Anti-PD-1 Binding Protein With GITRL Trimer for GITR Clustering
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Solution Overview
Problem
Current cancer treatments using PD-1 blockade and GITR engagement face challenges in efficiently blocking PD-1 while activating GITR, leading to resistance and limited therapeutic impact.
Innovation Solution
A binding protein is designed with a single-chain GITRL trimer fused to the heavy chain of an anti-PD-1 monoclonal antibody, allowing dual action by blocking PD-1 and activating GITR, specifically targeting antigen-experienced T cells in the tumor microenvironment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If PD-1 blockade and GITR engagement are administered as separate drugs, then both PD-1 blocking and GITR activation can be achieved, but the number of drug administrations increases and therapeutic efficiency decreases
Solution Approach 1:
The patent combines two separate therapeutic functions (PD-1 blockade and GITR activation) into a single bispecific binding protein molecule. This merging eliminates the need for separate drug administrations while achieving both immunomodulatory effects simultaneously, thereby improving therapeutic efficiency and reducing treatment complexity
Solution Approach 2:
The binding protein is designed with multiple functional domains: one domain specifically binds and blocks PD-1, while another domain specifically binds and activates GITR. This multi-functional design allows a single molecule to perform multiple therapeutic roles, addressing both resistance mechanisms and enhancing anti-tumor immunity in one administration
2Adaptability or versatility
If GITR activation is delivered systemically, then all T cells can be activated, but specificity for antigen-experienced T cells in the tumor microenvironment is reduced
Solution Approach 1:
The binding protein exhibits localized action by specifically targeting antigen-experienced T cells within the tumor microenvironment. The dual-specificity design ensures that GITR activation occurs preferentially where PD-1 is expressed (on exhausted T cells at the tumor site), rather than systemically activating all T cells, thereby improving therapeutic specificity
Solution Approach 2:
The binding protein acts as an intermediary that bridges PD-1 blocking and GITR activation functions. By requiring simultaneous binding to both PD-1 and GITR on the same cell, it ensures that only cells expressing both markers (antigen-experienced T cells in the tumor microenvironment) receive the full therapeutic effect, enhancing target cell specificity
3Ease of manufacture
If monomeric GITRL is used, then the structure is simpler, but the ability to cluster GITR receptors and trigger intracellular signaling is reduced
Solution Approach 1:
The binding protein employs a composite structure where a multimeric GITRL component (capable of receptor clustering) is integrated with the antibody framework. This composite design combines the structural organization of multimeric ligands with the targeting specificity of antibodies, enabling effective GITR clustering and signal transduction while maintaining manufacturability through established protein engineering techniques
Data Source
AI summary
The present invention relates to a binding protein that specifically binds at least two proteins, wherein said binding protein comprises (i) an antibody or antibody fragment specially binding a first protein and (ii) a multimer, wherein each monomer of the multimer specifically binds a second target and wherein the multimer is inserted between the VH domain and the CH1 domain of the antibody or antibody fragment. In some embodiments, the first target is an immune checkpoint molecule, the second target is a TNFRSF member and the multimer is a multimer of a TNFRSF ligand. The present invention also relates to a pharmaceutical composition comprising said binding protein and the use thereof for the treatment of cancer.