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

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-beta 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.