Anti-PD-1 Fusion Proteins for Dual PD-1 and TGF-β Blockade
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Solution Overview
Problem
Existing anti-PD-1 monoclonal antibodies have limited efficacy in treating various tumors due to low immune cell infiltration and high immunosuppressive cell presence, leading to low objective remission rates.
Innovation Solution
Development of novel anti-PD-1 antibodies and derivatives with specific CDR sequences and fusion proteins that enhance immune cell activity by blocking PD-1/PD-L1 and TGF-β/TGF-βR pathways, including variants and derivatives with improved affinity and biological activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing anti-PD-1 monoclonal antibodies are used for tumor treatment, then immune checkpoint inhibition is achieved, but objective remission rate remains low (less than 30%) due to low immune cell infiltration and high immunosuppressive cell presence
Solution Approach 1:
The patent combines anti-PD-1 antibody function with TGF-β receptor blocking capability into a single fusion protein molecule. The N-terminal anti-PD-1 binding domain and C-terminal TGF-βR extracellular domain are linked via peptide linkers, creating a bivalent molecule that simultaneously inhibits both PD-1/PD-L1 and TGF-β/TGF-βR pathways, thereby overcoming tumor immune escape mechanisms more effectively than monotherapy
Solution Approach 2:
The fusion protein employs a composite structure integrating two distinct functional domains: an anti-PD-1 antibody fragment (scFv or Fab) and a TGF-β receptor extracellular domain. This composite design allows the single molecule to exert dual immunomodulatory effects, addressing multiple immunosuppressive pathways concurrently present in the tumor microenvironment
2Reliability
If fusion proteins blocking both PD-1/PD-L1 and TGF-β/TGF-βR pathways are developed, then immune cell activity is enhanced and tumor infiltration increases, but molecular structure complexity increases
Solution Approach 1:
The fusion protein is segmented into distinct functional modules: an N-terminal anti-PD-1 binding domain (scFv or Fab fragment), flexible peptide linkers (e.g., (G4S)3 or (G4A)4), and a C-terminal TGF-β receptor extracellular domain. This modular segmentation allows each domain to independently perform its function while maintaining overall structural integrity and facilitating rational design and optimization
Solution Approach 2:
Flexible peptide linkers serve as intermediaries connecting the anti-PD-1 binding domain and the TGF-βR extracellular domain. These linkers provide structural flexibility, ensure proper spatial orientation of the two functional domains, and allow independent folding and function of each domain while maintaining the stability of the fusion protein structure
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
Enhances immune cell function, increases tumor infiltration, and improves objective response rates and patient survival by relieving T cell immunosuppression.
Implementation Method 1
an antibody or an antigen-binding fragment thereof capable of specifically binding to PD-1
Implementation Method 2
a fusion protein, comprising the antibody or antigen-binding fragment and a TGF-β/TGF-βR pathway inhibitor
Data Source
AI summary
The present invention relates to the technical field of biomedicine or biopharmaceutics, and more specifically to an anti-PD-1 monoclonal antibody, a derivative thereof and use thereof.