CD137 Antibodies Modulating T-Cell Activation
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Solution Overview
Problem
Current therapeutic anti-human CD137 antibodies have low efficacy and are associated with high toxicities and adverse events due to systemic overstimulation of T-cells.
Innovation Solution
Development of novel CD137 antibodies with improved affinity, efficacy, safety, and biophysical properties, such as enhanced solubility, developability, and stability, which specifically bind to human CD137 without directly inducing CD137 signaling upon binding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapeutic anti-human CD137 antibodies are used, then T-cell stimulation is achieved, but systemic overstimulation occurs leading to high toxicities and adverse events
Solution Approach 1:
The patent applies parameter changes by modifying the antibody structure to alter its binding characteristics. Specifically, the invention uses antibodies with modified CDR sequences that change the binding affinity and specificity parameters, allowing selective binding to activated T-cells while avoiding overstimulation of naive T-cells. This resolves the contradiction by adjusting the interaction parameters between the antibody and CD137 to achieve therapeutic efficacy without excessive toxicity.
Solution Approach 2:
The patent applies local quality by creating antibodies with non-uniform binding properties across different T-cell populations. The modified CDR sequences confer different binding affinities to activated versus naive T-cells, allowing the antibody to selectively target activated cells at the local level. This selective local action achieves tumor-fighting efficacy while sparing naive T-cells from overstimulation, thereby reducing systemic toxicities.
2Productivity
If CD137 signaling is strongly activated to improve anti-tumor efficacy, then T-cell effector functions are enhanced, but systemic overstimulation and liver toxicity increase
Solution Approach 1:
The patent applies partial action by designing antibodies that provide moderate, controlled stimulation rather than maximal activation. The modified CDR sequences enable the antibody to deliver a calibrated level of CD137 signaling that is sufficient to enhance anti-tumor immunity but below the threshold that triggers excessive immune activation and liver toxicity. This partial activation strategy maintains productivity while avoiding harmful overstimulation.
Solution Approach 2:
The patent uses the modified antibody structure as an intermediary that mediates between complete CD137 activation and no activation. The altered CDR sequences create an intermediate binding state that translates into controlled signaling intensity, serving as a buffer that prevents both insufficient anti-tumor activity and excessive toxic effects. This intermediary mechanism allows fine-tuning of the immune response.
3Reliability
If existing anti-CD137 antibodies are used at high doses to overcome low efficacy, then T-cell activation is increased, but adverse events and hepatotoxicity are exacerbated
Solution Approach 1:
The patent applies parameter changes by modifying the antibody's binding affinity parameters through CDR sequence optimization. The improved antibodies achieve higher affinity for activated T-cell CD137, which increases therapeutic efficacy per unit dose. This parameter optimization allows effective treatment at lower dosages, resolving the contradiction between efficacy and dosage quantity.
Data Source
AI summary
The present invention relates to an isolated antibody which specifically binds human CD137, and pharmaceutical compositions and methods of use thereof. The present invention further relates to a nucleic acid comprising a nucleotide sequence encoding said antibody, a vector comprising said nucleic acid, a host cell comprising said nucleic acid or said vector, and a method of producing said antibody.