CD137 Antibody Affinity Tuning to Limit Hepatotoxicity
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Solution Overview
Problem
The effectiveness of combining cancer therapies, particularly those targeting CD137 and PD-1 pathways, is unpredictable, and existing CD137 agonists often cause toxicities such as hepatotoxicity, limiting their therapeutic potential.
Innovation Solution
A novel combination therapy involving the blockade of the PD-1/PD-L1/PD-L2 signaling pathway with agonism of CD137 using specific anti-CD137 monoclonal antibodies that bind a unique epitope on human CD137 with optimal affinity, administered sequentially to enhance cytokine production and anti-tumor immunity while minimizing toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing CD137 agonists are used to enhance anti-tumor immunity, then tumor regression is improved, but hepatotoxicity increases
Solution Approach 1:
The patent modifies the affinity parameter of anti-CD137 antibodies, selecting antibodies with optimal affinity ranges that maximize tumor regression while minimizing hepatotoxicity. This parameter optimization resolves the contradiction between efficacy and safety by fine-tuning the binding strength to achieve therapeutic effect without excessive immune activation in the liver
Solution Approach 2:
The patent introduces sequential combination therapy where anti-CD137 antibodies are administered first to prepare the immune system, followed by anti-PD-1 antibodies. This intermediary approach allows the CD137 agonist to prime immune cells before the PD-1 antagonist is introduced, achieving synergistic anti-tumor effects while potentially reducing the dose and toxicity of individual agents
2Reliability
If combination therapy with CD137 agonists and PD-1 antagonists is used to enhance anti-tumor immunity, then synergistic effects are improved, but treatment complexity increases
Solution Approach 1:
The patent implements sequential administration where anti-CD137 antibodies are given first to activate and prime T cells and other immune cells, creating a pre-conditioned immune state. Subsequently, anti-PD-1 antibodies are administered to release the brakes on the already-activated immune cells. This preliminary action approach simplifies the overall treatment strategy by establishing a logical sequence that builds upon itself, making the combination therapy more manageable despite its dual-agent complexity
3Quantity of substance
If high affinity anti-CD137 antibodies are used to maximize immune activation, then cytokine production is improved, but toxicity increases
Solution Approach 1:
The patent systematically evaluates and selects anti-CD137 antibodies with optimal affinity parameters, avoiding both too-low affinity (insufficient immune activation) and too-high affinity (excessive immune activation and toxicity). The selected antibodies fall within a specific affinity range that maximizes cytokine production and T cell activation while maintaining safety margins, directly resolving the contradiction between quantity of immune response and toxicity
Data Source
AI summary
The present disclosure relates to combinations of antibodies, or antigen-binding fragments thereof, that bind to CD137, and PD-1 antagonists. The disclosure also relates to methods for treating or ameliorating one or more symptoms of a disease, such as cancer, by administering the combination.