An affinity threshold for maximum efficacy in anti-PD-1 immunotherapy

• Main Authors: Sarah C. Cowles (Author), Allison Sheen (Author), Luciano Santollani (Author), Emi A. Lutz (Author), Brianna M. Lax (Author), Joseph R. Palmeri (Author), Gordon J. Freeman (Author), K. Dane Wittrup (Author)
• Format: Book
• Published: Taylor & Francis Group, 2022-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.1080/19420862.2022.2088454; 1942-0870; 1942-0862
• Keywords: PD-1; antibody; affinity; pharmacokinetic modeling; cancer immunotherapy; Therapeutics. Pharmacology; RM1-950; Immunologic diseases. Allergy; RC581-607
• Source: mAbs, Vol 14, Iss 1 (2022)

Monoclonal antibodies targeting the programmed cell death protein 1 (PD-1) remain the most prevalent cancer immunotherapy both as a monotherapy and in combination with additional therapies. Despite the extensive success of anti-PD-1 monoclonal antibodies in the clinic, the experimental relationship between binding affinity and functional potency for anti-PD-1 antibodies in vivo has not been reported. Anti-PD-1 antibodies with higher and lower affinity than nivolumab or pembrolizumab are entering the clinic and show varied preclinical efficacy. Here, we explore the role of broad-ranging affinity variation within a single lineage in a syngeneic immunocompetent mouse model. By developing a panel of murine anti-PD-1 antibodies with varying affinity (ranging from KD = 20 pM - 15 nM), we find that there is a threshold affinity required for maximum efficacy at a given dose in the treatment of the MC38 adenocarcinoma model with anti-PD-1 immunotherapy. Physiologically based pharmacokinetic modeling complements interpretation of the experimental results and highlights the direct relationship between dose, affinity, and PD-1 target saturation in the tumor.