Modified IL-2 Polypeptides for Targeted T Cell Activation
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Solution Overview
Problem
Current IL-2 therapies, such as recombinant human IL-2 (rhIL-2), are associated with severe toxicity due to rapid receptor-mediated internalization and degradation, leading to vascular leak syndrome, and have limited efficacy in cancer treatment with response rates around 30% for antagonist antibodies to checkpoint receptors.
Innovation Solution
Development of modified IL-2 polypeptides with reduced affinity for CD25 and CD122, and/or IL-2R, and fusion with targeting moieties, such as antigen binding domains, to modulate T cell activity and specificity, thereby enhancing cancer treatment efficacy while minimizing toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type IL-2 is used to stimulate T cell proliferation, then anti-tumor activity is improved, but severe toxicity occurs due to rapid receptor-mediated internalization and degradation
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid residues in the IL-2 polypeptide sequence (e.g., positions 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100). These substitutions alter the binding affinity parameters of IL-2 for CD25 and CD122 receptors, reducing internalization and degradation rates while preserving T cell stimulatory activity, thereby improving the therapeutic index by reducing toxicity
Solution Approach 2:
The patent applies local quality by making specific localized modifications at particular amino acid positions within the IL-2 sequence rather than global changes. By targeting specific residues that are critical for receptor binding and internalization (such as positions involved in CD25 or CD122 interaction), the invention achieves selective modification of toxic pathways while preserving the essential immunostimulatory function of IL-2 on T cells
2Reliability
If IL-2 is used to stimulate T cell proliferation, then T cell activation is improved, but the half-life is extremely short due to rapid internalization and degradation
Solution Approach 1:
The patent applies parameter changes by substituting specific amino acid residues in IL-2 to alter kinetic parameters of receptor interaction. These modifications reduce the rate of receptor-mediated internalization and degradation, thereby extending the half-life of IL-2 in circulation and at the target site while maintaining its ability to activate T cells effectively
3Reliability
If rhIL-2 is administered to treat cancer, then T cell-mediated anti-tumor response is improved, but vascular leak syndrome occurs due to effects on endothelial cells
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions that differentially affect binding to T cell versus endothelial cell receptors. By modifying residues that are critical for high-affinity binding to CD25 (which is highly expressed on activated T cells but also present on endothelial cells), the invention achieves selective modulation of activity - reducing vascular toxicity while preserving anti-tumor efficacy through altered kinetic profiles or selective targeting strategies
4Reliability
If antagonist antibodies to checkpoint receptors are used, then cancer treatment efficacy is improved, but response rate is limited to about 30% of patients
Solution Approach 1:
The patent applies merging by combining modified IL-2 polypeptides with checkpoint inhibitor antibodies (anti-CTLA-4, anti-PD-1, or anti-PD-L1) in single-agent or combination therapies. This merger creates a synergistic effect where the modified IL-2 enhances T cell activation and proliferation while checkpoint inhibitors block inhibitory signals, together overcoming resistance mechanisms that limit antibody-only therapy response rates and expanding the proportion of patients who benefit from treatment
Data Source
AI summary
Provided herein are polypeptide comprising a modified IL-2, wherein the modified IL-2 has reduced affinity for the IL-2 receptor relative to wild type IL-2. In some embodiments, polypeptides comprising a modified IL-2 that bind and agonize activated T cells are provided. Uses of the polypeptides comprising a modified IL-2 are also provided.