Reversible Reagent T Cell Expansion Control
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Solution Overview
Problem
Current methods for expanding T cell populations in vitro for therapeutic and research purposes lack precision and control over signal duration and strength, leading to undesirable outcomes such as exhaustion or anergy.
Innovation Solution
The use of reversible reagents with multiple binding sites allows for temporal control of signal delivery to T cells by reversibly binding stimulatory agents, enabling modulation of T cell signals through specific receptors like CD28, and subsequent disruption to adjust or terminate the signal, thereby optimizing expansion and persistence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If continuous stimulation with receptor-binding agents is used to expand T cell populations, then T cell proliferation is enhanced, but T cell exhaustion and anergy occur
Solution Approach 1:
The patent applies periodic action by using reversible reagents that allow temporal control of signal delivery. The system alternates between bound states (providing stimulation) and unbound states (allowing rest), preventing continuous stimulation. This is achieved through reversible binding interactions that naturally cycle between bound and unbound configurations, enabling T cells to proliferate during bound phases while recovering during unbound phases, thus preventing exhaustion and anergy.
Solution Approach 2:
The patent implements dynamics by introducing reversible binding interactions that allow the system to adapt its state over time. The reversible reagents dynamically transition between bound and unbound states, creating a dynamic stimulation regime rather than static continuous stimulation. This dynamic behavior enables the system to respond to T cell needs, providing stimulation when proliferation is needed and withdrawal when recovery is required, maintaining T cell functionality while enabling expansion.
2Quantity of substance
If strong and prolonged signals are delivered to T cells to induce expansion, then T cell yield increases, but T cell activation-induced cell death increases
Solution Approach 1:
The reversible reagent system implements periodic action by creating cycles of signal delivery and withdrawal. During bound states, T cells receive stimulation signals that promote expansion. During unbound states, the signal is withdrawn, allowing T cells to avoid over-activation and activation-induced cell death. This periodic on-off signaling pattern enables sustained T cell yield increases while preventing the harmful effects of continuous strong stimulation.
Solution Approach 2:
The patent applies parameter changes by modulating the duration, strength, and timing of signals through reversible binding kinetics. The system changes the effective concentration and temporal profile of stimulatory signals dynamically, transitioning between high-signal (bound) and low-signal (unbound) states. This parameter modulation enables optimization of T cell expansion while avoiding the threshold for activation-induced cell death, achieving high yield with maintained cell viability.
3Manufacturing precision
If reversible reagents are used to control signal duration, then temporal precision of signal delivery is improved, but system complexity increases
Solution Approach 1:
The patent uses reversible reagents as intermediaries that mediate between the stimulatory agents and T cell receptors. These intermediary molecules provide the temporal control function through their reversible binding properties, without requiring complex external control systems. The intermediary reagents translate simple binding/unbinding events into precisely controlled signal delivery patterns, achieving temporal precision while maintaining relative system simplicity by offloading the control function to the chemical properties of the intermediary molecules.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach allows for precise control over T cell expansion and activation, reducing exhaustion and anergy, and enhancing the proliferation and persistence of T cells, leading to increased yields of functional T cell subsets.
Implementation Method 1
the receptor-binding agent is reversibly bound to a reagent containing a plurality of binding sites capable of reversibly binding to the receptor-binding agent
Data Source
AI summary
Provided herein are methods that relate, in some aspects, to the incubation or culturing, such as to induce stimulation of expansion (proliferation), activation, costimulation and/or survival, of a composition of cells, such as a population of lymphocytes. In some aspects, provided are methods and reagents for the stimulation, e.g., of expansion (proliferation), survival or persistence, activation, costimulation, or other effect, of cell populations that involve binding of agents to a molecule on the surface of the cells, thereby providing one or more signals to the cells. In some cases, the reagents are reagents containing a plurality of binding sites for agents, such as multimerization reagents, and thus the one or more agents are multimerized by reversibly binding to the reagent, e.g., thereby creating a stimulatory reagent (multimerized agent), having stimulatory agents multimerized thereon. In some aspects, the multimerized agent can provide for expansion or proliferation or other stimulation of a population of cells, and then such stimulatory agents can be removed by disruption of the reversible bond. Also provided are compositions, apparatus and methods of use thereof.