PD-L1/TGF-βRII Fusion Protein Composition for Storage Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing antibody medicaments targeting the PD-1/PD-L1 and TGF-β pathways for tumor treatment face instability due to large molecular weights and susceptibility to degradation, leading to low efficacy in clinical applications.
Innovation Solution
A pharmaceutical composition comprising a PD-L1/TGF-βRII fusion protein stabilized with a citrate buffer, sucrose, and polysorbate 80, with specific concentration and pH ranges, and a lyophilization process to maintain stability during storage and administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibody medicaments with large molecular weights are used to target PD-1/PD-L1 and TGF-β pathways, then tumor treatment efficacy is improved, but stability and susceptibility to degradation worsen
Solution Approach 1:
The patent segments the large molecular weight antibody medicament into a fusion protein consisting of PD-L1 antibody variable regions (for target recognition) fused to TGF-βRII extracellular domain (for TGF-β binding). This segmentation reduces molecular weight while maintaining dual pathway targeting capability, thereby improving stability without sacrificing tumor treatment efficacy.
Solution Approach 2:
The patent extracts only the essential functional domains from the full-length antibody - specifically the variable regions that bind PD-L1 - and combines them with the TGF-βRII extracellular domain. This extraction eliminates unnecessary portions of the large antibody molecule, reducing molecular weight and improving pharmacokinetic properties while maintaining therapeutic effect.
2Stability of the object's composition
If truncated forms of TGF-βRII extracellular domain are used, then stability and expression level are improved, but binding affinity to TGF-β may be reduced
Solution Approach 1:
The patent applies local quality by making a specific truncation at the N-terminus of the TGF-βRII extracellular domain while preserving the C-terminal region that contains the critical TGF-β binding interface. This localized modification improves overall protein stability and expression without compromising the essential binding function.
Solution Approach 2:
The patent changes the structural parameter of the TGF-βRII domain by truncating 14-26 amino acids from the N-terminus. This parameter change optimizes the balance between protein stability/expression and TGF-β binding affinity, creating a fusion protein with improved pharmacological properties while maintaining biological activity.
3Stability of the object's composition
If buffer replacement with citrate buffer is performed, then protein stability during storage is improved, but formulation complexity increases
Solution Approach 1:
The patent changes the buffer system parameter from conventional buffers to citrate buffer, optimizing pH and ionic conditions for the stability of the fusion protein during storage. This parameter optimization ensures maintained physical, chemical, and biological activity over extended periods.
Solution Approach 2:
The patent creates a composite formulation system combining citrate buffer with stabilizing excipients (such as sugars, amino acids, or surfactants) to provide comprehensive protection against degradation during storage. This composite approach addresses multiple stability concerns simultaneously while managing formulation complexity.
Data Source
AI summary
Disclosed in the present disclosure are a TGF-β receptor fusion protein pharmaceutical composition and a use thereof. Specifically, the pharmaceutical composition comprises a TGF-β receptor fusion protein in a sodium citrate buffer, and the TGF-β receptor fusion protein comprises a PD-L1 antibody targeting portion and a TGF-βRII extracellular region. In addition, the pharmaceutical composition may also comprise a sugar and a non-ionic surfactant.