Multimeric IL-15 Fusion Proteins for Disease-Targeted Immune Stimulation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing strategies to target effector molecules to disease sites often result in non-specific immune activity, leading to undesirable side effects.
Innovation Solution
Development of multi-specific IL-15-based protein complexes comprising IL-15N72D:IL-15RαSu-Ig Fc scaffolds fused to binding domains that recognize disease antigens or immune checkpoints, enhancing immune cell stimulation and activity against disease cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multi-specific IL-15-based protein complexes are used to target effector molecules to disease sites, then immune cell stimulation and activity against disease cells is enhanced, but the complexity of the molecule increases
Solution Approach 1:
The patent combines multiple functional domains into a single IL-15-based protein complex: the IL-15 superagonist domain for immune cell stimulation, the IL-15RαSu domain for receptor binding, the Fc domain for dimerization and half-life extension, and antigen-specific binding domains for targeting. This merging of multiple functions into one molecule achieves enhanced immune cell stimulation and disease cell activity while reducing the need for multiple separate therapeutic agents.
Solution Approach 2:
The IL-15-based protein complex is designed with multi-functionality to perform several roles simultaneously: stimulating immune cells via IL-15, binding to receptors via IL-15RαSu, providing structural stability and extended circulation via Fc dimerization, and targeting specific disease cells via antigen-binding domains. This universal design allows a single molecule to replace multiple separate therapeutic components.
2Reliability
If IL-15-based protein complexes are designed with multiple binding domains to recognize disease antigens and immune checkpoints, then binding to disease antigens is increased, but the manufacturing complexity increases
Solution Approach 1:
Multiple binding functions are merged into a single polypeptide chain through genetic fusion. The IL-15 superagonist, IL-15RαSu, Fc domain, and antigen-specific binding domains are encoded by linked nucleic acid sequences that direct the synthesis of a single fusion protein. This approach increases binding specificity to disease antigens while simplifying manufacturing compared to producing and assembling multiple separate proteins.
Solution Approach 2:
The fusion protein design provides universality by incorporating multiple functional domains within a single manufacturable entity. The molecule can bind to multiple targets (immune cell receptors via IL-15, disease antigens via specific binding domains) simultaneously, and the Fc domain provides universal properties like dimerization and extended half-life. This multi-functional design streamlines manufacturing processes.
3Duration of action of stationary object
If the IL-15RαSu/Fc domain is used to dimerize IL-15 superagonist molecules, then the half-life of the complex is extended, but the molecular weight increases
Solution Approach 1:
The patent merges the IL-15 superagonist domain with the IL-15RαSu/Fc domain to create a dimeric structure. The Fc domain naturally dimerizes through disulfide bonds, bringing two IL-15 superagonist molecules together. This merging achieves extended half-life through dimerization and Fc-mediated protection from degradation, while the increased molecular weight is an acceptable trade-off for the therapeutic benefit of prolonged circulation and enhanced immune stimulation.
Data Source
Figure 1
Figure 2
Figure 3
AI summary
The invention features multi- specific protein complexes with one domain comprising IL-15 or a functional variant and a binding domain specific to a disease antigen, immune checkpoint or signaling molecule.