Deimmunized Anti-Human CD40 Monoclonal Antibody
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Solution Overview
Problem
Current anti-CD40 monoclonal antibodies, such as 5D12, have immunogenicity issues and limited half-life in humans, leading to potential side effects and reduced efficacy in treating inflammatory disorders like Crohn's disease.
Innovation Solution
Development of deimmunized variants of the heavy and light chain variable domains of the 5D12 antibody, with specific amino acid modifications to reduce immunogenicity and enhance half-life, while maintaining binding properties, using a polypeptide sequence that can be incorporated into antibodies with improved production and immunological properties in humans.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If murine 5D12 antibody is used, then binding activity to CD40 is achieved, but immunogenicity increases and half-life decreases in humans
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid residues in the variable domains of the antibody at positions 29-37 of the heavy chain and corresponding positions in the light chain. These point mutations alter the immunogenicity parameters while preserving the binding activity to CD40, thereby reducing harmful immune reactions without sacrificing therapeutic efficacy.
Solution Approach 2:
The patent creates humanized copies of the murine 5D12 antibody by transferring the variable domain sequences to a human antibody framework. This copying process retains the original binding specificity while replacing immunogenic murine sequences with human sequences, reducing immunogenicity while maintaining therapeutic function.
2Reliability
If murine 5D12 antibody is used, then binding activity to CD40 is achieved, but half-life is limited in humans
Solution Approach 1:
The patent modifies the antibody structure by introducing humanized variable domains with specific amino acid changes that optimize pharmacokinetic parameters. These changes enhance the antibody's half-life in humans while preserving CD40 binding activity, allowing for extended duration of action and reduced dosing frequency.
3Object-affected harmful factors
If deimmunized variants are developed, then immunogenicity is reduced, but manufacturing complexity increases
Solution Approach 1:
The patent segments the antibody into distinct functional regions: the variable domains (heavy and light chains) that require deimmunization modifications, and the constant regions that can be produced using standard human antibody manufacturing protocols. This segmentation allows targeted modification of only the necessary portions while maintaining overall manufacturing feasibility.
Solution Approach 2:
The patent implements specific amino acid substitutions at defined positions in the variable domains, transforming the antibody sequence parameters to reduce immunogenicity. These controlled parameter changes are incorporated into existing manufacturing workflows, balancing reduced immunogenicity with manageable manufacturing complexity.
Data Source
AI summary
The present invention provides novel antagonistic anti-human CD40 monoclonal antibodies, methods for generating them and uses thereof.