Anti-human folate receptor beta antibodies and methods of use
Inventors
Low, Philip S. • Dimitrov, Dimiter S. • Feng, Yang • Shen, Jiayin
Assignees
Purdue Research Foundation • US Department of Health and Human Services
Publication Number
US-9914773-B2
Publication Date
2018-03-13
Expiration Date
2031-09-09
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Abstract
Human anti-human folate receptor beta antibodies and antigen-binding fragments thereof are described, as well as methods of using such antibodies and fragments to treat inflammatory disorders or cancers expressing cell surface FRβ.
Core Innovation
This invention provides fully human monoclonal antibodies, or antigen-binding fragments thereof, that specifically bind to human folate receptor beta (FRβ). These antibodies can be used to reduce the number of FRβ positive cells in a subject, thus enabling the treatment of inflammatory disorders and cancers that express cell surface FRβ. The antibodies are particularly useful for treating human subjects because their fully human nature reduces the likelihood of immune responses and side effects compared with murine, chimeric, or humanized antibodies.
Folic acid is essential for cell proliferation and metabolism, and certain cells utilize folate receptors, including FRβ, to facilitate folate uptake. FRβ is expressed on activated macrophages, myelomonocytic lineage cells, and various cancer cells, including multiple myeloma, chronic myeloid leukemia, and acute myeloid leukemia. However, there has been a need for reagents and methods to differentially target folate receptors, especially FRβ, to treat diseases characterized by the presence of FRβ positive cells.
Claims Coverage
The patent claims one independent claim focused on an isolated human monoclonal antibody or an antigen-binding fragment thereof targeting human FRβ, with multiple dependent claims elaborating specific properties and conjugations.
specific binding to human folate receptor beta
An isolated human monoclonal antibody or antigen-binding fragment comprising heavy and light chain variable region complementarity determining regions (CDRs) with amino acid sequences set forth in SEQ ID NOs:1-6 that specifically bind human FRβ.
selective binding properties and functional activities
The antibody or fragment does not detectably bind to human folate receptor alpha (FRα), binds to human macrophages but not mouse macrophages, exhibits a binding affinity (EC50) of 20 nM, a dissociation constant (Kd) of 6.39 nM, and mediates antibody-dependent cellular cytotoxicity (ADCC) of FRβ-expressing target cells.
binding to cell surface FRβ and antibody class
The antibody or fragment binds to cell surface FRβ and can be an IgG1 antibody.
de-fucosylation of the antibody or fragment
The antibody or fragment can be de-fucosylated to enhance Fc receptor binding and effector functions.
various antigen-binding fragment formats
The antibody or fragment can be in formats including Fab fragments, F(ab′)2 fragments, or single chain variable fragments (scFv).
conjugation with therapeutic or diagnostic agents
The antibody or fragment can be conjugated with pharmaceutical agents such as chemotherapeutics, linked to liposomes containing pharmaceutical agents, linked to toxins (covalently), or linked to detectable moieties such as fluorescent, luminescent, radioactive labels, CT or MRI contrast agents, and biotin.
framework region and sequence composition
The antibody or fragment can include framework regions as set forth in SEQ ID NO:7 and optionally comprises variable region amino acid sequences set forth in SEQ ID NO:10.
pharmaceutical composition
A composition comprising the antibody or antigen-binding fragment and a pharmaceutically acceptable carrier.
The claims collectively cover a fully human monoclonal antibody or antigen-binding fragment specifically targeting human FRβ, characterized by defined complementarity determining regions and functional properties including selective binding and induction of ADCC, with various formats and conjugation possibilities, suitable for use in pharmaceutical compositions.
Stated Advantages
The antibody is fully human, reducing the risk of inducing immune responses and side effects compared with murine, chimeric, or humanized antibodies.
The antibodies specifically bind FRβ with high affinity and do not detectably bind to related folate receptors such as FRα, FRγ, or FRδ, allowing for selective targeting.
The antibody or fragment can induce antibody-dependent cell-mediated cytotoxicity (ADCC), opsonization-mediated clearance, and complement-mediated lysis of FRβ expressing target cells.
Documented Applications
Treatment of inflammatory disorders characterized by FRβ positive activated macrophages and monocytes, including atherosclerosis, ischemia/reperfusion injury, transplantation rejection, vasculitis, inflammatory osteoarthritis, glomerulonephritis, restenosis, systemic sclerosis, fibromyalgia, sarcoidosis, and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), ulcerative colitis, psoriasis, Type 1 diabetes, Crohn's disease, multiple sclerosis, and Sjogren's disease.
Treatment of cancers expressing cell surface FRβ, including myeloid cancers such as acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), multiple myeloma, and solid FRβ expressing cancers such as non-epithelial malignancies and squamous cell carcinomas.
Depletion of activated macrophages from a human subject by reducing the number of FRβ positive cells.
Use of human T cells engineered with chimeric immune receptors containing an scFv targeting human FRβ for immunotherapy against FRβ expressing target cells.
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