Targeting CD137 (4-1BB) towards improved safety and efficacy for cancer immunotherapy

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• T cells are crucial for antitumor immunity, with their activation modulated by inhibitory and costimulatory receptors.
• Current cancer immunotherapies primarily target inhibitory receptors (e.g., CTLA-4, PD-1/L1).
• Developing agonist antibodies for costimulatory receptors (e.g., CD28, CD137/4-1BB) faces challenges due to adverse events.

Purpose of the Study:

• To review anti-CD137 (4-1BB) agonist monoclonal antibodies in clinical development.
• To discuss CD137 biology and its implications for drug discovery.
• To compare strategies for decoupling efficacy from toxicity in CD137-targeted therapies.

Main Methods:

• Analysis of anti-CD137 agonist antibody development, focusing on IgG isotypes.
• Examination of binding epitope selection relative to CD137 ligand (CD137L).
• Evaluation of Fc gamma receptor interactions and conditional activation mechanisms within the tumor microenvironment (TME).

Main Results:

• Different IgG isotypes impact antibody crosslinking and Fc gamma receptor engagement.
• Binding epitope and conditional activation strategies influence therapeutic potential.
• Rational combinations of CD137-targeting agents may enhance antitumor activity.

Conclusions:

• Optimizing anti-CD137 agonist antibodies requires careful consideration of antibody design, including epitope and isotype.
• Strategies to conditionally activate these antibodies in the TME are crucial for safety and efficacy.
• Further research into rational combinations holds promise for improving cancer immunotherapy outcomes.