Human monoclonal antibodies specific for FLT3 and uses thereof
Inventors
Dimitrov, Dimiter S. • Chen, Weizao • Fry, Terry J. • Chien, Christopher • Qin, Haiying
Assignees
US Department of Health and Human Services
Publication Number
US-11236171-B2
Publication Date
2022-02-01
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 describes fully human monoclonal antibodies that specifically bind to Fms-like tyrosine kinase 3 (FLT3), which is a receptor tyrosine kinase expressed on hematopoietic progenitor cells and frequently overexpressed or mutated in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The disclosed monoclonal antibodies, named m1006, m1007, m1008, m1009, and m1012, bind soluble recombinant FLT3 and cell-surface FLT3 with high affinity.
Further innovation includes the development of chimeric antigen receptors (CARs) incorporating the FLT3-specific antibodies that enable T cells to specifically recognize FLT3-expressing leukemia cells. These FLT3-specific CAR T cells demonstrate anti-leukemic activity by secreting cytokines such as IL-2 and IFN-gamma upon co-culture with FLT3-positive AML or ALL cells and are capable of eradicating these leukemias in animal models.
The problem being addressed stems from the need for selective and potent agents targeting FLT3, especially given the poor prognosis of AML patients with FLT3-internal tandem duplication (ITD) mutations occurring in about 25% of AML cases. Existing therapies are suboptimal for patients with ALL and FLT3-ITD AML, necessitating novel agents that can effectively recognize and treat FLT3-associated cancers.
Claims Coverage
The claims encompass one independent claim directed to an isolated monoclonal antibody binding FLT3 and several independent claims directed to compositions and methods incorporating this antibody. There are multiple inventive features relating to antibody structure, chimeric antigen receptors, immunoconjugates, antibody-drug conjugates, multi-specific antibodies, antibody-nanoparticle conjugates, fusion proteins, compositions, and therapeutic and diagnostic methods.
Monoclonal antibody binding FLT3 with specific CDR sequences
An isolated monoclonal antibody or antigen-binding fragment comprising a variable heavy (VH) domain with the complementarity determining region (CDR) sequences of SEQ ID NO: 1 and a variable light (VL) domain with the CDR sequences of SEQ ID NO: 2, determined by IMGT, Kabat, or Chothia numbering, including Fab, scFv, or other antigen-binding fragments, optionally of IgG isotype, and being fully human, chimeric or synthetic.
Chimeric antigen receptor comprising a FLT3-specific antibody
A chimeric antigen receptor (CAR) containing the FLT3-specific monoclonal antibody or antigen-binding fragment, further including a hinge region, transmembrane domain, costimulatory signaling moiety (such as 4-1BB), and signaling domain (such as CD3ζ). The CAR can comprise the amino acid sequence of SEQ ID NO: 19 with a CD8α hinge and transmembrane, and intracellular 4-1BB and CD3ζ domains.
Immunoconjugate including FLT3-specific antibody and effector molecule
An immunoconjugate comprising the monoclonal antibody or antigen-binding fragment linked to an effector molecule, which can be a toxin or detectable label.
Antibody-drug conjugate with FLT3-specific antibody
An antibody-drug conjugate comprising one or more cytotoxic or therapeutic drugs conjugated to the FLT3-specific monoclonal antibody or antigen-binding fragment.
Multi-specific antibody integrating FLT3-specific antibody
A multi-specific antibody, including bispecific or trispecific antibodies, that comprise the FLT3-specific monoclonal antibody and at least one additional monoclonal antibody or antigen-binding fragment.
Antibody-nanoparticle conjugate
A conjugate formed by linkage of the FLT3-specific monoclonal antibody or antigen-binding fragment to a nanoparticle.
Fusion protein with FLT3-specific antibody and heterologous protein
A fusion protein composed of the FLT3-specific monoclonal antibody or antigen-binding fragment fused to a heterologous protein or peptide, such as an Fc protein.
Compositions containing FLT3-specific antibody
Pharmaceutical compositions comprising a pharmaceutically acceptable carrier and the FLT3-specific monoclonal antibody or antigen-binding fragment.
Methods of treating FLT3-associated cancers using antibody or derivatives
Methods of treating or inhibiting metastasis of FLT3-associated cancer, including leukemia like ALL or AML, by administering the FLT3-specific monoclonal antibody or antigen-binding fragment or compositions containing them.
Methods of detecting FLT3 expression in samples
Methods of detecting FLT3 expression in biological samples by contacting the sample with the FLT3-specific monoclonal antibody or antigen-binding fragment and detecting antibody binding, useful for diagnosis or confirmation of FLT3-positive cancer.
The claims cover isolated FLT3-specific monoclonal antibodies characterized by specific CDR sequences, compositions incorporating these antibodies such as CARs, immunoconjugates, ADCs, multi-specific antibodies, nanoparticle conjugates, fusion proteins, pharmaceutical compositions, and methods for treating FLT3-associated cancers and detecting FLT3 expression. Collectively, these invention features provide a comprehensive platform for diagnosis and therapy of FLT3-expressing cancers.
Stated Advantages
The antibodies specifically bind to both soluble and cell-surface FLT3 with high affinity.
T cells expressing FLT3-specific CARs secrete cytokines such as IL-2 and IFN-gamma in response to FLT3-expressing leukemic cells, indicating potent activation.
FLT3-specific CAR T cells can eradicate FLT3-expressing ALL and AML in animal models.
Documented Applications
Treatment of FLT3-associated cancers such as acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
Methods for diagnosing or detecting FLT3 expression in biological samples including blood and bone marrow biopsies.
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