Orthogonal IL-21 Receptor-Cytokine Pairing for Targeted Cell Activation
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Solution Overview
Problem
Existing cytokines like IL-2 and IL-21 exhibit pleiotropic effects, complicating their clinical utility due to interactions with multiple cellular targets, leading to unwanted side effects such as proliferation of regulatory T cells and autoimmune responses, necessitating the development of orthogonal cytokine systems that limit activity to therapeutic cells.
Innovation Solution
Engineering orthogonal IL-21 receptor and cytokine variants with specific amino acid substitutions to impair binding to native partners, allowing them to interact exclusively with engineered receptors on therapeutic cells, thereby modulating IL-21 activity without affecting non-targeted endogenous cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If natural IL-21 cytokine is used, then broad immune activation and antitumor activity are achieved, but unwanted side effects including autoimmune responses and proliferation of regulatory T cells occur
Solution Approach 1:
The patent divides the IL-21 system into separate orthogonal components: a modified IL-21 cytokine (e.g., IL-21α) and a corresponding orthogonal receptor (e.g., IL-21Rα). This segmentation allows the cytokine to be selectively activated only by its orthogonal receptor on therapeutic cells, preventing off-target effects while maintaining antitumor activity.
Solution Approach 2:
The patent introduces local specificity by engineering the orthogonal receptor to be expressed only on therapeutic cells (such as CAR-T cells), while the modified cytokine binds exclusively to this engineered receptor. This creates a localized signaling pathway that activates immune responses only at the desired therapeutic site without affecting other cell types.
2Reliability
If orthogonal IL-21 receptor and cytokine variants are engineered, then binding specificity to therapeutic cells is improved, but system complexity increases
Solution Approach 1:
The patent achieves orthogonality through specific parameter changes in amino acid sequences. By modifying particular residues in the cytokine (e.g., positions 6, 9, 10, 11, 73, 76, 78, 80, 84, 104) and corresponding receptor binding sites, the system gains selective binding capability without requiring entirely new protein families, thus managing complexity through targeted mutations rather than complete system redesign.
Data Source
AI summary
Orthogonal IL-21 receptors and orthogonal IL-21 cytokines are described. The IL-21 receptor-cytokine pairs may include an orthogonal interleukin-21 receptor α chain (“ortho-IL-21Rα”) that has impaired binding to native interleukin-21 cytokine (“IL-21”) and an orthogonal IL-21 cytokine (“ortho-IL-21”) that has impaired binding to native IL-21Rα, wherein the ortho-IL-21Rα binds to the ortho-IL-21. The IL-21 receptor-cytokine pair may activate IL-21 signaling. Cells engineered to express the orthogonal IL-21 receptors are also described, as well as methods for using such cells for treatment of various diseases and disorders.