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Related Experiment Video

Updated: Sep 2, 2025

Monitoring PD-1-Blocking Antibodies Bound to T Cells Derived from a Drop of Peripheral Blood

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Published on: February 5, 2020

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

Sarah C Cowles^1,2, Allison Sheen^1,3, Luciano Santollani^1,2

¹Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

|August 4, 2022

Summary

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.

Keywords:

PD-1 affinity antibody cancer immunotherapy pharmacokinetic modeling

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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.