Abstract 4000: A novel pegylated bispecific antibody-drug conjugate (P-BsADC) targeting Her2+ cancers with improved efficacy and therapeutic window

Abstract

Abstract Despite the fact that ADCs improve the efficacy and target selectivity comparing to the non-specific small molecule cytotoxicity drugs in cancer treatment, traditional ADCs still suffer from many issues which include low tumor penetration and accumulation, inefficient internalization, undesired efflux of ADC from tumor cells, significant on-target off-tumor toxicity, Fc mediated uptake that results in off-target toxicity, limited extravasation across capillary walls due to big molecular size, poor diffusion into the tumor masses due to increased tumor interstitial fluid pressure, and the binding-site-barrier. To address these issues, we previously reported that the compound JY201, a Polyethylene Glycol (PEG)-based bispecific ADC (P-BsADC) targeting two epitopes of Her2, demonstrated advantages in tumor penetration, internalization efficiency, lysosome trafficking effectiveness, no Fc related toxicity, and better efficacy in tumor inhibition than transtuzumab deruxtecan (Ds-8201). Continuing from our previous study, here we further reveal that JY201 can penetrate the tumor deeply and distribute more homogeneously in entire tumor masses while Ds-8201 limits its diffusion to the regions very close to the blood vessels in the tumor. Furthermore, JY201 shows better efficacy than Ds-8201 in inhibiting tumors with low expression of Her2 in pdx (patient derived xenograft) and cdx models. In addition, JY201 can effectively inhibit tumors resistant to Ds-8201. In an in-vitro plasma stability test, JY201 demonstrated high stability in cynomolgus monkey and human serums. JY201 also has a biodistribution profile advocating better safety than Ds-8201 in tumor bearing mice. In the repeated-dosing toxicological study in Her2 transgenic mice, JY201 with the dose of 50mg/kg was well tolerated and did not induce any tissue/organ damage to the animals. Due to much shorter half-life (5 times shorter) in mice for PEGylated proteins than in primates, we expect JY201 will have much higher tolerated dose than the 50mg/kg in primates. In summary, the findings from this study provide solid preclinical evidence for JY201 to be developed further as an efficacious and safe clinical treatment for patients with Her2 positive cancers. Citation Format: Yu (Yvonne) Wen, Shuqiang Yin, Weidong Lyu, Yang Lei, Qiudong Zhuo, Zibin Wu, Bin Sun, Shuangyu Tan, Lidong Jiang, Teng Zhang, Bo Gao, Rui Xu, Yong Li, Liling Zheng, Shumin Liu, David (Dechun) Wu. A novel pegylated bispecific antibody-drug conjugate (P-BsADC) targeting Her2+ cancers with improved efficacy and therapeutic window. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4000.