Affinity-Matured Anti-CD155 Antibody for Apoptosis-Free Receptor Blocking
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Solution Overview
Problem
Existing anti-CD155 antibodies face challenges in blocking CD155 receptor binding without inducing apoptosis of CD155-positive cells, posing safety risks, and there is a need for antibodies that can effectively treat CD155-mediated diseases like tumors with improved safety and efficacy.
Innovation Solution
Development of affinity-matured humanized antibodies with specific CDR sequences (SEQ ID NO: 1-24) that block CD155 receptors TIGIT, CD96, and CD226 without inducing apoptosis, using hybridoma technology, humanization, and affinity maturation to enhance specificity and safety.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing anti-CD155 antibodies are used to block CD155 receptor binding, then the binding of CD155 to its receptors is blocked, but the antibodies induce apoptosis of CD155-positive cells causing safety risks
Solution Approach 1:
The patent applies local quality by designing the antibody to have different functional properties at different regions: the variable region (specifically CDR3-H) is engineered to block the CD155-receptor interface, while the constant region is configured to prevent Fc-mediated effector functions like apoptosis induction. This spatial differentiation of function allows the antibody to block binding without triggering cell death
Solution Approach 2:
The patent employs parameter changes by modifying the antibody's effector function parameters through constant region engineering (e.g., using IgG4 isotype with specific mutations like S228P) to reduce complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, while maintaining high affinity binding to CD155 through optimized variable region parameters
2Reliability
If high-affinity blocking antibodies are developed to improve treatment efficacy, then the blocking capability is enhanced, but the risk of inducing apoptosis of normal tissue cells increases
Solution Approach 1:
The patent inverts the conventional approach by designing an antibody that blocks the pathogenic interaction (CD155-receptor binding) without triggering the harmful immune response (apoptosis). Instead of relying on Fc-mediated effector functions to kill target cells, the invention uses the Fab region to block binding and explicitly engineering the Fc region to minimize effector functions, thus inverting the mechanism from cytotoxic to protective
3Reliability
If existing CD155 antibodies are used, then some blocking activity is achieved, but the half-life and dosing frequency are insufficient requiring higher dosages
Solution Approach 1:
The patent optimizes pharmacokinetic parameters by selecting the IgG4 isotype with extended half-life characteristics and introducing the S228P mutation in the constant region to enhance FcRn binding, thereby increasing serum persistence. This allows lower dosing frequencies while maintaining therapeutic blocking levels
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The antibodies demonstrate stronger specificity, longer half-life, and efficacy in treating CD155-mediated diseases at lower dosages with reduced toxicity and side effects, effectively blocking CD155 receptor binding in human and monkey cells.
Implementation Method 1
the antibody... can specifically bind to human or monkey CD155 protein, block the binding of CD155 to its receptors TIGIT, CD96, CD226
Data Source
AI summary
Provided in the present invention are an anti-CD155 antibody and the use thereof. Moreover, an obtained anti-CD155 chimeric antibody, a humanized anti-CD155 antibody, and a humanized affinity-matured anti-CD155 antibody can only specifically target and bind to a CD155 receptor and block the binding of CD155 to receptors TIGIT, CD96, and CD226 thereof, but also have the characteristic of not inducing the apoptosis of CD155 cells.