Abstract 4121: Preclinical characterization of CS1003, a novel clinical-stage PD-1 monoclonal antibody
Authors: Li Fu , Li Jingrong , Yin Ke , Zhang Juan , Li Zhenhu , Lu Liang , Bao Yuanwu , Pu Dan , Qin Zhen , Zheng Yong , Yang Baotian , Li Jing , Wang Xinzhong Jon 
Published: August 2019

Abstract
Background: The programmed cell death protein 1 receptor (PD-1) is an immune-checkpoint protein that negatively regulates the immune system to avoid collateral damage to self-tissues. Tumors hijack this mechanism as a way to avoid immune detection and destruction. Presently, the FDA has approved three anti-PD-1 antibodies for the treatment in more than ten cancer types. CS1003 is a novel anti-PD-1 mAb recognizing a unique epitope developed to disrupt the PD-1 interaction with PD-L1/PD-L2 to restore or improve T-cell function as stand-alone therapy or in combination with other approaches.
Methods: A panel of rat PD-1 mAbs were generated through conventional hybridoma technology. Several mAbs with favorable characteristics were further humanized. CS1003, a humanized, hinge-stabilized IgG4 mAb, was selected as our lead candidate for further characterization including antigen binding, biophysical properties as well as functional characterization.
Results: CS1003 binds mouse, cynomolgus monkey and human PD-1 with similar affinity. CS1003 bound PD-1-expressing cell lines and chronically-activated T cells, blocked PD-1 interactions with PD-L1/PD-L2, resulting in inhibition of PD-1 signaling, and enhanced T cell cytokine secretion and proliferation to levels comparable to those observed with nivolumab or pembrolizumab reference molecules. CS1003 showed significantly anti-tumor activity in conventional MC38 as well as in hPD-1 knock-in mice. CS1003 showed no unexpected cross-reactivity in human tissues, with specific staining observed primarily in lymphocytes of lymphoid organs. In a pharmacokinetic (PK) study in cynomolgus monkeys following single intravenous administration at multiple dose levels, PK properties were linear with the proportionally increasing exposures from 2-18 mg/kg. In a repeated-dose toxicity study, CS1003 was well tolerated in cynomolgus monkeys and the major finding was mononuclear infiltration in multiple organs, which was consistent with its pharmacologic activity. CS1003 demonstrated a favorable safety profile with the highest non-severely toxic dose (HNSTD) of 100 mg/kg.
Conclusion: CS1003 is a novel anti-PD-1 mAb with favorable preclinical characteristics and safety profile in cynomolgus monkeys. The unique feature of CS1003 is its cross-reactivity with both human and murine PD-1. This should greatly facilitate further evaluation its potential for combination therapy in various syngeneic mouse tumor models. A phase I study for CS1003 is being conducted to evaluate the safety, tolerability, PK and anti-tumor activity in patients with advanced tumors [NCT03475251].
Citation Format: Fu Li, Jingrong Li, Ke Yin, Juan Zhang, Zhenhu Li, Liang Lu, Yuanwu Bao, Dan Pu, Zhen Qin, Yong Zheng, Baotian Yang, Jing Li, Xinzhong Jon Wang. Preclinical characterization of CS1003, a novel clinical-stage PD-1 monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4121.