pH-Responsive Antigen-Binding Molecules for Tissue-Specific Cancer Targeting
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Solution Overview
Problem
Current antibody pharmaceuticals face challenges in achieving tissue-specific action, leading to side effects due to systemic activation, as they often target antigens expressed in both cancer and normal tissues, and there is a lack of methods for reversible action at lesion sites without affecting normal tissues.
Innovation Solution
Development of antigen-binding molecules with antigen-binding activity regulated by the concentration of small molecule compounds specific to target tissues, allowing for controlled pharmacological actions at lesion sites through the use of libraries of antigen-binding domains with varying sequences, enabling efficient production and screening of such molecules.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibody molecules are used to target antigens expressed in cancer cells, then cytotoxic activity against cancer cells is achieved, but side effects occur due to cytotoxic activity against normal cells expressing the same antigens
Solution Approach 1:
The antibody molecule is engineered to exhibit different binding properties in different locations: it binds to antigens in normal tissues with low affinity under normal conditions, but binds with high affinity in the acidic microenvironment of cancer tissues. This spatial variation in binding quality allows selective cancer targeting while sparing normal tissues.
Solution Approach 2:
The antibody's antigen-binding activity is made dynamic and reversible through pH-dependent conformational changes. The binding affinity transitions from low at physiological pH (7.4) to high at acidic pH (6.0-6.5), enabling the antibody to dynamically adapt its activity to the local environmental conditions and reversibly bind only in cancer tissues.
2Power
If improved antibody molecules are used to exert strong cytotoxic activity, then cytotoxic activity against cancer cells with low antigen expression is enhanced, but similar cytotoxic activity is exerted against normal tissues with low antigen expression
Solution Approach 1:
The antibody exhibits location-specific binding strength: weak binding in normal tissues (low cytotoxic activity) and strong binding in cancer tissues (high cytotoxic activity). The pH-dependent conformational change creates a quality difference in binding strength between different tissue environments, enabling selective power delivery to cancer cells while protecting normal tissues.
3Productivity
If antibodies are administered systemically to treat cancer, then cancer cells are targeted, but normal tissues are also affected due to systemic circulation
Solution Approach 1:
The antibody maintains systemic circulation but exhibits local activation only in cancer tissues through pH-dependent conformational changes. The binding quality is spatially differentiated: non-binding in normal tissues during systemic circulation and high-affinity binding in acidic cancer microenvironments, enabling systemic administration with localized action.
Solution Approach 2:
The pH difference between normal and cancer tissues acts as an intermediary trigger that activates the antibody's binding function only in cancer tissues. The acidic pH environment serves as a mediator that induces conformational changes, enabling the antibody to distinguish between healthy and diseased tissues during systemic circulation.
4Productivity
If conventional antibody libraries are used for screening, then antigen-binding molecules are obtained, but molecules with tissue-specific reversible action cannot be identified
Solution Approach 1:
The screening method incorporates pH as a critical parameter variable. Libraries are screened under different pH conditions to identify antibodies that undergo conformational changes and exhibit enhanced binding at acidic pH. This parameter-based screening approach enables identification of antibodies with pH-dependent binding properties that confer tissue-specific reversible action.
Solution Approach 2:
The screening process is designed to preliminarily select antibodies with pH-dependent binding characteristics before in vivo application. By pre-screening for conformational change capability and pH-responsive binding in vitro, the method ensures that only antibodies with tissue-specific reversible action potential proceed to therapeutic use.
Data Source
AI summary
An objective of the present invention is to provide target tissue-specific antigen-binding molecules, antigen-binding molecules whose antigen-binding activity varies depending on the concentration of an unnatural compound, libraries comprising a plurality of the antigen-binding molecules which are different from one another, pharmaceutical compositions comprising the antigen-binding molecules, methods of screening for the antigen-binding molecules, and methods for producing the antigen-binding molecules. The present inventors created antigen-binding domains whose antigen-binding activity varies depending on the concentration of a small molecule compound or antigen-binding molecules containing an antigen-binding domain, and libraries comprising a plurality of the antigen-binding domains which are different from one another or antigen-binding domains, and demonstrated that the above-noted objective could be achieved by using the libraries. Various diseases originating from target tissues can be treated in a target tissue-specific manner by using the antigen-binding molecules of the present invention.