Mutated PD1 Ectodomain CAR-NK Cells for PD-L1 Tumor Targeting
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Solution Overview
Problem
Current antibody therapies against PD-1/PD-L1 interactions in tumors are limited in reversing immune cell suppression and can induce immune system disorders, while NK-CAR cells are inhibited by the tumor microenvironment, allowing tumor cells to evade immune surveillance.
Innovation Solution
A chimeric antigen receptor (CAR) is developed using a mutated PD1 ectodomain in NK cells, comprising a signal peptide, hinge region, transmembrane domain, intracellular costimulatory signaling domain, and intracellular signaling domain, enhancing tumor cell killing ability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibody therapy is used to block PD-1/PD-L1 interaction, then immune cell suppression is reduced, but immune system disorders are induced due to Fc region effects
Solution Approach 1:
The invention extracts only the antigen-binding domain (ectodomain) of PD-1 to create the CAR structure, deliberately excluding the Fc region that causes ADCC and ADCP effects. This allows the CAR to block PD-1/PD-L1 interaction without inducing immune system disorders from Fc-mediated activities.
Solution Approach 2:
The mutated PD-1 ectodomain serves as an intermediary structure in the CAR that specifically binds to PD-L1 on tumor cells, mediating the blocking effect without requiring the full PD-1 receptor structure. This intermediary approach achieves the therapeutic effect while avoiding harmful Fc region interactions.
2Strength
If NK-CAR cells are used to kill tumor cells, then tumor cell killing ability is enhanced, but activity is inhibited by PD-L1 in the tumor microenvironment
Solution Approach 1:
The invention converts the harmful PD-L1 expression on tumor cells (which normally suppresses immune cells) into a beneficial targeting mechanism. By designing the CAR to specifically recognize PD-L1, the tumor cells' own immune evasion mechanism becomes the target for enhanced killing, allowing NK-CAR cells to selectively attack PD-L1+ tumors while overcoming the suppressive microenvironment.
Solution Approach 2:
Instead of trying to overcome PD-L1 suppression by blocking its inhibitory signal, the invention inverts the approach by making PD-L1 the target antigen for CAR recognition. This transforms the suppressive interaction into an activating one, where PD-L1 binding triggers NK cell activation and killing rather than inhibition.
3Reliability
If full PD-1 receptor structure is used in CAR, then PD-1/PD-L1 interaction blocking is achieved, but immune cell reversal effect is insufficient
Solution Approach 1:
The invention extracts only the essential antigen-binding ectodomain of PD-1 needed for PD-L1 recognition, removing the intracellular domains responsible for transmitting inhibitory signals. This extracted ectodomain is then incorporated into the CAR structure, achieving interaction blocking while enabling productive immune cell activation through the CAR's signaling domains.
Solution Approach 2:
The invention applies local quality by using only the specific region of PD-1 (the ectodomain) that is responsible for binding PD-L1, while replacing the intracellular signaling portions with CAR-specific signaling domains. This localized approach preserves the antigen-binding function while enhancing the immune activation capability.
Data Source
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AI summary
The present invention relates to a mutated PD1 ectodomain fragment and a CAR containing same, and an NK cell. Specifically, the present invention provides a polypeptide, which is the mutated PD1 ectodomain fragment containing an amino acid sequence as shown in SEQ ID NO: 1 or consisting of the amino acid sequence as shown in SEQ ID NO: 1. The CAR of the present invention contains the polypeptide. The present invention further provides the NK cell expressing the CAR. The tumor cell killing capability of the NK cell that expresses the CAR containing the mutated PD1 ectodomain fragment in the present invention is significantly stronger than that of an NK cell that expresses a CAR containing a wild-type PD1 ectodomain fragment.