Fc-free CD137-HER2 Fusion Polypeptide for Tumor Targeting
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Solution Overview
Problem
Current anti-CD137 therapies face challenges in specifically targeting and activating CD137 on tumor cells, leading to suboptimal response rates in cancer treatment, particularly for HER2-positive tumors, due to non-targeted clustering via Fc-gamma receptors.
Innovation Solution
A novel fusion polypeptide that simultaneously binds CD137 and HER2/neu, providing tumor-targeted activation of CD137 on lymphocytes, enhancing T-cell and NK-cell activation specifically at HER2-overexpressing tumor sites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-CD137 antibodies are used for cancer therapy, then CD137 activation is achieved, but non-specific clustering via Fc-gamma receptors causes off-target effects and reduced tumor specificity
Solution Approach 1:
The invention extracts and removes the Fc region from the antibody structure, creating an Fc-free anti-CD137 antibody. This eliminates the Fc-gamma receptor binding capability while preserving the antigen-binding specificity, thereby removing the source of non-specific clustering and off-target effects while maintaining tumor targeting ability
Solution Approach 2:
The invention modifies only the Fc region of the antibody while leaving the variable regions intact. This localized modification approach preserves the specific binding to CD137 on tumor cells while eliminating the harmful Fc-gamma receptor interactions, achieving selective removal of unwanted functionality
2Reliability
If soluble CD137L is used to activate CD137, then CD137 activation is achieved, but large concentrations are required and activation efficiency is limited
Solution Approach 1:
The invention employs the tumor cells themselves as the source of CD137 activation by expressing CD137L on the tumor cell surface. The endogenous CD137L on tumor cells naturally activates CD137 on infiltrating T cells, eliminating the need for exogenous administration of high concentrations of soluble CD137L and achieving efficient local activation at the tumor site
Solution Approach 2:
The invention uses the tumor cell membrane as an intermediary platform that presents CD137L in a spatially organized manner. This membrane-bound presentation serves as an effective mediator between the tumor cell and immune cells, enabling efficient CD137 activation without requiring high concentrations of soluble ligand
3Reliability
If forced expression of CD137L on tumor is used, then tumor rejection is achieved, but the method lacks specificity for HER2-positive tumors
Solution Approach 1:
The invention merges two specificities into a single antibody molecule: anti-HER2 specificity in the variable region for tumor targeting, and anti-CD137 specificity for immune activation. This dual-specificity approach ensures that CD137 activation occurs specifically at HER2-positive tumor sites, combining the benefits of tumor rejection with high specificity
Solution Approach 2:
The invention creates a multi-functional antibody that simultaneously serves as a tumor targeting agent (via HER2 binding) and an immune activation agent (via CD137 binding). This single molecule performs multiple functions that were previously required separate components, achieving both specificity and efficacy
Data Source
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AI summary
The disclosure provides a fusion polypeptide specific for both CD137 and HER2/neu, which fusion polypeptide can be useful for directing CD137 clustering and activation to HER2/neu- positive tumor cells. Such fusion polypeptide can be used in many pharmaceutical applications, for example, as anti-cancer agents and/or immune modulators for the treatment or prevention of human diseases such as a variety of tumors. The present disclosure also concerns methods of making the fusion polypeptide described herein as well as compositions comprising such fusion polypeptide. The present disclosure further relates to nucleic acid molecules encoding such fusion polypeptide and to methods for generation of such fusion polypeptide and nucleic acid molecules. In addition, the application discloses therapeutic and/or diagnostic uses of such fusion polypeptide as well as compositions comprising one or more of such fusion polypeptides.