CD6 Avidity Switch Polypeptides for Persistent Immune Cell Targeting
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Solution Overview
Problem
Current immune cell therapies face challenges in maintaining immune cell activation and proliferation and preventing therapeutic cell exhaustion, particularly in treating solid malignancies, with existing approaches like CAR T cells lacking persistence in vivo.
Innovation Solution
Development of nucleic acids encoding engineered avidity switch polypeptides, comprising extracellular stabilization, SRCR, hinge, transmembrane, and intracellular signaling domains, to enhance or decrease immune cell avidity, expressed in immune cells such as T cells, NK cells, and NKT cells, using vectors like retrovirus, lentivirus, or adeno-associated virus for genetic modification.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If CAR T cells are used to achieve rapid immune cell activation and response, then the speed of immune response is improved, but the ability to maintain initial activation and persistence in vivo deteriorates
Solution Approach 1:
The patent applies dynamics by making the immune cell's avidity adjustable rather than fixed. The engineered immune cells can dynamically modulate their avidity for target cells, allowing them to adapt their binding strength in response to physiological conditions. This dynamic control enables the cells to maintain persistence in vivo while preserving rapid activation capability, resolving the contradiction between speed and duration of action.
2Productivity
If immune cell activation is enhanced to improve treatment efficacy, then the killing efficiency is improved, but therapeutic cell exhaustion increases
Solution Approach 1:
The patent applies parameter changes by modifying the avidity parameter of immune cells through engineered receptors with varying binding strengths. By changing the avidity parameter, the system can optimize killing efficiency while avoiding excessive activation that leads to exhaustion. The ability to tune avidity levels allows maintaining high productivity without triggering reliability issues related to cell exhaustion.
3Productivity
If high avidity is maintained to increase killing efficiency, then the productivity is improved, but the adaptability to different target densities deteriorates
Solution Approach 1:
The patent applies dynamics by enabling immune cells to adjust their avidity based on target density. The engineered receptors allow cells to modulate binding strength dynamically, providing high avidity when target density is low to maintain productivity, and adapting to appropriate avidity levels when target density is high. This dynamic adaptability resolves the contradiction between maintaining killing efficiency and adapting to varying target conditions.
Data Source
AI summary
Disclosed herein, in some aspects, are engineered avidity switch polypeptides, polynucleotides encoding the same, immune cells comprising the same, and compositions comprising the polypeptides, polynucleotides, and/or immune cells. In certain embodiments, engineered avidity switch polypeptides comprise one or more CD6 derived amino acid sequences and/or domains. In certain embodiments, engineered avidity switch polypeptides comprise engineered arrangements of extracellular domains of CD6 polypeptides. Also disclosed are methods for disease treatment, such as cancer treatment, comprising administering such immune cells and/or compositions to a subject in need thereof.