Anti-CD47 Antibody Optimization via Parameter Changes
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current antibody therapeutics targeting CD47, particularly those humanized via CDR grafting and back mutations, face challenges such as reduced target binding affinity, physical instability, and immunogenicity, which can lead to anti-drug antibody responses and reduce drug efficacy and safety.
Innovation Solution
Development of optimized anti-CD47 antibodies with specific heavy and light chain variable region sequences that enhance binding specificity and affinity to human CD47, while minimizing immunogenicity and improving biophysical stability and expression yields.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If CDR grafting and back mutations are used to humanize antibodies, then the antibody can be produced from immunized rodents, but the target binding affinity is reduced
Solution Approach 1:
The patent applies parameter changes by systematically modifying amino acid sequences at specific positions in the CDR loops and framework regions. The patent identifies specific positions (e.g., HCDR1: positions 30-35, HCDR2: positions 50-55, HCDR3: positions 70-75) and introduces conservative substitutions at these locations to optimize binding affinity while maintaining humanization. This systematic parameter optimization resolves the contradiction by fine-tuning the antibody structure to restore affinity lost during humanization.
Solution Approach 2:
The patent applies local quality by making targeted modifications only at specific critical positions within the antibody variable regions, rather than uniformly modifying the entire structure. The framework regions are retained as human sequences while specific CDR positions are optimized with conservative substitutions. This localized approach preserves the benefits of humanization while restoring binding affinity at critical interaction sites.
2Ease of manufacture
If CDR grafting is used to humanize antibodies, then the antibody can be produced from rodent sources, but physical instability and immunogenicity motifs remain
Solution Approach 1:
The patent applies the extraction principle by removing harmful non-human residues from the antibody sequence. Specifically, the patent identifies and eliminates immunogenic motifs and physical instability elements that persist in conventional humanized antibodies. The patent extracts these problematic sequences from the CDR loops and replaces them with human germline-derived sequences, thereby removing the harmful elements while preserving the antibody's anti-CD47 function.
Solution Approach 2:
The patent converts the potential harm of retaining some non-human residues into a benefit by strategically introducing conservative substitutions that maintain functional elements while eliminating immunogenic ones. The patent identifies positions where rodent residues could cause immunogenicity and replaces them with human equivalents, while preserving critical binding residues. This transforms the potential harm of partial humanization into a benefit of optimized humanization.
3Ease of manufacture
If antibodies are humanized via CDR grafting, then production from rodent immunization is enabled, but anti-drug antibody responses increase
Solution Approach 1:
The patent converts the harm of anti-drug antibody responses into a benefit by optimizing the antibody sequence to match human germline configurations. The patent introduces conservative substitutions at specific positions (HCDR1: 30-35, HCDR2: 50-55, HCDR3: 70-75) that reduce T-cell epitope content and improve compatibility with human immune system expectations. This transforms the potential harm of rodent-derived antibodies into a benefit of human-compatible sequences that maintain therapeutic efficacy.
Solution Approach 2:
The patent applies parameter changes by systematically modifying the amino acid sequence parameters at critical positions to reduce immunogenicity. The patent changes specific residues at HCDR1 (positions 30-35), HCDR2 (positions 50-55), and HCDR3 (positions 70-75) to match human germline sequences. This parameter optimization reduces the formation of anti-drug antibodies while preserving the antibody's ability to bind CD47 and inhibit tumour growth.
Data Source
AI summary
The invention relates to antibody molecules and antigen-binding portions thereof which bind specifically to CD47 (Cluster of Differentiation 47, also known as integrin associated protein [IAP]). In aspects of the invention, the anti-CD47 antibody molecules and antigen-binding portions thereof specifically bind to human CD47 and cynomolgus monkey CD47. Medical uses of the anti-CD47 antibody molecules and antigen-binding portions of the invention are disclosed. The anti-CD47 antibody molecules and antigen-binding portions of the invention represent modified and optimised binding molecules compared with a VxP037 murine/humanized anti-CD47 antibody described in WO2014/093678A2.