LAG-3-Targeted IL-15 Fusion Proteins for Selective TIL Activation
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Solution Overview
Problem
Current cytokine-based cancer immunotherapies, such as IL-2 and IL-15, suffer from fast clearance and systemic toxicity, while immune checkpoint blockade therapies like PD-1 inhibitors have limited efficacy in some patients, necessitating safer and more effective combination therapies.
Innovation Solution
Development of LAG-3-targeted IL-15 heterodimeric fusion proteins with enhanced half-life and selective targeting to improve safety and synergize with checkpoint blockade antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If high doses of IL-2 or IL-15 are administered to overcome fast clearance, then the cytokine activity is sufficient, but systemic toxicity occurs
Solution Approach 1:
The invention segments the cytokine therapy by using a heterodimeric fusion protein that combines IL-15 with an antibody targeting LAG-3. This segmentation allows the cytokine activity to be localized to tumor sites where LAG-3 is expressed, rather than systemic distribution. The antibody portion targets the protein to specific cells (TILs expressing LAG-3), while the IL-15 portion provides the cytokine function, achieving both extended duration and reduced toxicity.
Solution Approach 2:
The LAG-3 antibody portion acts as an intermediary that mediates the delivery of IL-15 to the target site. Instead of administering IL-15 directly into the system, the antibody serves as a vehicle that carries IL-15 to cells expressing LAG-3, primarily at tumor sites. This intermediary approach extends the half-life of the cytokine while preventing systemic toxicity by limiting exposure to the target tissue.
2Reliability
If checkpoint blockade therapy is used alone, then immune escape is blocked, but many patients still fail to achieve sufficient response
Solution Approach 1:
The invention merges two therapeutic approaches: checkpoint blockade (via LAG-3 antibody) and cytokine therapy (via IL-15). By combining these mechanisms in a single heterodimeric fusion protein, the therapy simultaneously blocks immune checkpoint inhibition while providing cytokine-mediated T cell activation and proliferation. This combination approach addresses the limitation of checkpoint blockade alone by adding a second mechanism to overcome resistance and improve response rates.
Solution Approach 2:
The therapeutic agent is a composite molecular structure combining antibody and cytokine components. The heterodimeric fusion protein integrates the LAG-3 binding domain (antibody portion) with the IL-15 cytokine domain, creating a composite therapeutic that delivers both checkpoint blockade and cytokine stimulation functions in a single molecule, thereby improving overall efficacy and patient response rates.
3Object-affected harmful factors
If untargeted cytokine therapy is used, then cytokine activity is achieved, but selectivity for TILs is lost
Solution Approach 1:
The invention applies local quality by making the cytokine therapy selective for specific target cells. The LAG-3 antibody portion of the fusion protein provides specificity by binding only to cells expressing LAG-3, primarily tumor-infiltrating lymphocytes at the tumor site. This ensures that IL-15 activity is concentrated locally at the target tissue rather than being distributed systemically, achieving both selectivity and adequate cytokine delivery to the intended cells.
Data Source
AI summary
The present invention is directed to novel targeted heterodimeric fusion proteins comprising an IL-15/IL-15Rα Fc-fusion protein and a LAG-3 antibody fragment-Fc fusion protein.