αβhIL2 Mutein Compositions for Selective TIL Expansion
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Solution Overview
Problem
Current TIL therapy methods face challenges in selectively expanding and activating tumor antigen-experienced T cells ex vivo without causing differentiation or exhaustion, and systemic administration of wild-type IL2 leads to toxicity and autoimmunity, necessitating the development of agents that minimize lymphodepletion.
Innovation Solution
The use of αβhIL2 muteins to selectively stimulate the proliferation of antigen-experienced T cells ex vivo and optionally in vivo, providing a composition and method for preparing a population of cells enriched for these cells, which can be administered to a subject.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type IL2 is administered systemically to support TIL persistence, then TIL survival and clinical efficacy are enhanced, but systemic toxicity and autoimmunity occur
Solution Approach 1:
The patent uses engineered IL-2 muteins as intermediaries that selectively bind to CD122 on activated T cells without significantly binding to CD25 on Tregs. This intermediary approach allows IL-2 signaling to be delivered specifically to the desired cell population (activated TILs) while avoiding the harmful effects on other cell types that cause systemic toxicity and autoimmunity.
Solution Approach 2:
The patent modifies the IL-2 molecule to have different binding properties for different cell types. The muteins are designed with specific amino acid substitutions (e.g., Q126H, Q126M, Q126K) that alter their affinity profile to preferentially bind CD122 over CD25, creating local quality differences in molecular interaction that enable selective targeting of activated T cells while sparing Tregs and other CD25-expressing cells.
2Reliability
If lymphodepleting regimens are used prior to TIL reinfusion to remove cellular sinks, then antitumor efficacy is improved, but immune cell depletion and associated toxicities occur
Solution Approach 1:
The engineered IL-2 muteins serve as selective mediators that can support TIL persistence and function without requiring broad lymphodepletion. By specifically targeting CD122 on activated T cells, these muteins provide the necessary immune support to maintain antitumor efficacy while avoiding the harmful effects of depleting other immune cell populations that would otherwise require lymphodepleting regimens.
3Quantity of substance
If ex vivo expansion and activation of TILs is performed to increase cell numbers, then therapeutic cell dose is sufficient, but T cell differentiation and exhaustion occur
Solution Approach 1:
The patent employs engineered IL-2 muteins with modified amino acid sequences (such as Q126H, Q126M, Q126K substitutions) that change the binding parameters of IL-2 to preferentially interact with CD122 on activated T cells. This parameter change in molecular affinity enables selective proliferation support during ex vivo expansion while avoiding the differentiation and exhaustion that occur with wild-type IL-2 or other expansion conditions.
Data Source
AI summary
The present disclosures relates to methods of use to the use of interleukin-2 (IL2) muteins, pharmaceutical formulations thereof, methods useful in the treatment of human disease in combination with adoptive cell therapy. In particular, the present disclosure provides compositions and methods for the use of αβhIL2 muteins that selectively stimulate the proliferation of antigen experienced T cells ex vivo and optionally in vivo; methods of use of αβhIL2 muteins for the activation and expansion of antigen experienced T cells in an isolated population of cells; methods of use of αβhIL2 muteins ex vivo for the to prepare a population of cells enriched for antigen experienced T cells and administering the population of cells to a subject; methods of use of αβhIL2 mutein ex vivo to prepare a population of cells enriched for antigen experienced T cells and administering the population of cells to a subject and administering to said subject a therapeutically effective amount of a αβhIL2 mutein (e.g., such that the administered population of cells proliferate and have a therapeutic effect) and compositions comprising populations T cells of enriched for antigen activated cells.