D-Domain Polypeptide Scaffolds for Affinity and Manufacturability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for new target-binding compositions with alternative scaffolds that offer reduced production costs and comparable or superior reagent, diagnostic, and therapeutic properties compared to antibodies, while minimizing off-target effects.
Innovation Solution
Development of D Domain (DD) polypeptides based on non-antibody structural scaffolds that specifically bind targets such as BCMA, CD123, CS1, HER2, AFP, and AFP p26, which can be used as therapeutics or diagnostics, and are characterized by high target binding affinity and specificity, including monovalent, multivalent, monospecific, and multispecific configurations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If disulfide bonds are introduced to constrain peptide structure for higher affinity and specificity, then binding affinity and specificity are improved, but improper cysteine pairing occurs leading to lower expression and product quality
Solution Approach 1:
The patent extracts the disulfide bond constraint from the binding domain structure and replaces it with a reduced cysteine content design. The binding affinity and specificity are maintained through optimized amino acid sequences without requiring disulfide bonds, thereby eliminating the cysteine pairing problem while preserving the favorable thermodynamics of fixed-shape complementarity
Solution Approach 2:
The patent changes the structural parameter of cysteine content in the binding domain from high (requiring disulfide bonds) to low (reduced or no disulfide bonds). This parameter change maintains the structural constraint necessary for high affinity through alternative means, avoiding improper cysteine pairing while preserving binding effectiveness
2Productivity
If alternative affinity reagents are developed to reduce cost and improve efficiency, then production cost and productivity are improved, but binding affinity and specificity may be compromised
Solution Approach 1:
The patent optimizes parameters including domain length (15-50 amino acids), cysteine content (reduced to avoid improper pairing), and structural constraints to achieve high binding affinity in a compact format. These parameter optimizations enable cost-effective production through simplified expression systems while maintaining antibody-like or superior binding properties
Solution Approach 2:
The patent creates composite binding domains that combine structural constraint elements with target-specific sequences. The fixed-shape complementarity framework is复合ed with optimized residue presentations to achieve both high affinity and ease of manufacture, representing a composite approach to affinity reagent design
Data Source
AI summary
D domain (DD) containing polypeptides (DDpp) that specifically bind targets of interest (e.g., BCMA, CD123, CS1, HER2, AFP, and AFP p26) are provided, as are nucleic acids encoding the DDpp, vectors containing the nucleic acids and host cells containing the nucleic acids and vectors. DDpp such as DDpp fusion proteins, are also provided as are methods of making and using the DDpp. Such uses include, but are not limited to diagnostic and therapeutic applications.