CD137 Antibody Binding Tuned by Tumor Small Molecules
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Solution Overview
Problem
Existing CD137 agonist antibodies exhibit both antitumor efficacy and hepatotoxic side effects due to nonspecific binding to Fcγ receptors, necessitating a separation of drug efficacy and toxicity, and there is a need for antigen-binding molecules that can selectively target tumor tissues with reduced side effects.
Innovation Solution
Development of anti-CD137 antigen-binding molecules with binding activity that varies depending on small molecule compounds present in tumor tissues, enhancing efficacy while minimizing side effects by forming trimolecular complexes with CD137 and small molecule compounds like ATP, and altering the Fc region for increased binding to FcγRIIb.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CD137 agonist antibody binds to Fcγ receptor to enhance drug efficacy, then antitumor activity is improved, but hepatotoxic side effects increase
Solution Approach 1:
The patent applies local quality by creating tissue-specific binding properties through the Fc region modification. The antibody exhibits different binding characteristics in different tissues - strong binding to CD137 in tumor tissues for efficacy, and reduced binding to Fcγ receptors in non-tumor tissues to avoid hepatotoxicity. This spatial differentiation of binding properties resolves the contradiction between efficacy and safety.
Solution Approach 2:
The patent utilizes parameter changes by modifying the Fc region amino acid sequence to alter the antibody's binding parameters. Specifically, changes in the Fc region (such as amino acid substitutions) modify the antibody's affinity and specificity for Fcγ receptors, enabling enhanced antitumor activity while reducing hepatotoxic side effects through controlled parameter modification.
2Reliability
If CD137 agonist antibody binds to Fcγ receptor to activate immune cells, then cytotoxic activity against tumor cells is enhanced, but toxicity in non-tumor tissues increases
Solution Approach 1:
The patent achieves local quality by enabling the antibody to exhibit different functional properties in different tissue contexts. Through Fc region modification, the antibody selectively activates immune cells in tumor tissues (enhancing cytotoxic activity) while avoiding activation in non-tumor tissues (reducing toxicity), thus resolving the contradiction between efficacy and safety.
Solution Approach 2:
The patent employs an intermediary mechanism where the modified Fc region acts as a mediator between the antibody and Fcγ receptors. The Fc region modification serves as a selective interface that permits beneficial interactions in tumor tissues while blocking harmful interactions in non-tumor tissues, thereby resolving the contradiction between cytotoxic efficacy and tissue toxicity.
3Productivity
If binding activity to CD137 is increased to enhance antitumor effect, then drug efficacy is improved, but side effects due to nonspecific binding increase
Solution Approach 1:
The patent applies parameter changes by modifying the Fc region amino acid sequence to optimize binding parameters. This modification enhances the antibody's ability to bind CD137 in tumor tissues (improving antitumor effect) while simultaneously reducing nonspecific binding to Fcγ receptors in normal tissues (reducing side effects), thus resolving the contradiction between productivity and harmful effects.
Solution Approach 2:
The patent achieves local quality by creating tissue-specific binding characteristics through Fc region modification. The antibody exhibits enhanced binding to CD137 in tumor tissues for antitumor efficacy, while showing reduced binding to Fcγ receptors in non-tumor tissues to minimize side effects, thereby resolving the contradiction between antitumor productivity and harmful effects.
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 molecules achieve enhanced antitumor activity with reduced toxicity by selectively binding to CD137 in tumor tissues, allowing for higher dosages without increased side effects, and maintaining strong cytotoxic activity.
Implementation Method 1
binding of a costimulatory molecule on the surface of T cells to its ligands on the antigen-presenting cells and activation of the costimulatory molecule
Implementation Method 2
binding of the antibody to the Fcγ receptor via the antibody constant region
Data Source
AI summary
An objective of the present disclosure is to provide anti-CD137 antigen-binding molecules which have immunocyte-activating effect, cytotoxic activity, or anti-tumor activity, and meanwhile have reduced effect on non-tumor tissues such as normal tissues and produce less side effects, and methods of using the same.Anti-CD137 antigen-binding molecules which have immunocyte-activating effect, cytotoxic activity, or anti-tumor activity, and meanwhile have reduced effect on non-tumor tissues such as normal tissues and produce less side effects, are provided by discovering and producing CD137 antigen-binding molecules whose binding activity to CD137 depends on various substances (for example, small molecule compounds) in target tissues. Methods of using the same, pharmaceutical formulations, and such are also provided.The present disclosure also provides an antigen-binding molecule whose binding activity to an antigen varies depending on a small molecule compound, a preparation method thereof, and uses thereof.