Abstract 6345: Non-clinical pharmacology of HX009, a novel FIC PD1xCD47 BsAb
Authors: Zhang Faming , Ke Hang , Peng Feiyu , Chen Cen , Zhang Lei , Li Henry Qixiang 
Published: June 2023

Abstract
Immune checkpoint inhibitors (ICIs) have been widely tested as cancer therapeutics but with respective limitations such as marginal activity and/or poor safety profiles. It is possible that some of these limitations could be overcome by specially engineered molecules, e.g. bi-functional agents. Here we report a novel rationally designed bi-specific antibody (BsAb) targeting both PD1 and CD47, HX009, in order to improve both efficacy and safety over the two respective single-targeting ICIs. HX009 features IgG4 and 2 × 2 symmetric format, but with specifically weakened CD47 binding affinity. We performed a comprehensive preclinical pharmacology characterization of HX009 to test our hypothesis by confirming its candidacy as a novel first-in-class biologic for cancer therapy. The affinity constant (KD) of the HX009 binding to PD1 was determined to 3.96 × 10−11 M, while 5.06 × 10−9 M for binding to CD47, significantly reduced affinity as compared to the binding to PD1 and the binding between native SIRPα and CD47. HX009 has little binding to red blood cell (RBC) and platelets so to minimize hematological toxicity that usually associated with CD47 targeting. The antibody injectable formulation caused little cytokine release from PBMC (CRS or cytokine storm). HX009 cross-species binds to cynomolgus monkey PD1 and CD47 receptors, with the similar affinity as with the counterparts of human, but not to those of rodents. Cynomolgus monkey was thus chosen to investigate non-clinical pharmacokinetic (PK) and toxicology profiles of HX009. The intravenous (IV) infusion PK study revealed that HX009 is largely distributed within vasculature, with terminal half-life (T1/2) around 50hr and dose proportional exposure. Repeat dosing caused no accumulation. The production of antidrug antibody (ADA) were observed in the dosed animals, as expected for administration into different species, which impacted PK parameters of repeated dosing. The IV single dose toxicology study revealed the maximal tolerated dose (MTD) of 150mg/kg with 14-day observation, while the maximum non-severely toxic dose (HNSTD) was determined to be 15 mg/kg in the repeated dose study after once weekly dose for 4 consecutive weeks (5 times total). The main drug related toxicities observed seemed to be related to CD47 targeting as expected. Strong antitumor activity was also confirmed in in several preclinical cancer models, including humanized syngeneic models. In summary, the desired PK and safety profiles of HX009, along with anti-tumor activity, supporting further clinical development. Currently, HX009 is under clinical investigation (ClinicalTrials.gov Identifier: NCT05189093).
Citation Format: Faming Zhang, Hang Ke, Feiyu Peng, Cen Chen, Lei Zhang, Henry Qixiang Li. Non-clinical pharmacology of HX009, a novel FIC PD1xCD47 BsAb [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 6345.