Reducing affinity as a strategy to boost immunomodulatory antibody agonism

Area of Science:

• Immunology
• Molecular Biology
• Therapeutic Antibody Development

Background:

• Antibody affinity maturation aims for high-affinity binding for pathogen neutralization and therapeutic efficacy.
• The relationship between antibody affinity and function for immunomodulatory antibodies targeting receptor signaling remains underexplored.

Purpose of the Study:

• To investigate the affinity-function relationship of immunomodulatory antibodies targeting CD40, 4-1BB, and PD-1 receptors.
• To determine if lower antibody affinity can enhance receptor signaling and immune cell activation.

Main Methods:

• Examined antibody binding affinity and functional activity across three key immune receptors: CD40, 4-1BB, and PD-1.
• Engineered low-affinity variants of monoclonal antibodies, including nivolumab (anti-PD-1).
• Assessed immune cell activation, T cell expansion, and anti-tumor activity in preclinical models.

Main Results:

• Low antibody affinity, rather than high affinity, resulted in greater activity through enhanced receptor clustering.
• Low-affinity CD40 antibodies increased immune cell activation, T cell expansion, and anti-tumor efficacy.
• An inert anti-4-1BB antibody was converted to an agonist through affinity modification.
• Low-affinity variants of anti-PD-1 (nivolumab) showed enhanced signaling and T cell activation.

Conclusions:

• Antibody affinity can be engineered to optimize immunomodulatory antibody function, with lower affinity enhancing agonism.
• This approach provides a tunable strategy for developing potent antibody therapies across various receptor families.
• Findings offer a new paradigm for antibody-mediated receptor signaling and therapeutic development.