Anti-CD47 Antibody Humanization with Targeted CDR Substitutions
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Solution Overview
Problem
Current antibody therapeutics targeting CD47, such as anti-CD47 antibodies, face challenges in achieving accurate humanization while maintaining binding affinity and specificity, leading to potential immunogenicity and clinical development risks due to unpredictable human T-cell epitope content and physical instability.
Innovation Solution
The development of anti-CD47 antibodies with specific heavy and light chain variable regions, utilizing human framework sequences and conservative substitutions in CDRs, along with a method involving grafting anti-CD47 CDRs from non-human sources into human v-domains, followed by phage library screening and mutagenesis to enhance humanization and minimize immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If CDR grafting and back mutations are used to humanize antibodies, then immunogenicity is reduced, but binding affinity and specificity are compromised
Solution Approach 1:
The patent applies local quality by making targeted substitutions only at specific positions (1st and 2nd positions of HCDR1, and 1st position of LCDR1) rather than comprehensive humanization. This localized approach preserves the immunoglobulin framework's ability to maintain binding affinity while minimizing immunogenic epitopes, thus resolving the contradiction between reducing immunogenicity and maintaining binding reliability.
Solution Approach 2:
The patent changes the amino acid parameters at specific positions in the CDR regions to reduce immunogenicity while maintaining binding affinity. By substituting residues at key positions (HCDR1 positions 1-2 and LCDR1 position 1) with human-compatible amino acids, the antibody achieves reduced immunogenicity without compromising the structural integrity and binding capability of the variable domains.
2Object-affected harmful factors
If extensive humanization is performed to minimize T-cell epitopes, then immunogenicity decreases, but physical stability and binding potency are reduced
Solution Approach 1:
The patent applies local quality by limiting humanization modifications to specific local regions (HCDR1 and LCDR1) rather than throughout the entire variable domain. This localized substitution strategy minimizes T-cell epitope content while preserving the overall structural stability and physical composition of the antibody framework, thus resolving the contradiction between reducing immunogenicity and maintaining physical stability.
3Adaptability or versatility
If CDR sequences are grafted from non-human sources into human frameworks, then humanization is achieved, but binding affinity to human CD47 is reduced
Solution Approach 1:
The patent changes the amino acid parameters at critical binding positions within the CDR regions. By substituting residues at the 1st and 2nd positions of HCDR1 and the 1st position of LCDR1 with human-compatible amino acids, the antibody achieves better adaptation to human CD47 while maintaining high binding affinity, thus resolving the contradiction between humanization and binding reliability.
Data Source
AI summary
Provided herein are antibody molecules that bind specifically to CD47 and related nucleic acid molecules, vectors and host cells. Also provided herein are medical uses of such antibody molecules.