Humanized COL-1 Antibody Framework Residue Substitution
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Murine monoclonal antibodies targeting carcinoembryonic antigen (CEA) are immunogenic in humans, leading to a human anti-murine antibody response that limits their repeated administration and efficacy due to their inherent immunogenicity.
Innovation Solution
Development of humanized COL-1 monoclonal antibodies with specific amino acid substitutions in the heavy chain framework, reducing immunogenicity while maintaining high affinity for CEA, by incorporating murine framework residues from human antibody sequences such as VJI′CL and MO30, and additional substitutions at positions like 79, 20, 38, 48, 67, and 81.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If murine monoclonal antibodies are used to target CEA, then high binding affinity is achieved, but immunogenicity increases leading to HAMA response
Solution Approach 1:
The patent applies parameter changes by substituting specific amino acid residues in the antibody sequence. The humanized COL-1 antibody contains substitutions at positions 20, 38, 48, 67, 79, and 81 in the heavy chain framework regions, transforming the antibody from fully murine to partially humanized while maintaining CEA binding affinity and reducing immunogenicity
Solution Approach 2:
The patent creates a composite antibody structure by combining human framework regions with murine CDR regions. The humanized COL-1 antibody uses human heavy and light chain frameworks (VH and VL) while incorporating murine complementarity determining regions (CDRs) that provide CEA specificity, resulting in a hybrid molecule with reduced immunogenicity and retained binding function
2Object-affected harmful factors
If framework residues are substituted to reduce immunogenicity, then HAMA response decreases, but binding affinity may be compromised
Solution Approach 1:
The patent applies local quality by making substitutions only in specific framework regions while preserving the CDR regions intact. The substitutions are localized to positions 20, 38, 48, 67, 79, and 81 in the heavy chain framework, allowing reduction of immunogenicity in non-critical regions while maintaining high binding affinity through preservation of the antigen-binding CDR regions
Solution Approach 2:
The patent carefully selects which framework residues to substitute based on their impact on binding. By changing parameters (amino acid sequences) only in framework regions that do not directly contact the antigen, the patent reduces immunogenicity while preserving the critical binding interface formed by the CDR regions
Data Source
AI summary
The present disclosure provides humanized COL-1 monoclonal antibodies that retain CEA binding affinity, compared to a parent antibody. Also disclosed herein are humanized COL-1 monoclonal antibodies that have reduced immunogenicity, compared to a parent antibody. The disclosed humanized COL-1 antibodies include substitution of framework residues with residues from the corresponding positions of a homologous human sequence. In several embodiments, methods are disclosed for the use of a humanized COL-1 antibody in the detection or treatment of a CEA-expressing tumor or cell in a subject. Also disclosed is a kit including the humanized COL-1 antibodies described herein.