Abstract 4257: ADG153-G1, a highly differentiated anti-CD47 IgG1 SAFEbody, demonstrates potent in vivo anti-tumor activities with enhanced ADCC/ADCP effects and significantly reduced RBC-related and antigen sink liabilities

Abstract

Abstract Anti-CD47 antibodies of the IgG4 isotype have shown promising activities in clinical trials for hematologic malignancies, mainly in the combination setting. To overcome the fundamental challenge of developing an anti-CD47 antibody of an active Fc isotype for strong anti-tumor activities without the safety (e.g., anemia) and pharmacokinetic (e.g., antigen sink) liabilities, we set out to design anti-CD47 antibodies of active isotypes that allow us to decouple efficacy from safety and PK liabilities. Our NEObody࣪ technology enables us first to identify an anti-CD47 antibody targeting a novel epitope on CD47. Next, our SAFEbody® technology for precision masking enables us to mask the CD47 binding sites to create the masked antibody in active IgG1 isotype called ADG153-G1 SAFEbody, which can be conditionally activated to bind and inhibit CD47 on tumor cells for potent tumor killing with much improved safety and pharmacokinetic profiles. In vitro studies showed that the activated ADG153-G1 SAFEbody blocked CD47 binding to SIRPα, bound to the CD47 protein, CD47+ tumor cell lines, and human RBCs, and induced strong ADCC/ADCP activities. In contrast, the unactivated ADG153-G1 SAFEbody demonstrated high masking efficiency (ME) with significantly reduced activities (>110-1300× ME) in the same assays. While anti-CD47 antibodies such as the Hu5F9 analog caused in vitro human RBC hemagglutination, the ADG153-G1 SAFEbody in activated and unactivated forms did not show this effect at comparable concentrations. Consistent with its enhanced ADCC/ADCP potential in IgG1 isotype, in the CD47+ Raji tumor model in SCID mice (with functional NK cells and macrophages), the unmasked ADG153-G1 and masked SAFEbody demonstrated better anti-tumor activities than their IgG4 unmasked and masked SAFEbody counterparts. In exploratory single-dose toxicology studies in cynomolgus monkeys, the ADG153-G1 SAFEbody showed significantly less reduction than the Hu5F9 analog in RBCs and hemoglobin. The Hu5F9 analog at 10 mg/kg caused an ~49% maximum decrease in RBCs, while the ADG153-G1 SAFEbody at 10 and 30 mg/kg showed only 8% and 40% maximum reductions, respectively. Consistent with a reduced antigen sink effect due to lower RBC binding, the ADG153-G1 SAFEbody had more favorable pharmacokinetic properties than the Hu5F9 analog (~8× longer t1/2 and ~5× higher AUC) at 10 mg/kg. Taken together, these results indicate that the ADG153-G1 SAFEbody is a differentiated anti-CD47 IgG1 antibody prodrug with strong ADCC/ADCP potential and significantly reduced anemia-related and antigen sink liabilities, supporting its advancement into clinical development. Citation Format: Bin Cai, Aaron N. Nguyen, Songmao Zheng, Jianfeng Shi, Guizhong Liu, Yan Li, Felix Du, Peter Luo, Jiangchun Xu. ADG153-G1, a highly differentiated anti-CD47 IgG1 SAFEbody, demonstrates potent in vivo anti-tumor activities with enhanced ADCC/ADCP effects and significantly reduced RBC-related and antigen sink liabilities [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 4257.