Abstract Affibody, distinguished by its compact three-helix structure, offers significant advantages over conventional monoclonal antibodies, such as superior tissue penetration kinetics, picomolar binding affinity, and efficient production via prokaryotic expression. Leveraging these favorable properties, we developed LN019, a novel affibody-drug conjugate exhibited exceptional preclinical efficacy. In vitro, LN019 exhibited potent dose-dependent cytotoxicity against HER2-positive cell lines, with IC50 of 3. 6 nM in SKOV-3 (ovarian cancer) and 8. 1 nM in BT474 (breast caner). In vivo biodistribution assays revealed the excellent kinetics, LN019 achieving significant accumulation at the tumor sites within 10 min post-injection, validating the hypothesis of rapid target-tissue penetration. In xenograft models, LN019 showed remarkable antitumor efficacy at reduced dose. In SKOV-3 ovarian and N87 gastric cancer xenograft models, LN019 at 4. 8 mg/kg induced complete tumor regression with a tumor growth inhibition (TGI) of 105. 2% and 122. 3% respectively, dramatically surpassing the 90. 1% and 115. 3% TGI observed with DS-8201 at such high-dose 8 mg/kg. Notably, in BT474 breast cancer models, a low dose of 2. 4 mg/kg LN019 yielded a TGI of 112. 0%, outperforming the high-dose DS-8201 group (8 mg/kg, 105. 1% TGI). These findings suggest that LN019 leverages the unique properties of the affibody scaffold to achieve rapid tumor uptake and potent efficacy. Consequently, LN019 represents a promising next-generation therapeutic candidate for HER2-overexpressing malignancies, potentially offering an improved safety profile and efficacy in solid tumors where tissue penetration is a limiting factor. This work was supported by the Natural Science Foundation of Shanghai (25ZR1402262), the State Key Laboratory of Synergistic Chem-Bio Synthesis, Shanghai Jiao Tong University (sklscbs202547) Citation Format: Xuelin Xia, Ning Sun, Wei Huang, Zhigang Yan, Zhao Sun, Yong Liu, Wenming Li, Xiaobo Li, Xiaoxia Xia, Deyue Yan. LN019, a novel HER2-targeting affibody-drug conjugate, demonstrates superior antitumor efficacy compared to T-DXd in xenograft models 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 LB028.
Xia et al. (Fri,) studied this question.