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Published on: February 5, 2020
An affinity threshold for maximum efficacy in anti-PD-1 immunotherapy
Sarah C Cowles1,2, Allison Sheen1,3, Luciano Santollani1,2
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Abstract:
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.
Insights
Higher binding affinity is crucial for effective anti-programmed cell death protein 1 (PD-1) cancer immunotherapy. A minimum threshold affinity is required for maximum efficacy, demonstrating a link between dose, affinity, and target saturation.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Monoclonal antibodies targeting programmed cell death protein 1 (PD-1) are key cancer immunotherapies.
- The relationship between anti-PD-1 antibody binding affinity and in vivo functional potency is not well-established.
- New anti-PD-1 antibodies with varying affinities are emerging, necessitating research into their efficacy.
Purpose of the Study:
- To investigate the impact of varying binding affinities on the in vivo efficacy of anti-PD-1 antibodies.
- To determine if a threshold affinity exists for optimal anti-PD-1 immunotherapy response.
- To explore the interplay between antibody affinity, dose, and target engagement.
Main Methods:
- Development of a panel of murine anti-PD-1 antibodies with a wide range of affinities (20 pM to 15 nM).
- Evaluation of antibody efficacy in a syngeneic immunocompetent mouse model (MC38 adenocarcinoma).
- Utilizing physiologically based pharmacokinetic modeling to analyze dose, affinity, and target saturation.
Main Results:
- A threshold binding affinity was identified as necessary for achieving maximum therapeutic efficacy at a given dose.
- Antibodies with affinities below this threshold showed reduced efficacy.
- Pharmacokinetic modeling confirmed a direct correlation between dose, affinity, and PD-1 target saturation in the tumor microenvironment.
Conclusions:
- Binding affinity is a critical determinant of functional potency for anti-PD-1 antibodies in vivo.
- Optimizing antibody affinity is essential for maximizing the efficacy of PD-1 targeted cancer immunotherapy.
- Understanding the affinity-efficacy relationship can guide the development of more effective immunotherapies.
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