Adenosine-Responsive Anti-CTLA-4 Antibodies for Tumor Selectivity
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Solution Overview
Problem
Current anti-CTLA-4 antibodies, such as ipilimumab, enhance antitumor immunity but cause autoimmune diseases due to systemic immunoreactivity, and there is a need for a drug that maintains antitumor immune responses while minimizing side effects.
Innovation Solution
Development of anti-CTLA-4 antibodies with a variable region dependent on adenosine concentration and variant Fc regions with specific amino acid alterations at defined positions, enhancing binding and cytotoxic activity against CTLA-4-expressing cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-CTLA-4 antibodies are administered to enhance antitumor immunity, then antitumor immune responses are improved, but autoimmune diseases occur due to system wide immunoreactivity
Solution Approach 1:
The patent applies local quality by creating concentration-dependent binding antibodies that selectively target CTLA-4 in tumor tissues rather than system-wide. The antibody binds with high affinity only when adenosine concentration is high (in tumor microenvironment), leaving normal tissues unaffected. This spatial selectivity resolves the contradiction by localizing the immune stimulatory effect to tumors while avoiding systemic autoimmune reactions.
Solution Approach 2:
The patent employs dynamics by designing an antibody whose binding affinity dynamically changes based on adenosine concentration. The variable region's binding activity increases with adenosine concentration, allowing the antibody to activate immune responses only in high-adenosine tumor environments. This dynamic binding characteristic enables the same antibody to be both antitumor and safe for normal tissues.
2Productivity
If anti-CTLA-4 antibodies bind to CTLA-4 to suppress regulatory T cells, then antitumor efficacy is enhanced, but off-target effects increase
Solution Approach 1:
The patent applies parameter changes by modulating the antibody's binding parameters based on adenosine concentration. The binding affinity and kinetics are concentration-dependent, ensuring high-specificity binding only in tumor microenvironments with elevated adenosine levels. This parameter modulation prevents off-target binding to CTLA-4 in normal tissues, resolving the contradiction between antitumor efficacy and off-target effects.
Data Source
AI summary
The present disclosure provides anti-CTLA-4 antibodies and methods of producing and using the antibodies. The present disclosure also provides nucleic acids encoding the anti-CTLA-4 antibodies and host cells containing the nucleic acids. Furthermore, the present disclosure provides polypeptides containing a variant Fc region containing amino acid alterations in a parent Fc region and methods of producing and using the polypeptides.