IL2 Variants Enhancing Effector T Cell Activation
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Solution Overview
Problem
Current interleukin-2 (IL2) therapies face challenges due to its short plasma half-life, leading to severe side effects and preferential stimulation of regulatory T cells, which can suppress anti-tumor immune responses, necessitating the development of IL2 variants that enhance activation of effector T cells and NK cells while reducing activation of regulatory T cells.
Innovation Solution
Development of IL2 variants with specific mutations that enhance binding to the intermediate-affinity IL2Rβγ receptor complex and reduce binding to the high-affinity IL2Rαβγ receptor complex, such as the hAlb-hIL2_A4s8 variant, which is designed to stimulate effector T cells and NK cells more effectively at lower concentrations and avoid stimulating regulatory T cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type IL2 is used to stimulate immune cells, then effector T cells and NK cells are activated, but regulatory T cells are also preferentially stimulated, leading to suppression of anti-tumor responses
Solution Approach 1:
The patent modifies specific amino acid residues (positions 80, 81, 85, and 92) in the IL2 protein to create localized changes in binding affinity. These local mutations selectively enhance binding to the intermediate-affinity IL2Rβγ receptor complex on effector T cells and NK cells while reducing binding to the high-affinity IL2Rαβγ receptor complex on regulatory T cells, thereby achieving selective activation without harmful stimulation of Treg cells
Solution Approach 2:
The patent changes the binding affinity parameters of IL2 by introducing specific amino acid substitutions. The mutations at positions 80 (Leu→Phe), 81 (Arg→Glu), 85 (Leu→Val), and 92 (Ile→Phe) alter the receptor interaction characteristics, shifting the preference from high-affinity CD25+ receptors to intermediate-affinity CD25- receptors, thus changing the cellular target profile of IL2
2Reliability
If high doses of IL2 are administered to activate naïve and memory T cells and NK cells, then anti-tumoral potential is improved, but severe side effects such as vascular leak syndrome occur
Solution Approach 1:
The patent modifies the pharmacokinetic and pharmacodynamic parameters of IL2 by introducing amino acid mutations that change receptor binding affinity. The mutant IL2 (hAlb-hIL2_A4s8) has enhanced binding to intermediate-affinity receptors, which are prevalent on naïve and memory T cells as well as NK cells, allowing for more effective activation at lower doses and reducing the risk of dose-limiting toxicities
3Reliability
If recombinant IL2 is administered frequently due to short plasma half-life, then therapeutic effect is maintained, but loss of time and increased toxicity accumulate
Solution Approach 1:
The patent modifies the half-life parameter of IL2 by fusing it to serum albumin (hAlb-hIL2_A4s8), creating a conjugate with extended circulation time. This albumin fusion increases the plasma half-life of the cytokine, allowing for less frequent administration while maintaining therapeutic effect, thereby reducing the accumulation of time loss and associated toxicities from repeated dosing
Data Source
AI summary
The invention relates to variants of interleukin-2 (IL2). In particular, the invention relates to a polypeptide comprising a mutein of human IL2 or of a functional variant of human IL2, wherein the human IL2 or functional variant thereof is substituted such that affinity for the βγ IL2 receptor complex (IL2Rβγ) is enhanced. In one embodiment, the human IL2 or functional variant thereof is further substituted such that affinity for the αβγ IL2 receptor complex (IL2αβγ) is reduced. In one embodiment, the polypeptide activates effector T cells over regulatory T cells. The invention also relates to polynucleotides coding for the polypeptides of the invention, host cells comprising the polynucleotides, pharmaceutical compositions comprising the polypeptides, polynucleotides or host cells, therapeutic or prophylactic methods of treatment using the polypeptides, polynucleotides, host cells or pharmaceutical compositions and medical preparations comprising the polypeptides, polynucleotides, host cells or pharmaceutical compositions.