Abstract A124: CBB-120: A TROP2-targeted dual-payload ADC combining Top1i and ATRi mechanisms demonstrates superior efficacy in preclinical models and improved safety in non-human primates

Abstract Background: Antibody-drug conjugates (ADCs) have emerged as a powerful strategy for treating TROP2-expressing epithelial cancers, including breast and lung cancers. Among current therapies, Trodelvy® and Datroway® (Dato-DXd) carrying topoisomerase I inhibitors (Top1i) have demonstrated notable clinical benefits. However, improving toxicity profiles, inducing durable activity, and overcoming resistance are opportunities for next-generation TROP2 ADCs. To address these issues, we developed CBB-120, a site-specific, Fc-silenced, highly stable dual-payload ADC that utilizes proprietary EGCit linkers to conjugate Top1i and ATRi payloads. ATRi specifically inhibits DNA repair and thus has the potential to synergize with Top1i. This synergy should enable deeper and more durable activity over Top1i alone, while also preventing the onset/progression of acquired resistance to Top1i. Materials and Methods: CBB-120 was constructed using microbial transglutaminase-mediated conjugation to attach proprietary branched linkers to an Fc-silenced TROP2 antibody. This was followed by bio-orthogonal click chemistry, specifically strain-promoted alkyne-azide cycloaddition (SPAAC) and inverse electron-demand Diels–Alder (IEDDA) reactions, to enable site-specific attachment of dual payloads. The binding affinity of CBB-120 to human and cyno TROP2 was assessed using surface plasmon resonance and flow cytometry. Its anti-tumor activity was evaluated via in vitro cell viability assays using multiple TROP2-positive cancer cell lines, as well as in xenografts. Additionally, toxicology studies were conducted in cynomolgus monkeys to assess safety and tolerability. Results: CBB-120 bound with high affinity and comparably to both human and cynomolgus monkey TROP2 protein and tumor cells. It exhibited superior in vitro cytotoxicity relative to Dato-DXd across all cell lines. Importantly, CBB-120 also demonstrated synergistic potency both in vitro and in vivo, leading to tumor regression in multiple xenografts representing breast, lung, colon, pancreatic, and endometrial cancers. In these studies, CBB-120 also induced CRs up to 4 months, outperformed Dato-DXd and its Top1i ADC counterpart, and demonstrated potent efficacy in Top1-resistant models. In NHPs, CBB-120 also revealed no/minimal off-target toxicity while inducing expected on-target skin toxicities, but with a large therapeutic index. TK data also revealed a 4-5 day half-life and no evidence of payload deconjugation. Conclusion: CBB-120, a novel site-specific Fc-silenced dual-payload ADC targeting TROP2, enables targeted delivery of both its Top1i and ATRi payloads to TROP2-expressing tumors, achieving synergistic, highly potent anti-tumor efficacy while minimizing systemic toxicity. Our findings support the continued development of CBB-120 as a promising best-in-class next-gen ADC for TROP2-positive cancers. Our data also emphasizes the improved safety profile of our EGCit linker payload platform, which can be used to address unmet needs in other important tumor types. Citation Format: Yasuaki Anami, Veerakumar Balasubramaniyan, Roman A. Lara, Michael J. Torres, Daniel S. Pereira. CBB-120: A TROP2-targeted dual-payload ADC combining Top1i and ATRi mechanisms demonstrates superior efficacy in preclinical models and improved safety in non-human primates [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A124.