CD3 Antibodies Tuning CDR Affinity to Reduce Toxicity
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Solution Overview
Problem
CD3-based bispecific antibodies for cancer treatment face toxicity issues due to non-specific T-cell activation and cytokine release, limiting their therapeutic application.
Innovation Solution
Development of a family of antibodies with specific CDR sequences that bind to CD3 with tunable affinities, reducing toxicity by minimizing cytokine release while maintaining effective tumor cell lysis, and bispecific antibodies targeting CD3 and tumor-associated antigens or checkpoint proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CD3-based bisspecific antibodies are used to activate T cells for tumor cell lysis, then tumor cell killing efficacy is improved, but non-specific T-cell activation and cytokine release cause high toxicity
Solution Approach 1:
The patent applies local quality by designing antibodies with specific CDR sequences (CDR1, CDR2, CDR3) that confer selective binding properties. The CDR3 sequence in particular is engineered to recognize specific epitopes on CD3 that minimize off-target binding while maintaining strong tumor cell lysis activity, thereby reducing non-specific T-cell activation and associated toxicity
Solution Approach 2:
The patent employs parameter changes by systematically varying the CDR sequences, particularly CDR3, to optimize binding affinity and specificity. By adjusting amino acid compositions in the CDR regions, the antibody family achieves different binding characteristics that balance effective tumor cell engagement with reduced non-specific activation and cytokine release
2Reliability
If high affinity binding to CD3 is achieved to enhance T cell activation, then tumor cell lysis is improved, but cytokine release syndrome increases causing treatment limitations
Solution Approach 1:
The patent applies parameter changes by creating a family of antibodies with varying CDR sequences that produce different binding affinities for CD3. This allows selection of antibodies with optimal affinity ranges that achieve effective T cell activation and tumor cell lysis while avoiding excessive cytokine release that would cause treatment-limiting toxicity
Solution Approach 2:
The patent employs partial action by designing antibodies with moderate rather than maximal binding affinity to CD3. The CDR sequences are engineered to provide sufficient activation for therapeutic effect without excessive binding that would trigger severe cytokine release syndrome, achieving the optimal balance through controlled partial activation
3Productivity
If antibody affinity for CD3 is increased to improve therapeutic effect, then tumor cell killing is enhanced, but the range of safely applicable doses is reduced
Solution Approach 1:
The patent applies parameter changes by generating an antibody family with CDR sequences that produce a gradient of binding affinities. This enables clinicians to select antibodies with appropriate affinity levels and adjust dosing accordingly, providing flexibility in dose selection while maintaining therapeutic effectiveness across different patient responses
Data Source
AI summary
The present invention relates to novel human CD3 antigen-binding polypeptides and their preparation and use in the treatment and/or diagnosis of various diseases, and also relates to bispecific antibody molecules capable of activating immune effector cells and their use in diagnosis and/or treatment of various diseases.