Bispecific NK Cell Agonist scfv-CD16A Trimer-4-1BBL Fusion Protein
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Solution Overview
Problem
Existing NK cell agonists have limited ability to activate NK cells, and there is a need for improved strategies to enhance their antiviral and antitumor capabilities, as well as promote NK cell proliferation and T cell function.
Innovation Solution
A bispecific NK cell agonist medicament, scfv-CD16A/Trimer-4-1BBL, is designed using a CD16A receptor and 4-1BB receptor as targets, with a CD16A single-chain antibody linked to three 4-1BBL extracellular domains, synergistically activating NK cells and enhancing their antiviral and antitumor abilities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing NK cell agonists are used, then NK cells can be activated, but the activation ability is limited and cannot sufficiently enhance antiviral and antitumor capabilities
Solution Approach 1:
The patent combines two different activating ligands (anti-CD16A antibody and 4-1BBL) into a single bifunctional fusion protein. This merging allows the molecule to simultaneously engage both CD16A and 4-1BB receptors on NK cells, producing synergistic activation effects that overcome the limitations of single-ligand agonists and significantly enhance antiviral and antitumor capabilities.
Solution Approach 2:
The fusion protein employs a composite structure comprising an anti-CD16A single-chain antibody fragment linked to a trimeric 4-1BBL extracellular domain. This composite design integrates the advantages of both ligands: CD16A engagement provides strong activating signal, while 4-1BB engagement enhances persistence and proliferation, creating a material with superior functional properties compared to individual components.
2Reliability
If tumor microenvironment immunosuppression is present, then NK cell activity is inhibited, but the patent aims to restore NK cell function
Solution Approach 1:
The bifunctional fusion protein preemptively counteracts the immunosuppressive effects of the tumor microenvironment by simultaneously delivering two potent activating signals to NK cells. This preliminary anti-action prevents NK cell exhaustion before it occurs, maintaining their cytotoxic activity and ability to eliminate tumor cells despite the presence of suppressive factors such as TGF-β and PD-L1.
3Quantity of substance
If single-ligand NK cell agonists are used, then some activation effect is achieved, but proliferation and persistence enhancement is insufficient
Solution Approach 1:
The 4-1BBL component acts as an intermediary that bridges NK cell activation with enhanced persistence and proliferation. While the anti-CD16A portion provides immediate strong activation, the trimeric 4-1BBL domain serves as a persistent stimulator that promotes NK cell survival and expansion over time, thereby achieving both high activation effect and enhanced proliferation.
Data Source
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AI summary
The present disclosure relates to the field of biomedicine, and specifically relates to a bispecific NK cell agonist, a preparation method, and a use. The present disclosure provides a fused protein. The fused protein uses a CD16A receptor and a 4-1BB receptor as targets to obtain a new bispecific NK cell agonist medicament, i.e., scfv-CD16A-Trimer-4-1BBL; the medicament has the activity of activating and amplifying an NK cell in vitro, enhancing the antivirus and antitumor capabilities of the NK cell, and has the potential effects of promoting NK cell proliferation and enhancing a T cell function, and has the application potential of culturing and amplifying the NK cells in vitro; and the amplified NK cells have good cytotoxicity.