Humanized Anti-TAG-72 Antibodies With Higher Affinity and Lower Immunogenicity
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Solution Overview
Problem
Current humanized antibodies against tumor-associated glycoprotein-72 (TAG-72) have limitations in antigen binding capacity and affinity, and induce immune responses in humans due to their immunogenicity, necessitating the development of antibodies with enhanced binding ability and reduced immunogenicity.
Innovation Solution
A humanized antibody with a modified heavy chain variable region, where specific amino acid residues in the CDR3 region are replaced, and a humanized light chain variable region are used to create antibodies like 3E8 and 3E8/BSM22, which exhibit improved antigen binding affinity and reduced immunogenicity by random mutagenesis and recombinant DNA techniques.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If murine monoclonal antibodies are used against TAG-72, then antigen binding affinity is achieved, but immune responses are induced in humans
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence parameters of the antibody heavy and light chains. Specifically, it replaces murine framework region amino acids with human equivalents while preserving CDR regions, thereby changing the immunogenicity parameter without significantly altering antigen binding capability
Solution Approach 2:
The patent creates a composite antibody structure by combining human framework region sequences with murine CDR region sequences. This chimeric construction merges the low immunogenicity of human antibodies with the high antigen binding affinity of murine antibodies, resolving the contradiction between these two properties
2Object-affected harmful factors
If humanized antibodies are constructed by grafting CDRs onto human framework regions, then immunogenicity is reduced, but antigen binding capacity is compromised
Solution Approach 1:
The patent applies local quality by making the antibody structure non-uniform: the framework regions are composed of human sequences with properties optimized for low immunogenicity, while the CDR regions retain murine sequences with properties optimized for high antigen binding affinity. Each region has different composition tailored to its specific function
Solution Approach 2:
The patent performs preliminary action by carefully selecting and preserving specific murine framework residues (such as Tyr32, Ser52, Tyr55, Ser98, and Trp103 in VH; Ser24, Ser50, and Trp52 in VL) that are critical for maintaining the three-dimensional structure of the antigen binding site, thereby pre-establishing the conditions for high antigen binding capacity before the actual grafting process
3Object-affected harmful factors
If conventional humanized antibodies are used, then reduced immunogenicity is achieved, but antigen binding affinity is insufficient
Solution Approach 1:
The patent applies parameter changes by optimizing the amino acid sequence parameters of the human framework regions. It selects human framework sequences that most closely match the original murine sequences in terms of three-dimensional structure requirements, thereby changing the sequence composition parameter while maintaining structural integrity and enhancing antigen binding affinity
Solution Approach 2:
The patent employs feedback by using the known three-dimensional structure of the CC49 antibody antigen binding site as a reference to guide the selection of human framework residues. The structural information provides feedback on which amino acid positions are critical for maintaining binding capability, allowing iterative optimization of the humanized antibody sequence
Data Source
AI summary
The present invention relates to humanized antibodies specific to a tumor-associated glycoprotein, TAG-72, and anticancer compositions comprising the humanized antibodies. In detail, the present invention relates to a humanized antibody which has enhanced antigen binding affinity by mutating a heavy chain of a humanized antibody PXA/HzK specific for TAG-72, an antibody which is prepared by replacing a light chain of the humanized antibody with a human light chain, and anticancer compositions including the antibodies.