An affinity threshold for maximum efficacy in anti-PD-1 immunotherapy
Author(s)
Cowles, Sarah C.
Sheen, Allison
Santollani, Luciano
Lutz, Emi A.
Lax, Brianna M.
Palmeri, Joseph R.
Freeman, Gordon J.
Wittrup, K. Dane
Date Issued
August 4, 2022
Journal
mAbs
Publisher
Taylor & Francis
Citation
Cowles, Sarah C., Sheen, Allison, Santollani, Luciano, Lutz, Emi A., Lax, Brianna M. et al. 2022. "An affinity threshold for maximum efficacy in anti-PD-1 immunotherapy." mAbs, 14 (1).
Version
Author's final manuscript
Abstract
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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1080/19420862.2022.2088454
