Chimeric Polypeptide for Constitutive Cytokine Signaling
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Solution Overview
Problem
Current methods for enhancing CAR-T cell persistence and survival in cancer treatment, such as systemic cytokine administration and engineering cells to secrete cytokines, face challenges like toxicity and uncontrolled proliferation, and require complex engineering of cytokine receptors.
Innovation Solution
A chimeric polypeptide that constitutively binds to endogenous cytokine receptors, using an antigen-binding domain and a cytokine receptor endodomain to induce cytokine signaling without external cytokine presence, which can be expressed in cells alone, reducing the need for complex receptor engineering and avoiding over-expression of the common gamma chain.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If systemic cytokine administration is used to enhance CAR-T cell persistence and survival, then cell persistence is improved, but toxicity increases
Solution Approach 1:
The invention extracts the signaling function of cytokine receptors from the natural cytokine-dependent system. By using a chimeric polypeptide that constitutively activates the cytokine receptor signaling pathway through its endodomain, the beneficial survival and persistence signals are decoupled from the need for systemic cytokine administration, thereby eliminating cytokine-related toxicity while maintaining enhanced CAR-T cell persistence
Solution Approach 2:
The chimeric polypeptide acts as an intermediary molecule that bridges the extracellular space and intracellular signaling pathway. It comprises an antigen-binding domain that can bind to target antigens and a cytokine receptor endodomain that activates intracellular survival signaling, thereby mediating between antigen recognition and cell survival without requiring external cytokines
2Duration of action of moving object
If cells are engineered to secrete cytokines, then CAR-T cell survival is improved, but uncontrolled proliferation and transformation occur
Solution Approach 1:
The invention extracts the intracellular signaling function from the secreted cytokine system. Instead of engineering cells to secrete cytokines that then bind to autocrine/paracrine receptors, the chimeric polypeptide directly activates the receptor endodomain intracellularly, removing the uncontrolled proliferation risk associated with high-level cytokine secretion while maintaining survival benefits
Solution Approach 2:
The invention inverts the traditional cytokine signaling direction. Rather than having cells secrete cytokines that act on receptors (extracellular to intracellular signaling), the chimeric polypeptide presents the receptor endodomain in a way that constitutively activates signaling from the intracellular side, reversing the conventional signaling paradigm to achieve controlled survival without uncontrolled proliferation
3Duration of action of moving object
If constitutive cytokine production is engineered, then CAR-T cell persistence is improved, but transformation risk increases
Solution Approach 1:
The invention extracts the signaling activation function from the constitutive cytokine production system. By using a chimeric polypeptide with a cytokine receptor endodomain that is constitutively active, the survival signaling is achieved without the need for constitutive cytokine production, thereby eliminating the transformation risk associated with unregulated cytokine expression while maintaining persistent CAR-T cell function
4Duration of action of moving object
If complex cytokine receptor engineering is performed, then constitutive signaling is achieved, but device complexity increases
Solution Approach 1:
The invention merges the antigen-binding function and cytokine receptor signaling function into a single chimeric polypeptide molecule. This consolidation eliminates the need for separate engineering of cytokine secretion pathways, receptor expression systems, and signaling components, thereby achieving constitutive cytokine signaling with reduced overall complexity compared to traditional approaches requiring multiple engineered elements
Solution Approach 2:
The chimeric polypeptide serves multiple functions simultaneously: it acts as an antigen-binding molecule through its variable domain, functions as a signaling receptor through its endodomain, and provides constitutive activation of survival pathways. This multi-functionality reduces the number of separate genetic elements and engineering steps required compared to traditional CAR designs that require separate cytokine expression cassettes and receptor components
Data Source
AI summary
The present invention provides a chimeric polypeptide comprising: an antigen-binding domain which constitutively binds to an ectodomain of a first chain of a cytokine receptor; a transmembrane domain; and an endodomain from a second chain of the cytokine receptor which chimeric polypeptide, when expressed in a cell, binds to the endogenous first chain of the cytokine receptor causing constitutive cytokine signalling.