2. Academic Validation
  3. Optimal target saturation of ligand-blocking anti-GITR antibody IBI37G5 dictates FcγR-independent GITR agonism and antitumor activity

Optimal target saturation of ligand-blocking anti-GITR antibody IBI37G5 dictates FcγR-independent GITR agonism and antitumor activity

  • Cell Rep Med. 2022 Jun 21;3(6):100660. doi: 10.1016/j.xcrm.2022.100660.
Huisi Liu 1,  Weiwei Wu 2,  Gangyu Sun 3,  Tiongsun Chia 1,  Lei Cao 2,  Xiaodan Liu 1,  Jian Guan 1,  Fenggen Fu 4,  Ying Yao 2,  Zhihai Wu 4,  Shuaixiang Zhou 4,  Jie Wang 2,  Jia Lu 2,  Zhihui Kuang 2,  Min Wu 2,  Luan He 1,  Zhiyuan Shao 4,  Dongdong Wu 2,  Bingliang Chen 2,  Wenqing Xu 3,  Zhizhi Wang 5,  Kaijie He 6
Affiliations

Affiliations

  • 1 Department of Immunology, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China.
  • 2 Department of Pharmacology and Preclinical Studies, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China.
  • 3 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 4 Department of Antibody Discovery and Protein Engineering, Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China.
  • 5 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. Electronic address: wangzhzh@shanghaitech.edu.cn.
  • 6 Department of Immunology, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China. Electronic address: kaijie.he@innoventbio.com.
PMID: 35732156 DOI: 10.1016/j.xcrm.2022.100660
Abstract

Glucocorticoid-induced tumor necrosis factor receptor (GITR) is a co-stimulatory receptor and an important target for Cancer Immunotherapy. We herein present a potent FcγR-independent GITR agonist IBI37G5 that can effectively activate effector T cells and synergize with anti-programmed death 1 (PD1) antibody to eradicate established tumors. IBI37G5 depends on both antibody bivalency and GITR homo-dimerization for efficient receptor cross-linking. Functional analyses reveal bell-shaped dose responses due to the unique 2:2 antibody-receptor stoichiometry required for GITR activation. Antibody self-competition is observed after concentration exceeded that of 100% receptor occupancy (RO), which leads to antibody monovalent binding and loss of activity. Retrospective pharmacokinetics/pharmacodynamics analysis demonstrates that the maximal efficacy is achieved at medium doses with drug exposure near saturating GITR occupancy during the dosing cycle. Finally, we propose an alternative dose-finding strategy that does not rely on the traditional maximal tolerated dose (MTD)-based paradigm but instead on utilizing the RO-function relations as biomarker to guide the clinical translation of GITR and similar co-stimulatory agonists.

Keywords

GITR; agonist antibody; cancer immunotherapy; costimulatory receptor; receptor occupancy.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P991464
    抗TNFRSF18/GITR/CD357单克隆抗体
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