Abstract 4263: A novel pegylated biparatopic antibody-drug conjugate (pb-adc) targeting cancers with low HER2+ expression

Abstract

Abstract ADCs have demonstrated much improved target selectivity and efficacy comparing to the nonspecific cytotoxic small molecule drug. The goal of ADC technology is to resolve the toxicity issue inherent in potent small molecule drugs. Yet, the main problem facing current ADC technology is still a toxicity issue, evidenced by 9 out of 12 FDA approved ADCs carrying black box warning labels and many failed clinical programs due to their toxicities. Many factors contribute to the ADC’s toxicity including but not limited to random conjugation of payloads to the antibody, premature release of payload, Fc related toxicity, on-target/off-tumor toxicity etc. In this study, we developed a novel pegylated BsAb-ADC formed by site-specific conjugating a fusion protein of two scFvs that target at two different epitopes of Her2, with PEG-MMAE, a pegylated cytotoxic payload MMAE. As expected, the compound is homogeneous without any Fc related toxicity. Although the compound showed lower affinity to Her2 positive cells, it demonstrated higher in vitro cytotoxicity than T-DM1, especially for Her2 low expressing cell lines when its DAR is 4. Furthermore, the compound was comparable to or better than T-DM1 or DS-8201 in inhibiting xenograft tumor models (including Her2+ low expressing models) even when DAR is only 2. The compound also demonstrated efficient internalization without detectable efflux, suggesting improved endosome and lysosome trafficking, most probably due to the lack of Fc promoted efflux mechanism and formation of complex between biparatopic Her2 antibody and Her2. In addition, unlike T-DM1 and DS-8201, the compound did not generate cytotoxicity to megakaryocyte cell line Dami, and is less toxic to the non-cancerous HaCaT cells than T-DM1 or DS-8201. The compound is stable with no detectable release of the payload when incubating with human Plasma for a week at 37°C. The circulation T1/2 of the compound in rat is about 30 hours. In conclusion, our pegylated BsAb-ADC compound demonstrated improved efficacy with better safety profile than T-DM1 and DS-8201. Citation Format: Shumin Liu, Shuqiang Yin, Weidong Lyu, Yang Lei, Qiudong Zhuo, Zibin Wu, Shuangyu Tan, Liling Zheng, Yu (Yvonne) Wen, David Wu. A novel pegylated biparatopic antibody-drug conjugate (pb-adc) targeting cancers with low HER2+ expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4263.