Fully Human MSLN-Targeting CAR With PD-1 and mIL-15 Coexpression
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Solution Overview
Problem
Current CAR-T cell therapy for solid tumors is insufficient due to the complex tumor microenvironment and high tumor heterogeneity, necessitating a more specific and effective targeting approach.
Innovation Solution
Development of a fully human antibody capable of specifically recognizing MSLN, integrated into a chimeric antigen receptor (CAR) that co-expresses with PD-1 antibody and/or mIL-15, to target and eliminate MSLN-expressing cells in a non-MHC-restricted manner.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional therapeutic methods (surgery, radiotherapy, chemotherapy) are used for solid tumors, then treatment can be administered, but therapeutic effectiveness is poor
Solution Approach 1:
The patent introduces CAR-T cells as an intermediary therapeutic agent that mediates the immune system's attack on tumor cells. The chimeric antigen receptor serves as a bridge between the immune system and tumor-specific targeting, enabling precise recognition and elimination of MSLN-positive tumor cells while sparing healthy tissues.
Solution Approach 2:
The patent employs the patient's own immune system (T cells) to fight the tumor. By genetically modifying autologous T cells to express MSLN-specific CARs, the therapy leverages the body's inherent immune capabilities, making the immune system serve itself in the fight against cancer.
2Adaptability or versatility
If CAR-T cell therapy is applied to solid tumors, then non-MHC-restricted targeting is achieved, but therapeutic effect remains insufficient due to complex tumor microenvironment and high tumor heterogeneity
Solution Approach 1:
The patent employs fully human antibodies with high affinity specifically for MSLN, concentrating the targeting capability at the local level of tumor cell recognition. This localized high-affinity binding ensures precise targeting of MSLN-positive cells while maintaining specificity despite the complex tumor microenvironment.
Solution Approach 2:
The CAR construct integrates multiple functional components: a fully human antibody variable region for antigen recognition, hinge and transmembrane domains for structural stability, and intracellular signaling domains for T cell activation. This composite structure combines the advantages of different molecular elements to achieve both specificity and effective T cell engagement.
3Object-affected harmful factors
If a fully human antibody is developed for MSLN recognition, then low immunogenicity and high specificity are achieved, but development complexity increases
Solution Approach 1:
The patent changes the key parameter of antibody origin from non-human (mouse or chimeric) to fully human, thereby eliminating human anti-chimeric antibody responses and reducing immunogenicity. This parameter change fundamentally alters the immune compatibility profile while maintaining high affinity for MSLN through careful selection and optimization of human antibody sequences.
Data Source
AI summary
The present invention relates to the field of biomedicine, and in particular, the present invention relates to an antibody or antigen-binding fragment thereof which specifically binds to MSLN, and a chimeric antigen receptor (CAR) comprising said antibody or antigen-binding fragment thereof. The present invention also relates to modified immune cells expressing said CAR, or co-expressing said CAR and additional bioactive molecules (e.g. PD-1 antibody and/or mIL-15), and a method for preparing said modified immune cells. The present invention also relates to the use of such antibodies, CARs, and immune cells for the prevention and/or treatment of diseases associated with the expression of mesothelin, such as malignant pleural mesothelioma, pancreatic cancer, lung cancer, breast cancer, and ovarian cancer, and a method for the prevention and/or treatment of diseases associated with the expression of mesothelin, such as malignant pleural mesothelioma, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, and other MSLN-positive tumors.