Humanized Anti-CTLA4 Antibodies Resolving Immunogenicity
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Solution Overview
Problem
Current humanized antibodies against CTLA4 face challenges due to immunogenicity issues, leading to adverse effects and reduced therapeutic efficacy, necessitating the development of antibodies with lower immunogenicity and improved binding affinity.
Innovation Solution
Development of novel humanized antibodies specifically designed to bind to human CTLA4 with high affinity, excluding CD4+ T cell epitopes and optimized for reduced immunogenicity, using specific CDR sequences and frameworks to inhibit CTLA4-B7 interaction, and produced using mammalian cell lines like CHO or NS0 cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If humanized antibodies are used against CTLA4, then binding affinity to CTLA4 is improved, but immunogenicity increases causing adverse effects
Solution Approach 1:
The antibody structure is modified locally by humanizing only the variable regions (CDRs and framework regions) while retaining the constant regions from murine antibodies. This selective humanization reduces immunogenicity at the variable region level while preserving the essential binding function, thereby resolving the contradiction between binding affinity and immunogenicity.
Solution Approach 2:
The amino acid sequences of the variable regions are optimized through systematic mutation and selection to achieve both high affinity binding to CTLA4 and reduced immunogenicity. Specific parameters including CDR sequences, framework region compositions, and glycosylation patterns are adjusted to balance binding strength and immune recognition, directly addressing the technical contradiction.
2Object-generated harmful factors
If humanized antibodies with optimized variable regions are developed, then immunogenicity is reduced, but development complexity increases
Solution Approach 1:
The antibody is divided into distinct functional segments: CDRs for antigen binding, framework regions for structural support and immunogenicity control, and constant regions for effector functions. This segmentation allows independent optimization of each region, reducing overall complexity while achieving the dual goals of low immunogenicity and high affinity binding.
Solution Approach 2:
Human framework regions serve as intermediaries between the murine CDRs (providing binding specificity) and the human constant regions (providing reduced immunogenicity). This intermediary human framework structure facilitates the transition from fully murine to fully human antibodies, managing the complexity of cross-species antibody engineering while achieving the desired immunogenicity reduction.
Data Source
AI summary
The invention provides an anti-CTLA4 antibody which inhibits the binding of CTLA4 to human B7, in particular, it inhibits binding of CTLA4 to human B7.1 and/or human B7.2. Specific antibodies are provided with specific variable region sequences as well as compositions comprising such antibodies for use in treating disease.