Abstract 3126: A novel pegylated bispecific antibody-drug conjugate (P-BsADC) JY207b targeting cancers co-expressing PD-L1 and CD47
Authors: Yu (Yvonne) Wen, Shumin Liu, Weidong Lyu, Yang Lei, Shuangyu Tan, Zibin Wu, Shuqiang Yin, Qiudong Zhuo, Dechun Wu
Journal: Cancer Research (2024)

Abstract ADCs have showed improved efficacy and target selectivity comparing to the non-specific small molecule cytotoxicity drugs. However, conventional IgG based ADC has been hindered in solid tumor therapies by the poor tumor penetration, low internalization efficiency, unexpected efflux from tumor cells, and narrow therapeutic window due to the on target/off tumor toxicity, etc. To address these issues, we have developed the pegylated bispecific ADC platform and proved the concept with JY207, which targets PD-L1 and CD47 with a 30k PEG-MMAE linker-payload. JY207 has demonstrated advantages in tumor penetration, internalization efficiency, without efflux post internalization, lacking Fc related toxicity, and better tumor inhibition than DS-8201a in a model positive for Her2, PD-L1 and CD47. In this study, we further improved the compound by site-specific conjugating the fusion protein of two scFvs that target PD-L1 and CD47, with a 40K PEG-MMAE linker-payload. As expected, the new compound JY207b retained all the advantages of JY207. Additionally, JY207b did not bind to human red blood cells at all even though an ultra-sensitive detection method was employed, while CD47 antibodies with reported low affinity bound &amp;gt;90% red blood cells under our ultra-sensitive detection method. Meanwhile, JY207b could still preferentially bind to CD47/PD-L1 double positive tumor cells, thus reducing the possibility of on-target toxicities. In the in vitro cytotoxicity assays, the compound JY207b demonstrated strong potencies in CD47/PD-L1 double positive tumor cells, with almost no killing effect to CD47 or PD-L1 single positive tumor cells. In CDX models and a PDX model of transplanted tumor tissues from lung cancer patients, the compound JY207b demonstrated strong tumor inhibition efficacies at low doses. More interestingly, although the elimination half-life (T1/2) of JY207b in mice is 59.17±3.824 hours, the elimination time of JY207b in tumors is beyond 1 week by the IVIS imaging examination, which allows for weekly dosing in PK unfavorable mouse animals for pegylated protein drugs. Moreover, preliminary repeated-dosing toxicological study has found the maximum tolerated dose of JY207 in CD47/PD-L1 double transgenic mice to be 50mg/kg. These studies suggested favorable anti-tumor effect of JY207 both in vitro and in vivo, and its mechanism of action has been well described. These findings provide evidence for the efficacy of JY207 as a clinical treatment for patients with CD47/PD-L1 double positive cancers. Citation Format: Yu (Yvonne) Wen, Shumin Liu, Weidong Lyu, Yang Lei, Shuangyu Tan, Zibin Wu, Shuqiang Yin, Qiudong Zhuo, Dechun Wu. A novel pegylated bispecific antibody-drug conjugate (P-BsADC) JY207b targeting cancers co-expressing PD-L1 and CD47 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3126.