Abstract 342: LYW-105: A novel bispecific antibody-drug conjugate with enhanced antitumor efficacy and broader therapeutic index.

Abstract Introduction: Antibody-drug conjugates (ADCs) have made remarkable progress in cancer therapy; however, the development of ADCs with a wide therapeutic window that can effectively combat drug resistance and tumor recurrence remains a significant challenge. The fourth-generation ADC developed by LyncBio features homogeneous conjugation, a target-fit linker-payload design, and superior drug-like properties, aiming to break through the limitations of existing ADC therapeutic indices. LYW-105 is an innovative bispecific ADC designed to achieve more extensive and profound tumor regression through a dual-target approach. Its bispecific antibody components utilize a 1+1 format, with each arm demonstrating high affinity and efficient internalization, thereby enhancing therapeutic efficacy by addressing tumor heterogeneity and minimizing resistance. The linker design of LYW-105 allows for rapid lysosomal release and excellent buffer stability, resulting in reduced systemic toxicity and favorable pharmacokinetics. The payload is a topoisomerase I inhibitor with optimal potency and membrane permeability, effectively balancing tumor cytotoxicity with bystander effects. Methods: We assessed the binding affinity of the bispecific antibody to its targets using ELISA, FACS, and BLI techniques. Internalization activity was measured using the pHrodo method, while developability was evaluated through methods such as SEC and HIC. The efficacy of LYW-105 was tested both in vitro and in vivo using established solid tumor models. Results: In vitro studies showed that LYW-105 exhibited strong binding affinity to its targets and demonstrated approximately 2- to 30-fold greater internalization activity in tumor cell lines compared to reference monoclonal antibodies. Additionally, LYW-105 displayed 2- to 25-fold enhanced inhibition of tumor cell proliferation compared to in-house benchmark ADCs. Biophysical properties and stability assessments at 40°C indicated good developability, comparable to that of monoclonal antibodies. In vivo, LYW-105 demonstrated robust antitumor activity in mouse models, showing superior efficacy and prolonged tumor suppression compared to benchmark ADCs. Body weight changes remained stable across treatment groups, indicating that LYW-105 is well-tolerated. Conclusions: In summary, LYW-105 has been thoroughly compared to benchmark single-target ADCs in preclinical settings. It demonstrated potent cytotoxicity in vitro and significant antitumor activity in vivo across various tumor cell lines, showcasing a broader therapeutic index than benchmark ADCs. Citation Format: Qianqian Zhao, Zhangsheng Lu, Xun Cao, Xiaobing Tang, Liguo Wang, Peixiang Liu, Lu Wang, Jiajie Feng, Cexiong (Winston) Fu. LYW-105: A novel bispecific antibody-drug conjugate with enhanced antitumor efficacy and broader therapeutic index 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 342.