Fusion Polypeptide Co-Stimulation for CAR T-Cell Relapse
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Solution Overview
Problem
Existing cell-based immunotherapy for cancer treatment, such as CAR T-cell therapy, faces challenges with treatment failure and relapse due to insufficient activation and efficacy of immune cells targeting tumor antigens.
Innovation Solution
Development of fusion polypeptides comprising an antigen-binding fragment and a co-stimulatory ligand polypeptide, which enhance the activity of T cells by binding to immune checkpoint molecules like PD-L1 and incorporating co-stimulatory molecules like CD80 and 4-1BB, thereby improving immune cell activation and cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR T-cell therapy is used to target tumor antigens, then T cells can be introduced to recognize cancer cells, but treatment failure and relapse occur due to insufficient activation and efficacy of immune cells
Solution Approach 1:
The patent combines multiple functional domains into a single fusion polypeptide: an antigen-binding fragment (to recognize tumor antigens), a co-stimulatory ligand domain (to provide activation signals), and an intracellular signaling domain (to transmit activation signals into the T cell). This merging of functions into one molecule enhances T cell activation reliability without requiring multiple separate components, thereby resolving the contradiction between treatment efficacy and mechanism complexity
Solution Approach 2:
The fusion polypeptide acts as a composite molecular structure integrating different functional elements: the antigen-binding fragment (e.g., scFv or nanobody), the co-stimulatory ligand (e.g., CD80 or 4-1BBL), and the intracellular signaling domain. This composite structure enables simultaneous antigen recognition and co-stimulation, improving treatment efficacy while maintaining a unified molecular design rather than requiring multiple separate therapeutic agents
2Productivity
If fusion polypeptides with multiple co-stimulatory domains are introduced, then T cell activation and cytotoxicity are enhanced, but the structural complexity of the therapeutic molecule increases
Solution Approach 1:
The fusion polypeptide is segmented into distinct functional modules: an N-terminal antigen-binding fragment, a middle co-stimulatory ligand domain, and a C-terminal intracellular signaling domain. Each segment performs a specific function, allowing the molecule to achieve high T cell productivity through multiple co-stimulatory signals while maintaining a organized, modular structure that is easier to design and manufacture compared to non-modular complex proteins
3Measurement precision
If the antigen-binding fragment is engineered to bind specific immune checkpoint molecules like PD-L1, then targeting precision is improved, but the manufacturing and characterization of the therapeutic becomes more difficult
Solution Approach 1:
The patent employs antibody fragments (scFv, Fab, or nanobodies) instead of full-length antibodies as the antigen-binding component. These fragments are smaller, easier to manufacture, and can be produced more efficiently than complete antibodies. While they have shorter half-lives in vivo, their ease of production and characterization offsets this limitation, resolving the contradiction between binding precision and manufacturing ease
Data Source
AI summary
The presently disclosed subject matter provides methods and compositions for enhancing immune responses toward tumor and pathogen antigens. It relates to fusion polypeptide that can be expressed in cells (e.g., immunoresponsive cells comprising an antigen-recognizing receptor) to improve the activity and/or efficiency of the cells. In certain embodiments, the fusion polypeptide comprises an extracellular domain comprising an antigen-binding fragment and a co-stimulatory ligand polypeptide, and an intracellular domain comprising a first co-stimulatory molecule polypeptide.