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

• Main Authors: Cowles, Sarah C. (Author), Sheen, Allison (Author), Santollani, Luciano (Author), Lutz, Emi A. (Author), Lax, Brianna M. (Author), Palmeri, Joseph R. (Author), Freeman, Gordon J. (Author), Wittrup, K. Dane (Author)
• Format: Article
• Language: English
• Published: Taylor & Francis, 2022-08-09T14:40:28Z.
• Subjects: Article
• Online Access: Get fulltext

 Monoclonal antibodies targeted to 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 the 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.