Penpulimab, an Fc-Engineered IgG1 Anti-PD-1 Antibody, With Improved Efficacy and Low Incidence of Immune-Related Adverse Events

• Published in: Frontiers in immunology Vol. 13; p. 924542
• Main Authors: Huang, Zhaoliang, Pang, Xinghua, Zhong, Tingting, Qu, Tailong, Chen, Na, Ma, Shun, He, Xinrong, Xia, Dennis, Wang, Max, Xia, Michelle, Li, Baiyong
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 27.06.2022
• Subjects: Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; binding kinetics; Clinical Trials as Topic; Cytokines; Fc engineering; Humans; IgG1 anti-PD-1 antibody; immune-related adverse events; Immunoglobulin G; Immunology; Incidence; penpulimab; penpulimab; binding kinetics; Fc engineering; immune-related adverse events; IgG1 anti-PD-1 antibody
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.924542

IgG4 anbibodies are deficient in stability and may contribute to tumor-associated escape from immune surveillance. We developed an IgG1 backbone anti-programmed cell death protein-1 (PD-1) antibody, penpulimab, which is designed to remove crystallizable fragment (Fc) gamma receptor (FcγR) binding that mediates antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and proinflammatory cytokine release. Aggregation of different anti-PD-1 antibodies was tested by size exclusion chromatography, and melting temperature midpoint (Tm) and aggregation temperature onset (Tagg) were also determined. The affinity constants of penpulimab for PD-1 and human FcγRs were measured by surface plasmon resonance and biolayer interferometry. ADCC and ADCP were determined in cellular assays and antibody-dependent cytokine release (ADCR) from human macrophages was detected by ELISA. Binding kinetics of penpulimab to human PD-1 was determined by Biacore, and epitope/paratope mapping of PD-1/penpulimab was investigated using x-ray crystallography. Additionally, patients from six ongoing trials were included for analysis of immune-related adverse events (irAEs). Penpulimab demonstrated better stability and a lower level of host-cell protein residue compared with IgG4 backbone anti-PD-1 antibodies. As expected, penpulimab exhibited no apparent binding to FcγRIa, FcγRIIa_H131, FcγRIIIa_V158 and FcγRIIIa_F158, elicited no apparent ADCC and ADCP activities, and induced no remarkable IL-6 and IL-8 release by activated macrophages . Penpulimab was shown in the co-crystal study to bind to human PD-1 -glycosylation site at N58 and had a slower off-rate from PD-1 nivolumab or pembrolizumab. Four hundred sixty-five patients were analyzed for irAEs. Fifteen (3.2%) patients had grade 3 or above irAEs. No death from irAEs was reported. IgG1 backbone anti-PD1 antibody penpulimab has a good stability and reduced host cell protein residue, as well as potent binding to the antigen. Fc engineering has eliminated Fc-mediated effector functions of penpulimab including ADCC, ADCP and reduced ADCR, which may contribute to its more favorable safety profile. www.ClinicalTrials.gov, identifier: AK105-101: NCT03352531, AK105-201: NCT03722147, AK105-301: NCT03866980, AK105-202:NCT03866967, AK105-203: NCT04172571, AK105-204: NCT04172506.