FLT3-specific chimeric antigen receptors and methods using same
Inventors
Chien, Christopher D. • Fry, Terry J.
Assignees
US Department of Health and Human Services
Publication Number
US-12202902-B2
Publication Date
2025-01-21
Expiration Date
2037-05-26
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Abstract
An embodiment of the invention provides a chimeric antigen receptor (CAR) comprising an antigen binding domain specific for FLT3, a transmembrane domain, and an intracellular T cell signaling domain. Nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies, or antigen binding portions thereof, and pharmaceutical compositions relating to the CARs are disclosed. Methods of detecting the presence of a proliferative disorder, e.g., cancer, in a mammal and methods of treating or preventing a proliferative disorder, e.g., cancer, in a mammal are also disclosed.
Core Innovation
The invention provides chimeric antigen receptors (CARs) with an antigen binding domain specific for FLT3, a transmembrane domain, and an intracellular T cell signaling domain. The CAR may further include a 4-1BB intracellular domain, a spacer, or both. Related nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies, antigen binding portions thereof, and pharmaceutical compositions associated with the CARs are also disclosed.
The CARs redirect T-cell specificity toward FLT3-expressing target cells in a non-MHC-restricted manner, enabling immune recognition and destruction of FLT3-expressing cancer cells, including both wild type and mutant forms of FLT3. This approach facilitates immune cell infiltration to tumors and enhances anti-cancer responses. The CARs are designed to overcome tumor escape mechanisms and treat proliferative disorders such as cancers expressing FLT3.
The problem being solved arises from sub-optimal standard therapies for certain leukemic patient populations, particularly infants with pre-B cell precursor acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), which have survival rates less than 40% and 60%, respectively. Conventional treatments targeting CD19 antigen are insufficient due to non-responsiveness or relapse via antigen loss. Thus, there is a need for additional treatments targeting FLT3, a protein highly expressed and mutated in infant ALL and AML, providing a new therapeutic avenue.
Claims Coverage
The patent includes 15 independent claims focused on distinct aspects of the FLT3-specific chimeric antigen receptor and its uses, covering NK cells, populations thereof, pharmaceutical compositions, and therapeutic methods.
NK cells expressing a FLT3-specific CAR comprising defined scFv CDR sequences
The invention claims isolated NK cells expressing a CAR with an antigen binding domain specific for FLT3 comprising a scFv with heavy chain variable region CDR1, CDR2, CDR3 of SEQ ID NOS: 6, 8, 10 and light chain variable region CDR1, CDR2, CDR3 of SEQ ID NOS: 14, 16, 18.
Inclusion of CD8α hinge and transmembrane domains in CAR structure
The CAR expressed by NK cells further comprises a CD8α hinge with sequence SEQ ID NO: 25 and a CD8 transmembrane domain with sequence SEQ ID NO: 26.
Intracellular signaling domains comprising CD3ζ or CD28 in CARs
The intracellular T cell signaling domain of the CAR comprises the CD3ζ amino acid sequence of SEQ ID NO: 28 and may also further comprise a CD28 co-stimulatory domain.
Pharmaceutical compositions comprising FLT3-specific CAR NK cells
Pharmaceutical compositions are claimed that include the NK cells expressing the FLT3-specific CAR or populations thereof together with pharmaceutically acceptable carriers.
Therapeutic use of FLT3 CAR NK cells to treat acute myeloid leukemia
Methods are claimed for treating subjects having acute myeloid leukemia by administering therapeutically effective amounts of the NK cells expressing the FLT3-specific CAR or populations thereof.
The independent claims collectively cover isolated NK cells expressing FLT3-specific CARs defined by precise scFv CDR sequences and structural domains, pharmaceutical compositions comprising such NK cells or their populations, and methods for treating AML using these engineered NK cells.
Stated Advantages
The CARs provide targeted destruction of FLT3-expressing cancer cells, overcoming tumor escape via antigen loss observed in CD19-targeted therapies.
The inclusion of 4-1BB intracellular domain enhances T cell costimulation, differentiation, and long-term survival, improving therapeutic efficacy.
The CARs can recognize both wild type and mutant forms of FLT3, allowing broad targeting of leukemias expressing FLT3.
The invention enables non-MHC-restricted antigen recognition, bypassing tumor evasion due to antigen processing deficiency.
Documented Applications
Methods of detecting the presence of proliferative disorders, including cancers such as pre-B cell precursor acute lymphoblastic leukemia and acute myeloid leukemia, by binding CARs or antibodies to samples and detecting complexes.
Use of the CARs, nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies, or pharmaceutical compositions for treating or preventing cancers characterized by FLT3 expression in mammals.
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