Antibodies to Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 receptor ligand (FLT3L) and uses thereof for treating autoimmune and inflammatory diseases
Inventors
Hansen, Anna • Xiao, Xiaodong • Pavlik, Peter • Chen, Yan • Ettinger, Catherine Rachel
Assignees
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Publication Number
US-12209123-B2
Publication Date
2025-01-28
Expiration Date
Abstract
Provided herein are anti-FLT3L antibodies and methods of using the antibodies to treat autoimmune and other inflammatory diseases.
Core Innovation
The patent describes human monoclonal antibodies comprising a heavy chain with a variable region (VH) comprising the amino acid sequence of SEQ ID NO:1 and a human IgG1 heavy chain constant domain, and a light chain with a variable region (VL) comprising the amino acid sequence of SEQ ID NO:2 and a human lambda light chain constant domain. The antibodies are directed to FLT3L and related FLT3-mediated signaling, and the document further discusses antigen-binding fragments and biologics associated with neutralizing FLT3L and inhibiting FLT3-mediated downstream signaling.
The document describes functional screening and lead characterization for anti-FLT3L antibodies, including conversion of panning outputs to scFv-Fc/IgG and use of an HTRF FLT3L/FLT3 interaction inhibition assay workflow. It identifies lead antibodies including Dyax3, Dyax5, CAT8, CAT26, and CAT5D9, and describes profiling of these antibodies for functional inhibition, receptor down-modulation, signaling inhibition as measured by phospho-ERK/MEK, and epitope binning in which CAT5D9 competes with FLT3 at the FLT3L binding region.
The patent reports affinity and selectivity profiling for CAT5D9, including Biacore kinetics and selectivity against SCF/CSF1, and describes affinity maturation of CAT5D9 to improved clones AM40 and SC4017, reporting enhanced binding and functional FLT3 down-modulation for these matured antibodies. It also includes in vivo and pathology-related examples in non-human primates and mouse models, including DC frequency changes, reduced proteinuria and nephritis score, suppressed DC populations, reduced tissue pathology and TLS formation, and suppressed T-cell subsets with prophylactic or therapeutic anti-FLT3L dosing.
The document further relates disease activity to serum FLT3L and FLT3L-expressing CD4+ T cells, including increases in FLT3L in systemic lupus erythematosus (SLE) and myositis in connection with disease activity measures, and describes correlations involving FLT3L expression on CD4+ T cells and SLEDAI in SLE. In addition to antibody sequence definition and format, the disclosure includes nucleic acids encoding the described human monoclonal antibodies, vectors, host cells, and pharmaceutical compositions, together with specificity requirements including a lack of cross-reactivity to structurally related cytokine ligands huSCF and huCSF1.
Claims Coverage
The partial content provides three independent claim groups covering a method of treating an autoimmune disease with a defined human monoclonal antibody, the human monoclonal antibody itself with defined heavy- and light-chain regions, and nucleic acids encoding that antibody. The core inventive elements are the precise heavy-chain and light-chain sequence definition using SEQ ID NO:1 and SEQ ID NO:2 together with IgG1 heavy-chain and human lambda light-chain constant domains, tied to therapeutic use for autoimmune disease.
Autoimmune treatment with defined human monoclonal antibody sequences
Administering to a subject in need thereof a pharmaceutically effective amount of a human monoclonal antibody comprising a heavy chain with a variable region (VH) comprising the amino acid sequence of SEQ ID NO:1 and a human IgG1 heavy chain constant domain, and a light chain with a variable region (VL) comprising the amino acid sequence of SEQ ID NO:2 and a human lambda light chain constant domain.
Human monoclonal antibody with defined heavy- and light-chain variable regions
A human monoclonal antibody comprising a heavy chain with a variable region (VH) comprising the amino acid sequence of SEQ ID NO:1 and a human IgG1 heavy chain constant domain, and a light chain with a variable region (VL) comprising the amino acid sequence of SEQ ID NO:2 and a human lambda light chain constant domain.
Nucleic acid encoding the defined human monoclonal antibody sequences
A nucleic acid encoding a human monoclonal antibody comprising a heavy chain with a variable region (VH) comprising the amino acid sequence of SEQ ID NO:1 and a human IgG1 heavy chain constant domain, and a light chain with a variable region (VL) comprising the amino acid sequence of SEQ ID NO:2 and a human lambda light chain constant domain.
The independent claims consistently define the invention around a human monoclonal antibody having specified heavy-chain (SEQ ID NO:1) and light-chain (SEQ ID NO:2) variable regions together with IgG1 and human lambda constant domains, with coverage extending to therapeutic use, antibody composition, and nucleic acids encoding the antibody.
Stated Advantages
Enhanced binding and functional FLT3 down-modulation for affinity-matured antibodies.
Neutralizing FLT3L and inhibiting FLT3-mediated downstream signaling.
Lack of cross-reactivity to structurally related cytokine ligands huSCF and huCSF1.
Reduced proteinuria, nephritis score, tissue pathology, TLS formation, and suppressed DC and T-cell subsets in the reported models.
Documented Applications
Treating an autoimmune disease in a subject by administering a pharmaceutically effective amount of the specified human monoclonal antibody.
Treating systemic lupus erythematosus (SLE).
Treating multiple sclerosis.
Use in non-human primate and mouse model studies involving DC frequency changes, lupus nephritis, and Sjögren’s syndrome.
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