IL-15 Mutant Polypeptide for Soluble Receptor-Mediated Activation
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Solution Overview
Problem
Existing IL-15 therapies are limited by the requirement for cell-to-cell contact for activation, restricting their use in immunotherapy and other applications.
Innovation Solution
Development of a novel IL-15 mutant polypeptide with modified binding properties for IL-15Rβ and γc receptors, enhancing or reducing binding activity through specific amino acid mutations, allowing for enhanced therapeutic potential.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If IL-15 is used in trans-presentation mode requiring cell-to-cell contact, then biological activity is activated, but therapeutic application is restricted
Solution Approach 1:
The patent extracts the functional domain of IL-15Rα from the cell membrane and presents it in a soluble form (sIL-15Rα). This soluble form can bind IL-15 in circulation without requiring cell-to-cell contact, thereby maintaining biological activity activation while removing the restriction on therapeutic application. The soluble receptor domain captures IL-15 from the bloodstream and presents it to CD122+ cells, achieving therapeutic effect without the need for direct cell contact.
Solution Approach 2:
The patent introduces a soluble IL-15Rα fusion protein as an intermediary molecule that mediates between circulating IL-15 and target cells. This intermediary binds IL-15 with high affinity and presents it to CD122+ cells through FcγR-mediated mechanisms, enabling long-acting trans-presentation without requiring direct cell-to-cell contact. The Fc portion of the fusion protein serves as an additional intermediary that enhances binding to Fcγ receptors on antigen-presenting cells.
2Reliability
If IL-15 binding affinity to CD122 is increased, then T cell proliferation is enhanced, but off-target binding to IL-2 may increase
Solution Approach 1:
The patent applies local quality changes by introducing specific point mutations at defined positions in the IL-15 molecule (e.g., positions 30, 32, 61, 64, 65, 72, 108, 109, 111, 112). These localized amino acid substitutions selectively enhance binding affinity to the CD122 component of the IL-15 receptor complex while preserving or maintaining selectivity against IL-2 receptor binding. Each mutation is designed to affect specific interaction interfaces without globally altering the cytokine's binding properties.
Solution Approach 2:
The patent systematically changes the binding parameters of IL-15 by introducing multiple point mutations that alter electrostatic interactions, hydrogen bonding, and van der Waals forces at the receptor interface. These parameter changes include substituting amino acids to enhance complementarity with CD122 binding grooves while maintaining steric exclusion from IL-2Rα binding sites. The cumulative effect of multiple mutations achieves high-affinity binding to CD122 with reduced cross-reactivity to IL-2.
Data Source
AI summary
Provided in the present application are an IL-15 mutant polypeptide, and a preparation method therefor and the use thereof. Further provided are a nucleic acid encoding the IL-15 mutant polypeptide, a vector containing the nucleic acid, and a host cell.