Alpha-4-Beta-7 Antibody Hinge Mutations for Reduced Immunogenicity
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Solution Overview
Problem
Current therapeutic agents targeting the alpha4beta7/MAdCAM-1 pathway, such as vedolizumab, face challenges including neutralizing anti-humanized antibody responses and adverse effects like progressive multifocal leukoencephalopathy, necessitating a safer alternative to disrupt this pathway effectively.
Innovation Solution
Development of an alpha4beta7 heterodimer-specific antigen binding protein, including monoclonal antibodies and their fragments, with specific mutations in the hinge region to prevent intra-chain disulfide bonding, which are designed to bind to human alpha4beta7 and non-human primate species, inhibiting the interaction with MAdCAM-1 and reducing alpha4beta7-mediated trafficking.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If humanized antibodies (vedolizumab) are used to target alpha4beta7/MAdCAM-1 pathway, then therapeutic efficacy is improved, but neutralizing anti-humanized antibody responses and adverse effects occur
Solution Approach 1:
The patent introduces specific mutations in the hinge region of the antibody (e.g., replacing cysteine residues with serine or alanine) to alter the structural and functional parameters of the antibody molecule. These parameter changes eliminate intra-chain disulfide bonding while preserving antigen binding capability, thereby resolving the contradiction between therapeutic efficacy and immunogenicity
Solution Approach 2:
The patent creates a modified copy of the humanized antibody by introducing specific hinge region mutations. This copied antibody structure maintains the antigen-binding properties (therapeutic efficacy) while modifying the hinge region to prevent disulfide bond formation, thereby reducing immunogenicity and adverse effects
2Reliability
If alpha4beta7-specific antibodies are used to disrupt the alpha4beta7/MAdCAM-1 pathway, then binding inhibition is improved, but cell-surface alpha4beta7 down-regulation occurs
Solution Approach 1:
The patent applies local quality modification by specifically altering the hinge region of the antibody while leaving the antigen-binding regions intact. This localized change allows the antibody to maintain strong binding inhibition capability while preventing unwanted effects on cell-surface alpha4beta7 stability through modified hinge region properties
3Stability of the object's composition
If conventional antibodies with intact hinge regions are used, then structural stability is maintained, but intra-chain disulfide bonding occurs causing immunogenicity
Solution Approach 1:
The patent extracts the problematic hinge region sequence responsible for intra-chain disulfide bonding and replaces it with modified sequences lacking cysteine residues. This extraction of the harmful element (disulfide-bonding capability) while retaining the overall antibody structure resolves the contradiction between structural stability and immunogenicity
Data Source
AI summary
There are disclosed alpha4beta7 heterodimer-specific antigen binding proteins, nucleic acids encoding them, and methods of making and using them.