Triplex Scaffold Polypeptides for High-Affinity Binding
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Solution Overview
Problem
Current protein-based binding reagents, such as monoclonal antibodies, face challenges with low affinity and high mitogenic effects, which limit their therapeutic efficacy and stability, especially when targeting multiple antigens or requiring reduced immune activation.
Innovation Solution
Development of trimeric protein complexes comprising triple helix coil scaffold domains fused with heterologous binding domains, allowing for high affinity, low mitogenic effect, and multivalent or multi-specific binding capabilities, enhancing stability and therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional monoclonal antibodies are used for binding to antigens, then they can provide immunosuppressive or therapeutic effects, but they exhibit high mitogenic effects causing adverse side effects and limited therapeutic efficacy
Solution Approach 1:
The patent extracts and removes the Fc region from the antibody structure, retaining only the antigen-binding Fab regions. This extraction eliminates the mitogenic effects associated with Fc region interactions while preserving the therapeutic antigen-binding capability. The resulting F(ab')2 or single-chain antibody fragments provide therapeutic efficacy without the harmful mitogenic side effects of conventional IgG antibodies.
Solution Approach 2:
The patent introduces triplex scaffolds as intermediary structures that replace the Fc region's function of mediating effector activities. These scaffolds serve as structural intermediaries that maintain antibody stability and solubility while preventing unwanted Fc-mediated mitogenic interactions. The triplex scaffold acts as a neutral intermediary that supports the binding domains without triggering harmful immune responses.
2Object-affected harmful factors
If humanization of murine mAbs is performed using CDR grafting, then immunogenicity is reduced, but binding affinity decreases compared to murine counterparts
Solution Approach 1:
The patent segments the antibody into separate functional modules: the antigen-binding CDR regions are isolated and grafted onto human framework regions, while the Fc region is completely removed. This segmentation allows independent optimization of each module - the CDRs retain their high-affinity binding characteristics from murine antibodies, while the human framework reduces immunogenicity, and the removed Fc eliminates mitogenic effects.
Solution Approach 2:
The patent applies local quality by preserving the murine CDR regions with their high-affinity binding properties while replacing only the immunogenic framework regions with human sequences. The critical antigen-binding local regions maintain their original high-affinity characteristics, while the non-critical framework regions are humanized to reduce immunogenicity without affecting binding affinity.
3Reliability
If multimerization of antigen binding sites is implemented, then overall binding strength (avidity) increases, but the complexity of antibody structure and engineering increases
Solution Approach 1:
The patent merges multiple antigen-binding sites into a single polypeptide chain or complex through systematic design. By combining two Fab regions to form F(ab')2 or by designing single-chain antibodies with multiple CDRs, the patent achieves multivalent binding (increased avidity) while maintaining relatively simple structural organization based on well-understood antibody frameworks, thus balancing enhanced binding strength with manageable structural complexity.
Solution Approach 2:
The patent creates universal modular antibody fragments that can be configured in multiple valencies (monovalent, bivalent, multivalent) using the same basic F(ab')2 or single-chain architecture. This universal design allows the same structural framework to provide different binding strengths and specificities by simply varying the number and arrangement of CDR regions, reducing the complexity increase that would otherwise accompany multimerization.
4Adaptability or versatility
If conventional IgG antibodies are used, then they provide bivalent binding capability, but they cannot bind to more than two different antigens simultaneously
Solution Approach 1:
The patent designs universal polypeptide platforms that can incorporate multiple different antigen-binding CDR regions within a single molecule. These multi-specific antibodies can simultaneously bind to multiple different antigens (e.g., CD3 and tumor-associated antigens), providing versatile therapeutic functionality. This multi-functionality allows a single dosage to achieve multiple therapeutic effects, reducing the need for combination therapies and associated dosing complexity.
Data Source
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AI summary
Disclose is a protein complex that includes triple-helix-coil forming fusion polypeptide chains, each having a scaffold domain and a heterologous domain. Also disclosed are related isolated fusion polypeptide, nucleic acids, vectors, host cells, and preparation methods.