Penpulimab: A Next-Generation Fc-Engineered PD-1 Inhibitor in Cancer Immunotherapy.

Abstract

Penpulimab (AK105) is a novel Fc-engineered, humanised IgG₁ monoclonal antibody targeting programmed cell death protein-1 (PD-1). Unlike conventional PD-1 inhibitors, penpulimab has been designed to eliminate Fcγ receptor and complement C1q binding, thereby reducing Fc-mediated effector functions while maintaining antitumour immune activity. Preclinical studies have demonstrated enhanced structural stability, prolonged receptor occupancy, and high-affinity binding to PD-1. Clinical investigations across haematological and solid malignancies, including classical Hodgkin lymphoma, nasopharyngeal carcinoma, non-small-cell lung cancer, and hepatocellular carcinoma, have shown promising efficacy with durable responses and improved progression-free survival. Penpulimab has also demonstrated favourable outcomes when combined with chemotherapy and targeted therapies. The safety profile is generally manageable, with hypothyroidism, fatigue, rash, pyrexia, and gastrointestinal toxicities being the most commonly reported adverse events. Emerging evidence suggests that Fc engineering may contribute to reduced immune-related toxicity. Overall, penpulimab offers a promising next-generation PD-1 inhibitor with potential applications across multiple malignancies.