Trispecific Binding Proteins with Cross-Over Polypeptide Chains
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Solution Overview
Problem
Current monoclonal antibody technologies are limited in their ability to target multiple antigens simultaneously with high specificity and efficacy, particularly in treating complex diseases like cancer and inflammatory disorders, where multispecific binding proteins that can effectively bind multiple targets are needed.
Innovation Solution
Development of trispecific and trivalent binding proteins comprising four polypeptide chains that form three antigen binding sites, with specific configurations of variable domains allowing for cross-over orientations and hinge regions, enabling the proteins to bind one, two, or three antigen targets with high specificity, including cytokines and tumor targets.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If monoclonal antibody technology is used to target multiple antigens, then the ability to treat complex diseases is improved, but the specificity and efficacy in binding multiple targets simultaneously deteriorates
Solution Approach 1:
The binding protein is divided into four separate polypeptide chains (first light chain, first heavy chain, second heavy chain, third heavy chain) that can be independently designed and optimized. Each chain contains specific variable domains (VL1, VL2, VL3, VH1, VH2, VH3) that can be configured to bind different antigens, allowing simultaneous targeting of multiple antigens while maintaining high specificity for each interaction.
Solution Approach 2:
The binding protein is designed with multi-functionality by incorporating three antigen binding sites within a single molecular structure. The first binding site (VL1-VH1) can target one antigen, the second binding site (VL2-VH2) can target a second antigen, and the third binding site (VL3-VH3) can target a third antigen, enabling the protein to perform multiple therapeutic functions simultaneously.
2Adaptability or versatility
If binding proteins are designed with complex polypeptide chain configurations to bind multiple antigens, then the versatility is improved, but the structural complexity increases
Solution Approach 1:
The patent merges multiple antibody chains into a single binding protein complex. The first light chain (with VL1-L1-VL2-L2-CL structure) is combined with three heavy chains (VH1-L3-VH2-L4-CH1-hinge-CH2-CH3, VH3-CH1-hinge-CH2-CH3, and VL3-CL) to form a unified structure that binds multiple antigens, reducing the need for separate therapeutic agents.
Solution Approach 2:
The binding protein utilizes cross-over orientations between light and heavy chains, where the first light chain pairs with multiple heavy chains in a non-conventional configuration. This dimensional reorganization of polypeptide chain associations enables multiple binding sites while managing structural complexity through novel spatial arrangements.
Data Source
Figure 1A~1B
Figure 1C
Figure 2
AI summary
The disclosure provides trispecific and/or trivalent binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more target proteins, wherein a first pair of polypeptides forming the binding protein possess dual variable domains having a cross-over orientation and wherein a second pair of polypeptides forming the binding protein possess a single variable domain. The disclosure also provides methods for making trispecific and/or trivalent binding proteins and uses of such binding proteins.