pH-Dependent Anti-CTLA4 Antibodies for Tumor Selectivity
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Solution Overview
Problem
Current anti-CTLA4 antibodies for cancer therapy often have significant autoimmune side effects and limited selectivity for tumor tissue, leading to reduced efficacy and increased side effects.
Innovation Solution
Development of anti-CTLA4 antibodies with specific heavy and light chain variable region sequences that exhibit higher binding affinity to CTLA4 in tumor microenvironments, reducing side effects and allowing for higher dosages while maintaining therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current anti-CTLA4 antibodies are used for cancer therapy, then therapeutic efficacy is achieved, but autoimmune side effects increase and selectivity for tumor tissue is reduced
Solution Approach 1:
The patent applies local quality by engineering antibodies with pH-dependent binding characteristics that create different binding affinities in different physiological environments. The antibodies exhibit high affinity for CTLA4 at acidic pH (tumor microenvironment, pH 6.5-7.0) and low affinity at neutral pH (normal tissues, pH 7.4), thereby achieving localized therapeutic action at the tumor site while sparing normal tissues from autoimmune side effects
Solution Approach 2:
The patent utilizes parameter changes by modifying the binding affinity of antibodies as a function of pH. Through specific amino acid substitutions in the antibody variable regions (particularly in CDR loops), the antibodies are engineered to undergo conformational changes that enhance CTLA4 binding at acidic pH while reducing binding at neutral pH, thus dynamically adjusting therapeutic activity based on environmental conditions
2Reliability
If current anti-CTLA4 antibodies are used, then cancer treatment is provided, but selectivity for tumor tissue is limited
Solution Approach 1:
The patent implements local quality by designing antibodies with spatially differentiated binding properties based on pH gradients. The tumor microenvironment's acidic pH triggers high-affinity binding specifically at the tumor site, while neutral pH in healthy tissues results in low-affinity binding, thereby achieving precise spatial selectivity for tumor tissue
Solution Approach 2:
The patent applies dynamics by creating antibodies with environmentally responsive binding affinity. The antibodies dynamically adjust their binding strength to CTLA4 based on local pH conditions, transitioning from low affinity in normal tissues to high affinity in the acidic tumor microenvironment, thus achieving adaptive tumor-selective targeting
3Reliability
If higher dosages of anti-CTLA4 antibodies are administered, then therapeutic efficacy may be increased, but side effects increase
Solution Approach 1:
The patent applies local quality by engineering antibodies that concentrate their therapeutic effect specifically in the acidic tumor microenvironment while maintaining low activity in neutral pH normal tissues. This spatial differentiation allows for effective tumor targeting at lower overall dosages, reducing systemic side effects while maintaining or enhancing local therapeutic efficacy
Solution Approach 2:
The patent converts the harmful acidic pH of the tumor microenvironment (which can promote tumor growth and metastasis) into a beneficial feature for selective antibody binding. The acidic conditions that characterize aggressive tumors also trigger high-affinity antibody binding, thereby transforming a pathological feature into a selective targeting mechanism that enhances efficacy while reducing off-target side effects
Data Source
AI summary
A polypeptide having a heavy chain variable region and/or light chain variable region that specifically binds to CTLA4 protein as well as antibodies and antibody fragments containing the heavy chain variable region and/or the light chain variable region that bind to CTLA4 protein. Pharmaceutical compositions and kits comprising the polypeptide or antibodies and antibody fragments containing the polypeptide are also provided.