Recombinant Antibody CH2 Domain Replacement
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Solution Overview
Problem
Current therapeutic antibodies, such as human IgG1 and IgG3, have limitations in complement-dependent cytotoxic activity and antigenicity, necessitating the development of antibodies with enhanced effector functions and improved therapeutic effects.
Innovation Solution
A recombinant antibody composition is created by replacing the CH2 domain of a human IgG1 antibody with a polypeptide corresponding to the same position of a human IgG3 antibody, as indicated by the EU index, to enhance complement-dependent cytotoxic activity, while maintaining binding activity to protein A and incorporating complex type N-glycoside-linked sugar chains with reduced fucose binding to N-acetylglucosamine.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If human IgG1 or IgG3 antibodies are used as therapeutic agents, then they exhibit certain complement-dependent cytotoxic activity, but their therapeutic effects are limited and antigenicity remains a problem
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of the CH2 domain in the Fc region of human IgG1 antibodies. Specifically, amino acids at positions 231-340 (EU index) are replaced with corresponding amino acids from human IgG3, creating a chimeric Fc region that enhances complement-dependent cytotoxic activity while reducing antigenicity, thereby improving therapeutic effectiveness
Solution Approach 2:
The patent creates a composite antibody structure by combining the variable region of human IgG1 with a chimeric Fc region that integrates sequences from both human IgG1 and human IgG3. This composite structure leverages the advantages of both antibody types: the binding specificity of IgG1 and the enhanced effector functions of IgG3, resulting in superior therapeutic properties
2Reliability
If the CH2 domain of human IgG1 is replaced with human IgG3 polypeptide, then complement-dependent cytotoxic activity is enhanced, but the structural complexity increases
Solution Approach 1:
The patent applies local quality by making targeted modifications only to the CH2 domain of the Fc region while leaving the rest of the antibody structure intact. This localized approach allows enhancement of complement-dependent cytotoxic activity through specific amino acid replacements without unnecessarily increasing overall structural complexity, maintaining simplicity in non-critical regions
3Reliability
If complex type N-glycoside-linked sugar chains with reduced fucose binding are incorporated, then ADCC activity is enhanced, but the manufacturing complexity increases
Solution Approach 1:
The patent applies parameter changes by modifying the glycosylation pattern of the antibody, specifically incorporating complex type N-glycoside-linked sugar chains with reduced fucose content at the N-glycosylation site in the Fc region. This biochemical parameter change enhances ADCC activity by optimizing the interaction between the antibody and Fcγ receptors, while the modification is achieved through controlled cellular glycosylation processes
Data Source
AI summary
The present invention relates to a recombinant antibody composition having higher complement-dependent cytotoxic activity than a human IgG1 antibody and a human IgG3 antibody, wherein a polypeptide comprising a CH2 domain in the Fc region of a human IgG1 antibody is replaced by a polypeptide comprising an amino acid sequence which corresponds to the same position of a human IgG3 antibody indicated by the EU index as in Kabat, et al.; a DNA encoding the antibody molecule or a heavy chain constant region of the antibody molecule contained in the recombinant antibody composition; a transformant obtainable by introducing the recombinant vector into a host cell; a process for producing the recombinant antibody composition using the transformant; and a medicament comprising the recombinant antibody composition as an active ingredient.