CD33-Specific CAR Immune Cells With 4-1BB for AML Relapse Control
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Solution Overview
Problem
Current therapies for acute myeloid leukemia (AML) are toxic and often fail to achieve a complete cure due to the presence of leukemia stem cells that survive chemotherapy, leading to high relapse rates, and existing monoclonal antibodies targeting CD33 have safety issues and limited efficacy.
Innovation Solution
Development of CD33-specific chimeric antigen receptors (CARs) expressed in immune cells, such as T-cells, which redirect their specificity toward CD33+ malignant cells, utilizing different scFV sequences and incorporating signaling domains from CD3 zeta and 4-1BB for enhanced activation and proliferation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional monoclonal antibodies targeting CD33 are used for immunotherapy, then the treatment can be administered, but they exhibit limited efficacy and safety issues
Solution Approach 1:
The patent combines the antigen-binding domain (scFv) with signaling domains (CD3zeta and 4-1BB) to create a chimeric antigen receptor that merges the targeting capability of monoclonal antibodies with the activation capability of T-cell receptors, thereby improving both efficacy and safety while maintaining targeting specificity
Solution Approach 2:
The CAR construct uses a composite structure combining different functional domains: the scFv domain for antigen recognition, the transmembrane domain for membrane anchoring, and the cytoplasmic signaling domains for T-cell activation, creating a multifunctional receptor that overcomes the limitations of conventional monoclonal antibodies
2Reliability
If first generation CARs with CD3zeta signaling domain are used, then T-cell cytotoxicity can be redirected, but prolonged expansion and anti-tumor activity are not achieved
Solution Approach 1:
The patent merges the CD3zeta signaling domain (providing activation signal) with the 4-1BB costimulatory domain (providing proliferation signal), creating a dual-signal CAR that simultaneously achieves T-cell cytotoxicity redirection and prolonged expansion, resolving the limitation of first-generation CARs
3Reliability
If combination of signaling domains from CD19 ScFv is used, then successful therapeutic trials are achieved, but the combination is antigen-specific and cannot be expanded to other antigen markers
Solution Approach 1:
The patent creates a universal CAR platform where the scFv domain can be exchanged to target different antigens while the standardized transmembrane and signaling domains (CD3zeta and 4-1BB combination) provide consistent therapeutic efficacy across different target antigens, enabling expansion beyond CD19 to other markers like CD33
4Reliability
If chemotherapy is used to treat AML, then complete remission can be achieved for 65-80% of patients, but high relapse rates occur due to surviving leukemia stem cells
Solution Approach 1:
The patent employs the patient's own T-cells (autologous cells) that have been genetically engineered with CARs to continuously seek out and eliminate CD33+ leukemia stem cells, providing a self-sustaining immunotherapy that prevents relapse without the toxic effects of repeated chemotherapy
Data Source
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AI summary
The present invention relates to Chimeric Antigen Receptors (CAR) that are recombinant chimeric proteins able to redirect immune cell specificity and reactivity toward selected membrane antigens, and more particularly in which extracellular ligand binding is a scFV derived from a CD33 monoclonal antibody, conferring specific immunity against CD33 positive cells. The engineered immune cells endowed with such CARs are particularly suited for treating lymphomas and leukemia.