Cleavable Ligand Binding Molecule for Targeted Cytokine Activation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current cytokine-based therapies face challenges such as systemic toxicity, narrow therapeutic windows, and limited efficacy when administered systemically, due to their strong activity across the entire body.
Innovation Solution
Development of a ligand binding molecule with a cleavage site that attenuates ligand binding activity upon cleavage, allowing for targeted activation of cytokines or chemokines specifically in target tissues through protease-specific cleavage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cytokines are administered systemically to achieve therapeutic effects, then the antitumor effect is improved, but systemic toxicity increases
Solution Approach 1:
The invention divides the cytokine delivery system into two separate components: an antibody that accumulates at the tumor site and a cytokine that is activated only after cleavage by tumor-associated proteases. This segmentation allows the cytokine to be delivered systemically without exerting systemic effects until it reaches the target tissue, where protease cleavage activates it locally.
Solution Approach 2:
The antibody is administered systemically in advance and accumulates at the tumor site before the cytokine is activated. The antibody serves as a pre-positioned delivery vehicle that waits at the target location, ready to release and activate the cytokine when the protease cleaves the linker, ensuring localized action before systemic distribution.
2Reliability
If cytokines are administered at high doses to improve therapeutic effect, then the antitumor activity is enhanced, but adverse reactions increase
Solution Approach 1:
The invention creates local quality by ensuring the cytokine is activated only at the tumor site through protease-specific cleavage. The antibody accumulates preferentially at the tumor location, and the cytokine is released and activated only where the protease is present, creating a localized high-concentration zone of therapeutic activity without systemic distribution.
3Reliability
If a linker is used to connect cytokine and antibody, then targeted delivery is achieved, but the cytokine remains active before cleavage causing toxicity
Solution Approach 1:
The invention extracts the cytokine's biological activity from the intact fusion protein by using a protease-cleavable linker. The cytokine is kept inactive while connected to the antibody, and its activity is extracted and activated only after protease cleavage releases it at the target site, eliminating systemic toxicity during circulation.
4Reliability
If cytokines are administered systemically to achieve sufficient therapeutic effect, then the antitumor efficacy is improved, but the therapeutic window narrows
Solution Approach 1:
The invention creates a steep concentration gradient by localizing cytokine activation to the tumor site. The antibody accumulates at the tumor, and protease cleavage activates the cytokine only where needed, creating extremely high local concentrations at the target while maintaining very low systemic levels, thereby dramatically expanding the therapeutic window.
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
This approach enables selective activation of ligands in target tissues, potentially enhancing therapeutic effects while minimizing systemic adverse reactions.
Implementation Method 1
a ligand binding molecule which is a molecule capable of binding to a ligand, wherein the molecule is a polypeptide having at least one cleavage site, and the ligand binding of the molecule cleaved at the at least one cleavage site is attenuated
Data Source
AI summary
The present invention relates to a ligand binding molecule whose ligand binding activity is attenuated by the cleavage of a cleavage site and a method for producing the same, a complex formed by the ligand binding molecule and a ligand, a fusion protein comprising the ligand binding molecule and a ligand, and a pharmaceutical composition comprising the ligand binding molecule or a fusion protein of the ligand binding molecule and a ligand.