Anti-Jagged1 Antibody Stability via HVR-H3 Mutation
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Solution Overview
Problem
Anti-Jagged1 antibodies are prone to cleavage under heat treatment and freeze-thaw conditions, affecting their stability and therapeutic efficacy, and there is a need for modifications that enhance their stability without compromising their affinity for Jagged1.
Innovation Solution
Mutating the amino acid at position 101 in the heavy chain hypervariable region (HVR-H3) of the anti-Jagged1 antibody reduces cleavage while maintaining significant binding affinity, using specific amino acid sequences for the heavy and light chain variable regions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the anti-Jagged1 antibody is used under heat treatment and freeze-thaw conditions, then the antibody provides therapeutic activity, but the antibody undergoes cleavage in the heavy chain reducing its stability
Solution Approach 1:
The patent applies parameter changes by mutating the amino acid at position 101 in the HVR-H3 region from serine to a different amino acid. This single amino acid substitution changes the chemical parameters of the antibody at the cleavage site, making it resistant to proteolytic cleavage while preserving the antibody's binding affinity and therapeutic function.
2Reliability
If the amino acid sequence of the antibody is modified to reduce cleavage, then the antibody stability improves, but the affinity for Jagged1 may be reduced
Solution Approach 1:
The patent applies local quality by making a targeted amino acid substitution specifically at position 101 in the HVR-H3 region, where the cleavage occurs. This localized modification addresses the stability issue at the cleavage site without altering other regions of the antibody that are critical for Jagged1 binding, thereby preserving overall binding affinity while improving stability.
3Stability of the object's composition
If the amino acid at position 101 in HVR-H3 is mutated, then cleavage is reduced, but there may be a loss of affinity for Jagged1
Solution Approach 1:
The patent changes the amino acid parameter at position 101 from serine to a different residue, which alters the local chemical environment to prevent proteolytic cleavage. This parameter change is specifically designed to affect only the cleavage susceptibility while leaving the overall structure and binding interface intact, thus maintaining affinity.
Data Source
AI summary
The invention provides anti-Jagged1 antibodies and methods of using the same.