Chimeric Binding Domains for Novel Epitope Antibody Recognition
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Solution Overview
Problem
Existing humanized transgenic animals and phage display libraries struggle to generate antibodies that recognize novel epitopes on human antigens due to evolutionary similarity with humans, leading to immunologically blind or inefficient antibody responses.
Innovation Solution
Utilize binding domains and antibodies comprising variable regions derived from evolutionarily distant species like chickens, ducks, or ostriches, paired with human variable regions, to generate stable chimeric antibodies that can bind unique epitopes and are cross-reactive across mammalian species.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If humanized transgenic animals and phage display libraries are used to generate antibodies, then the antibodies can be produced for human therapy, but they fail to recognize novel epitopes on human antigens due to evolutionary similarity
Solution Approach 1:
The antibody is segmented into variable regions from evolutionarily distant species (chicken, duck, or ostrich) and constant regions from human. This segmentation allows the variable regions to recognize novel epitopes while the human constant regions ensure proper folding, stability, and reduced immunogenicity in human therapy
Solution Approach 2:
Evolutionarily distant bird species serve as intermediaries between completely non-human antibodies and human antibodies. These bird species are sufficiently distant from humans to recognize novel epitopes but can still be engineered to produce antibodies with human constant regions, bridging the gap between novel epitope recognition and human therapeutic compatibility
2Adaptability or versatility
If variable regions from evolutionarily distant species are used, then unique epitopes can be bound, but stability and proper folding of the antibody may be compromised
Solution Approach 1:
Different parts of the antibody have different origins optimized for their specific functions: variable regions from bird species provide diverse epitope binding capabilities, while human constant regions provide structural stability, proper folding, and appropriate half-life in human circulation
Solution Approach 2:
The antibody is constructed as a composite molecule with variable regions from evolutionarily distant bird species and constant regions from human. This composite structure combines the epitope-binding diversity of bird antibodies with the structural stability and therapeutic compatibility of human antibodies
3Object-affected harmful factors
If completely human antibodies are used, then immunogenicity is reduced, but the ability to recognize diverse epitopes is limited
Solution Approach 1:
The phylogenetic distance parameter is optimized by selecting bird species that are sufficiently distant from humans to provide epitope diversity but can still be engineered to produce antibodies with human constant regions. This parameter change balances immunogenicity reduction with epitope recognition diversity
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The approach allows for the production of stable, cross-reactive chimeric antibodies that can bind diverse antigens, including those not identified by human-derived antibodies, through the use of structural homology and electrostatic interactions between bird and human variable regions, facilitating the generation of bispecific and multispecific antibodies.
Implementation Method 1
through the use of structural homology and electrostatic interactions between bird and human variable regions
Data Source
AI summary
A binding domain or a multimer or a variant thereof which comprises a variable region encoded by a nucleic acid based on, derived or obtained from an animal phylogenetically distal from a human, which variable region is paired with a human variable region.