Human monoclonal antibodies specific for FLT3 and uses thereof
Inventors
Dimitrov, Dimiter S. • Chen, Weizao • Fry, Terry J. • Chien, Christopher
Assignees
US Department of Health and Human Services
Publication Number
US-12012455-B2
Publication Date
2024-06-18
Expiration Date
2037-12-21
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Abstract
Human monoclonal antibodies that specifically bind Fms-like tyrosine kinase 3 (FLT3) are described. Chimeric antigen receptors (CARs) and other antibody conjugates that include the FLT3-specific monoclonal antibodies are also described. Methods for the diagnosis and treatment of FLT3-associated cancer, such as acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML), are further described.
Core Innovation
The invention discloses fully human monoclonal antibodies that specifically bind to Fms-like tyrosine kinase 3 (FLT3), including antibodies named m1006, m1007, m1008, m1009, and m1012. These antibodies bind both soluble recombinant FLT3 and cell-surface FLT3 with high affinity. The invention also includes chimeric antigen receptors (CARs) comprising these antibodies, as well as other antibody conjugates such as immunoconjugates, antibody-drug conjugates (ADCs), multi-specific antibodies, and antibody-nanoparticle conjugates that incorporate the FLT3-specific antibodies or fragments thereof.
The disclosed CARs use the FLT3-specific antibodies as the binding moiety, enabling engineered T cells expressing the CARs to recognize and eradicate FLT3-expressing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) cells. The methods include administering these antibodies, CARs, or conjugates thereof to subjects for diagnosis, treatment, or inhibition of metastasis of FLT3-associated cancers.
The problem being addressed is that FLT3 is frequently overexpressed in ALL and frequently mutated in AML, particularly the FLT3-internal tandem duplication (ITD) mutation associated with poor prognosis in AML. Despite FLT3 being a critical target in these leukemias, there is a need for the development of selective and potent agents against FLT3 for effective treatment. The disclosed fully human antibodies binding FLT3 and corresponding CARs and conjugates provide such selective agents for therapeutic and diagnostic purposes.
Claims Coverage
The patent claims cover an isolated monoclonal antibody specific for FLT3 and various compositions and methods involving this antibody. Two main inventive features are identified, concerning the antibody itself and its incorporation into therapeutic and diagnostic constructs.
Isolated monoclonal antibody specific for FLT3 with defined CDR sequences
An isolated monoclonal antibody or antigen-binding fragment thereof comprising a variable heavy (VH) domain with the complementarity determining region (CDR) sequences of SEQ ID NO: 5, and a variable light (VL) domain with the CDR sequences of SEQ ID NO: 6. The CDR sequences can be determined using IMGT, Kabat or Chothia numbering schemes. The antibody may be fully human, chimeric, or synthetic, and may have specific residues at defined positions as specified in dependent claims.
Compositions and uses incorporating the FLT3-specific antibody
Chimeric antigen receptors (CARs) comprising the FLT3-specific antibody; isolated cells expressing such CARs; immunoconjugates combining the antibody with an effector molecule; antibody-drug conjugates (ADCs) with a drug linked to the antibody; multi-specific antibodies including the FLT3 antibody and at least one additional antibody; antibody-nanoparticle conjugates; fusion proteins of the antibody and a heterologous protein or peptide; compositions containing the antibody with pharmaceutically acceptable carriers; nucleic acid molecules or vectors encoding the antibody; methods of treating FLT3-associated cancers including leukemias by administering the antibody; methods of inhibiting metastasis by administering the antibody; and methods of detecting FLT3 expression by contacting a sample with the antibody and detecting binding.
Overall, the claims cover a specifically defined human monoclonal antibody binding FLT3 and a broad range of therapeutic, diagnostic, and composition forms incorporating this antibody, including CARs, conjugates, and methods of treatment and detection.
Stated Advantages
The FLT3-specific monoclonal antibodies bind with high affinity to both soluble and cell-surface FLT3.
T cells expressing FLT3-specific CARs secrete high levels of IL-2 and IFN-γ upon co-culture with FLT3-expressing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) cells, demonstrating functional activation.
FLT3 CAR T cells eradicate FLT3-expressing ALL and AML in animal models, indicating potent anti-tumor activity.
Documented Applications
Treatment of FLT3-associated cancers, including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
Diagnostic detection of FLT3 expression in biological samples such as blood or bone marrow biopsies to identify FLT3-positive cancers.
Inhibition of metastasis of FLT3-associated cancers in subjects.
Use of FLT3-specific antibodies in compositions such as CARs, immunoconjugates, antibody-drug conjugates, multi-specific antibodies, antibody-nanoparticle conjugates, and fusion proteins.
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