Multivalent Protein Scaffolds for Bispecific Therapeutic Screening
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Solution Overview
Problem
Existing protein-based therapeutics, particularly antibodies, face challenges such as high production costs, complex post-translational modifications, poor tumor targeting, large size leading to slow diffusion, and immunogenicity, limiting their scalability and effectiveness in treating diseases like cancer.
Innovation Solution
Development of multivalent protein scaffolds with customizable, reproducible, and adaptable constructs that allow for multiple binding geometries and functionalities, using engineered polypeptides with modified N and C termini to form bispecific binding constructs, which can be recombinantly produced or chemically conjugated, and assembled into oligomeric proteins for therapeutic, diagnostic, or analytical applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional antibody therapeutics are used, then high clinical success and therapeutic efficacy are achieved, but high production costs and complex post-translational modifications occur
Solution Approach 1:
The antibody molecule is segmented into distinct functional domains: variable regions (Fv) for antigen binding and constant regions (Fc) for effector functions. This segmentation allows independent optimization and production of binding fragments (scFv, Fab) without requiring complex Fc glycosylation, thereby reducing manufacturing complexity while maintaining therapeutic efficacy
Solution Approach 2:
The Fc portion is extracted from the complete antibody structure to create Fc-free antigen-binding fragments. This extraction eliminates the need for complex post-translational modifications associated with Fc glycosylation, significantly simplifying production processes and reducing costs while preserving antigen-binding functionality
2Reliability
If traditional antibody therapeutics are used, then therapeutic activity is achieved, but poor tumor targeting and slow diffusion occur due to large size
Solution Approach 1:
The large Fc portion is removed to create compact antigen-binding fragments (scFv, Fab) with molecular weights of 25-50 kDa compared to 150 kDa for full antibodies. This size reduction enables faster diffusion and penetration into tumor tissues while maintaining therapeutic activity through preserved variable region functionality
Solution Approach 2:
The patent employs flexible linkers (e.g., (GGGGS)n) that provide dynamic conformational freedom to the antigen-binding fragments. This flexibility allows the small fragments to adapt their orientation and access epitopes effectively, compensating for their reduced size and maintaining therapeutic activity despite faster diffusion
3Reliability
If traditional antibody therapeutics are used, then immunoglobulin-based treatment is provided, but immunogenicity and detrimental immune reactions occur
Solution Approach 1:
The immunogenic Fc portion is extracted to create Fc-free fragments that eliminate Fc-receptor activation and complement-dependent cytotoxicity. This extraction reduces immunogenicity and detrimental immune reactions while preserving antigen-specific therapeutic coverage through the variable regions
Solution Approach 2:
The patent creates simplified copies of the antigen-binding functionality using non-immunogenic scaffolds (nanobodies, DARPins, monobodies) that replicate the paratope function without the immunogenic constant regions. These copies maintain therapeutic coverage while avoiding immune system recognition and adverse reactions
4Adaptability or versatility
If bisspecific antibodies are used, then multiple antigen targeting is achieved, but lack of modularity and limited scalability occur
Solution Approach 1:
The patent creates universal scaffolds (nanobodies, DARPins, monobodies) that can be configured in various valencies and specificities. A single scaffold type can be adapted to bind multiple different antigens through combinatorial pairing of variable regions, providing universal multi-antigen targeting capability without requiring complex structural redesign
Solution Approach 2:
Bispecific functionality is achieved through segmentation into independent modular domains that can be independently selected and assembled. Different variable regions can be paired with compatible scaffolds to create bispecific constructs, enabling flexible combination of antigen specificities without increasing overall structural complexity
Data Source
AI summary
Provided herein are multivalent protein scaffolds useful as therapeutics, and useful in identifying new therapeutic compounds. The invention also relates to multi-domain polypeptide constructs having multiple binding domains and a structural domain. Also provided herein are methods of using the provided multivalent protein scaffolds to identify new candidate therapeutics, and new therapeutics thereby identified.