Fibronectin Scaffold Proteins Reducing Immunogenicity
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Solution Overview
Problem
Protein pharmaceuticals often exhibit immunogenicity, leading to reduced efficacy and potential harmful immune responses due to their inherent ability to trigger an immune reaction in patients.
Innovation Solution
Development of fibronectin-based scaffold polypeptides with novel combinations of modified loops and scaffold regions, specifically the β-strands and loops of the human fibronectin type 3 tenth (10Fn3) domain, to enhance target binding while reducing immunogenicity by modifying amino acid sequences and maintaining structural stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If protein pharmaceuticals are used for therapeutic purposes, then therapeutic efficacy is achieved, but immunogenicity increases leading to harmful immune responses
Solution Approach 1:
The patent creates fibronectin-based scaffold proteins that copy the essential binding functions of natural proteins but with modified sequences. These scaffold proteins replicate the target-binding capabilities while using human-derived sequences to reduce immunogenicity, effectively creating a safer alternative copy of therapeutic proteins
Solution Approach 2:
The patent systematically modifies amino acid sequences of fibronectin type III domains by changing specific parameters such as loop region compositions, charge distributions, and hydrophobicity patterns. These parameter changes maintain structural stability and target binding while reducing immunogenic epitopes, thereby resolving the contradiction between efficacy and safety
2Object-affected harmful factors
If amino acid sequences are modified to reduce immunogenicity, then safety is improved, but target binding affinity may be compromised
Solution Approach 1:
The patent divides the fibronectin type III domain into distinct functional segments: framework regions that maintain structural integrity and binding capability, and loop regions that are modified to reduce immunogenicity. This segmentation allows independent optimization of each region to simultaneously achieve low immunogenicity and high binding affinity
Solution Approach 2:
The patent applies different modification strategies to different local regions of the protein. Framework regions retain sequences optimized for structural stability and target interaction, while surface-exposed loop regions undergo modifications to minimize immunogenic epitopes. This local differentiation ensures that binding affinity is preserved while immunogenicity is reduced
3Stability of the object's composition
If fibronectin type III domain structures are optimized for stability and solubility, then structural robustness is improved, but design complexity increases
Solution Approach 1:
The patent develops a universal fibronectin type III domain scaffold that serves multiple functions simultaneously: structural stability, solubility, target binding, and reduced immunogenicity. This multi-functional design reduces overall complexity by using a single platform for diverse therapeutic applications rather than designing separate proteins for each function
Solution Approach 2:
The patent establishes specific parameter ranges for fibronectin type III domain design that inherently promote stability and solubility, such as optimized beta-sheet content, controlled disulfide bonding, and balanced hydrophobicity. These predefined parameter guidelines simplify the design process by providing clear design rules rather than requiring complex iterative optimization
Data Source
AI summary
Fibronectin type III (10Fn3) binding domains having novel designs that are associated with reduced immunogenicity are provided. The application describes alternative 10Fn3 binding domains in which certain immunogenic regions are not modified when producing a binder in order to maintain recognition as a self antigen by the host organism. The application also describes 10Fn3 binding domains in which HLA anchor regions have been destroyed thereby reducing the immunogenic contribution of the adjoining region. Also provided are 10Fn3 domains having novel combinations of modified regions that can bind to a desired target with high affinity.