Mutated IL-2 Variants for Selective Treg Activation
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Solution Overview
Problem
Current IL-2 therapies for autoimmune and inflammatory disorders face challenges due to short half-life, severe toxicity, and non-specific stimulation of immune cells, leading to undesirable expansion of immunosuppressive regulatory T cells and limited therapeutic efficacy.
Innovation Solution
Development of mutated IL-2 variants with specific amino acid substitutions that preferentially stimulate regulatory T cells over effector T cells and NK cells, reducing affinity for the IL-2Rβγ receptor complex and eliminating toxic motifs to minimize endothelial damage, while maintaining binding to the IL-2Rαβγ receptor, thereby enhancing therapeutic efficacy and reducing toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If native IL-2 is used for immunotherapy, then immune response is boosted, but severe toxicity and short half-life limit optimal dosing
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at positions 53 and 72 of the IL-2 molecule. These localized changes modify the receptor binding interface to preferentially engage the IL-2Rαβγ heterotrimeric receptor while reducing affinity for the IL-2Rβγ intermediate affinity receptor, thereby creating a molecule with differentiated binding properties at specific locations without altering the overall IL-2 structure
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid residues at positions 53 and 72 to optimize receptor selectivity. The substitutions include L53Q, L53E, L53D, L53N, L53S, L53A, L53G, L53P, L53T, L53V, L53I, L53M, L53F, L53W, L53Y, L53C, L53H, L53K, L53R, L53Q, L53E, L53D, L53N, L53S, L53A, L53G, L53P, L53T, L53V, L53I, L53M, L53F, L53W, L53Y, L53C, L53H, L53K, L53R combined with W72F, W72L, W72Y, W72C, W72A substitutions, which collectively alter binding affinity parameters and selectivity profiles
2Reliability
If IL-2 binds to heterotrimeric receptor IL-2Rαβγ with greater affinity, then immune response is enhanced, but immunosuppressive regulatory T cells are preferentially expanded
Solution Approach 1:
The patent applies inversion by reversing the conventional approach: instead of attempting to block Treg expansion, the invention designs IL-2 variants that selectively activate effector T cells through enhanced IL-2Rαβγ binding while deliberately reducing IL-2Rβγ interaction. The amino acid substitutions at positions 53 and 72 invert the selectivity profile to favor high-affinity receptor engagement over intermediate-affinity receptor binding, thereby converting the harmful Treg expansion effect into a beneficial effector cell activation outcome
Solution Approach 2:
The patent applies local quality by introducing specific amino acid substitutions at positions 53 and 72 of the IL-2 molecule. These localized changes modify the receptor binding interface to preferentially engage the IL-2Rαβγ heterotrimeric receptor while reducing affinity for the IL-2Rβγ intermediate affinity receptor, thereby creating a molecule with differentiated binding properties at specific locations without altering the overall IL-2 structure
3Reliability
If low dose IL-2 is used to target Treg cells, then Treg levels increase, but severe safety and tolerability issues occur
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at positions 53 and 72 of the IL-2 molecule. These localized changes modify the receptor binding interface to preferentially engage the IL-2Rαβγ heterotrimeric receptor while reducing affinity for the IL-2Rβγ intermediate affinity receptor, thereby creating a molecule with differentiated binding properties at specific locations without altering the overall IL-2 structure
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid residues at positions 53 and 72 to optimize receptor selectivity. The substitutions include L53Q, L53E, L53D, L53N, L53S, L53A, L53G, L53P, L53T, L53V, L53I, L53M, L53F, L53W, L53Y, L53C, L53H, L53K, L53R, L53Q, L53E, L53D, L53N, L53S, L53A, L53G, L53P, L53T, L53V, L53I, L53M, L53F, L53W, L53Y, L53C, L53H, L53K, L53R combined with W72F, W72L, W72Y, W72C, W72A substitutions, which collectively alter binding affinity parameters and selectivity profiles
Data Source
AI summary
The present invention relates to polypeptides which share primary sequence with human Interleukin 2 (IL-2), except for several amino acids that have been mutated. One panel of IL-2 variants comprise mutations with impressive manufacturability that preferentially promotes the proliferation, survival, activation and/or function of immunosuppressive regulatory T cells (Tregs) (Treg: CD4+CD25+FoxP3+) over effector T cells and Natural Killer Cells (NK). cells. Also includes therapeutic uses of such IL-2 selective agent, used alone, or in combination with immune modulating agents or disease-tissue targeting antibody, protein or peptide to treat Treg cell-deficiency, various autoimmune and inflammatory disorders, organ transplantation and graft-versus-host disease. In another aspect the present invention relates to pharmaceutical compositions comprising the polypeptides disclosed. Finally, the present invention relates to the therapeutic use of the polypeptides and pharmaceutical compositions disclosed due to their selective modulating effect of the immune system on diseases like autoimmune and inflammatory disorders.