Multivalent Antigen-Binding Proteins for GITR Agonism
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Solution Overview
Problem
Current antibody agonists for human glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) have limited potency in activating human GITR, as they require multimerization into stable trimers or superclusters for robust activation, which is difficult to achieve.
Innovation Solution
Development of multivalent antigen-binding proteins (ABPs) with specific CDR sequences that bind human GITR, enhancing agonistic activity by directly interacting with GITR and potentially multimerizing it on the cell surface.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibody agonists are used to activate human GITR, then they can bind to GITR, but their potency is limited because they require multimerization into stable trimers or superclusters for robust activation
Solution Approach 1:
The patent combines multiple antigen-binding domains (at least two, preferably three or four) into a single multivalent ABP molecule. This merging of binding domains allows the ABP to simultaneously bind multiple GITR molecules, effectively multimerizing GITR on the cell surface without requiring the complex stable trimer or supercluster structures needed by conventional antibodies. The multivalent structure integrates multiple binding functions into one molecular entity, resolving the contradiction between achieving robust activation and avoiding complex multimerization requirements.
Solution Approach 2:
The patent transitions from conventional bivalent antibody structures to multivalent ABPs with three or four antigen-binding domains. This dimensional change in valency allows the ABP to engage multiple GITR molecules simultaneously, creating higher-order clusters on the cell surface. By increasing the valency dimension, the ABP achieves more effective GITR multimerization and robust activation without relying on the stable trimer configurations required by conventional antibodies.
2Reliability
If GITR is multimerized into stable trimers or superclusters for robust activation, then agonistic activity is enhanced, but it is difficult to achieve this multimerization with conventional antibodies
Solution Approach 1:
The patent merges multiple antigen-binding domains into a single ABP molecule, enabling one ABP to simultaneously engage multiple GITR molecules. This combining approach directly creates GITR multimers on the cell surface through the ABP's multivalent structure, rather than relying on difficult-to-achieve stable trimer or supercluster formation. The merged structure simplifies the manufacturing challenge by designating multivalency as an inherent property of the ABP rather than a post-manufacturing assembly challenge.
Solution Approach 2:
The patent changes the valency parameter of the ABP from conventional bivalence to multivalence (three or four binding domains). This parameter change enables the ABP to naturally facilitate GITR multimerization with higher ease, as the increased number of binding domains allows simultaneous engagement of multiple GITR molecules. By modifying the valency parameter, the patent achieves robust activation while simplifying the multimerization process.
3Reliability
If multivalent ABPs with specific CDR sequences are developed, then potency in activating human GITR is increased, but the complexity of the ABP structure increases
Solution Approach 1:
The patent merges multiple antigen-binding domains containing specific CDR sequences into a single multivalent ABP structure. This merging achieves high agonistic potency by enabling simultaneous binding to multiple GITR molecules with the specific CDR-GITR interactions. While the structure becomes more complex, the merging approach consolidates multiple binding functions into one integrated molecule, making the complexity manageable through modular domain organization rather than separate molecular components.
Solution Approach 2:
The patent designs the multivalent ABP to perform multiple functions: binding to multiple GITR molecules simultaneously, multimerizing GITR on the cell surface, and providing robust agonistic activation. The specific CDR sequences provide universal binding capability across multiple GITR molecules, while the multivalent structure enables multi-functionality. This multi-functional design achieves high potency while organizing complexity into integrated functional units.
Data Source
AI summary
Provided herein are antigen-binding proteins (ABPs) that selectively bind to GITR and its isoforms and homologs, and compositions comprising the ABPs. Also provided are methods of using the ABPs, such as therapeutic and diagnostic methods.