-specific CD8⁺ T cells in both TDLNs and the TME, supporting ABN202-driven CD8⁺ T cell-mediated antitumor immunity against tumor recurrence. Exploratory nonhuman primate studies indicated that ABN202 was well tolerated, with no mortality or severe systemic toxicitiy observed following repeated dosing. Conclusions: ABN202 overcomes resistance to TROP2-targeted ADCs and demonstrates greater antitumor activity than an ADC plus anti-PD-1 combination in preclinical models. By inducing durable CD8⁺ T cell-mediated immunity, ABN202 offers a promising therapeutic strategy for patients with TROP2-positive solid tumors who have failed standard ADC-based treatments. Citation Format: Hee Geon Park, Myeung Ryun Seo, Hyun Kyung Lee, Sang Moo Lee, Su Jin Ryu, Ho Jin Lee, Rae Eon Kim, Sung Hyun Hong, Su Jin Lee, Sang In Lee, Seung Hwa Jeong, Jae Mun Kim, Sung Youl Hong, Jangsoon Lee, Naoto T. Ueno, Yeon Hee Park, Young Kee Shin. ABN202, a TROP2-targeted IFN-β mutein fusion protein, overcomes ADC resistance and elicits durable CD8⁺ T cell-dependent antitumor immunity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB252.