Long-acting IL-2Rbeta Agonist for T Cell Persistence
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Solution Overview
Problem
Current adoptive cell transfer therapies for cancer treatment face challenges such as low persistence of effector T cells, expansion of both effector and regulatory T cells, and associated toxicities, leading to limited anti-tumor responses and high dropout rates in patients.
Innovation Solution
Administering a long-acting IL-2Rβ-biased agonist in combination with adoptive cell transfer therapy to preferentially expand effector T cells and inhibit the accumulation of regulatory T cells, thereby enhancing the therapeutic effectiveness and persistence of tumor-killing immune cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If high dose IL-2 is used to expand T cells in adoptive cell transfer therapy, then the number of T cells increases, but both effector T cells and regulatory T cells are expanded indiscriminately, reducing anti-tumor effectiveness
Solution Approach 1:
The patent modifies the IL-2 molecule to create a variant with altered receptor binding properties that selectively activates IL-2Rβ and IL-2Rγ chains while avoiding IL-2Rα-containing receptors. This creates a localized functional difference in receptor interaction, allowing preferential expansion of effector T cells over regulatory T cells.
Solution Approach 2:
The patent changes the molecular parameters of IL-2 by substituting specific amino acids (e.g., Lysine at position 7, Arginine at position 39) to alter its binding affinity and specificity for different IL-2 receptor subtypes. This parameter modification enables selective biological activity.
2Productivity
If conventional IL-2 is used for T cell expansion, then T cells proliferate, but the half-life is short leading to poor persistence of effector T cells
Solution Approach 1:
The patent employs a modified IL-2 molecule with extended half-life that maintains continuous biological activity for prolonged periods. This continuous action ensures sustained T cell proliferation and persistence without the intermittent effects of short-acting IL-2.
Solution Approach 2:
The modified IL-2 molecule inherently possesses extended stability and half-life properties due to its structural modifications, allowing it to self-maintain its therapeutic effect without requiring frequent re-administration or external support systems.
3Reliability
If adoptive cell transfer therapy is administered alone, then tumor specific T cells are infused, but persistence in circulation is barely 0.1 percent one week after administration
Solution Approach 1:
The patent uses a modified IL-2 molecule as an intermediary substance that mediates between the infused T cells and the host immune environment. This intermediary provides sustained signals that enhance T cell survival, persistence, and anti-tumor activity in the circulation.
Solution Approach 2:
The modified IL-2 is administered in conjunction with adoptive cell transfer to preliminarily establish a supportive environment for T cell persistence before the T cells encounter tumor targets, thereby enhancing their survival and functionality.
4Adaptability or versatility
If lymphodepleting preconditioning is used to suppress regulatory T cells, then optimal environment is created for infused T cells, but patient toxicities including hypotension, pulmonary congestion, and bone marrow suppression occur
Solution Approach 1:
The patent extracts the lymphodepleting step from the treatment protocol and replaces it with a modified IL-2 molecule that selectively suppresses regulatory T cells through its biased receptor activity, thereby achieving the desired immune environment without the toxicities of conventional lymphodepletion.
Solution Approach 2:
The modified IL-2 molecule copies and enhances the desired effect of lymphodepletion (suppression of regulatory T cells) while avoiding the harmful mechanisms that cause toxicities, creating a safer alternative that achieves the same therapeutic goal.
Data Source
AI summary
Provided are methods and compositions directed towards the treatment of an individual having cancer by providing adoptive cell transfer therapy and administering to the individual a long-acting IL-2Rβ-biased agonist.