Multivalent Protein Scaffolds for Scalable Multi-Receptor Targeting
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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 and autoimmune disorders.
Innovation Solution
Development of multivalent protein scaffolds with customizable, reproducible, and adaptable constructs that allow for multiple binding sites on the same face of the scaffold, enabling high-throughput screening and identification of novel therapeutics without an Fc region, using recombinant expression or chemical conjugation to form bispecific or multispecific binding constructs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional antibody therapeutics are used, then therapeutic activity is achieved, but production costs are high and scalability is limited
Solution Approach 1:
The antibody structure is segmented into functional modules: an Fc region for effector functions and multiple independent binding sites for target engagement. This allows the binding sites to be independently optimized and combined in different configurations on a single scaffold, enabling diverse therapeutic activities from a unified platform without requiring de novo design of each therapeutic
Solution Approach 2:
The protein scaffold is designed as a universal platform that can accommodate multiple different binding sites (e.g., antibody fragments, protein domains) that recognize different targets. This multi-functional scaffold can be used to create therapeutics against various diseases by simply changing the binding sites while retaining the same Fc region, thereby reducing production costs and improving scalability
2Reliability
If conventional antibodies are used, then binding to a single receptor type is achieved, but versatility for targeting multiple receptors is limited
Solution Approach 1:
The antibody is divided into separate binding sites that can independently bind to different receptor types. Each binding site is a functional unit that can be independently selected and combined, allowing the same scaffold to target multiple different receptors simultaneously or in different configurations
Solution Approach 2:
The scaffold serves as a universal platform that can display multiple different binding sites, each capable of recognizing different targets. This enables a single therapeutic platform to be adapted for multiple receptor types and disease indications by simply exchanging the binding sites while maintaining the scaffold structure
3Reliability
If antibody-based therapeutics are used, then therapeutic function is provided, but large size causes slow diffusion and poor tumor targeting
Solution Approach 1:
The size parameter of the therapeutic molecule is optimized by using a minimized Fc region structure and compact binding site configurations. By carefully selecting and positioning binding sites on the scaffold, the overall molecular size is reduced while maintaining therapeutic function, thereby improving diffusion rate and tumor penetration
4Reliability
If traditional antibody platforms are used, then therapeutic development is achieved, but complex post-translational modifications limit reproducibility and scalability
Solution Approach 1:
The complex post-translational modification steps are extracted and eliminated from the production process by using a simplified scaffold design that does not require such modifications for stability or function. The therapeutic activity is achieved through the protein scaffold structure and binding site interactions alone, avoiding the need for complex glycosylation or other PTMs that complicate manufacturing and reduce scalability
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.