IL-7R-alpha specific antibodies for treating acute lymphoblastic leukemia
Inventors
Durum, Scott • Hixon, Julie • Li, Wen Qing • Walsh, Scott • Kashi, Lila
Assignees
University of Maryland College Park • US Department of Health and Human Services
Publication Number
US-10392441-B2
Publication Date
2019-08-27
Expiration Date
2036-10-07
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Abstract
Antibodies and antigen binding fragments that specifically bind to IL-7Rα are disclosed. Nucleic acids encoding the antibodies and antigen binding fragments, and vectors including the nucleic acid molecules are also provided. Methods for detecting a ca cancer or a cell that expresses IL-7Rα using the antibodies and antigen binding fragments are disclosed, as is the use of the antibodies and antigen binding fragments to prevent and/or treat a subject with a cancer that expresses IL-7Rα, such as acute lymphoblastic leukemia.
Core Innovation
This invention provides isolated monoclonal antibodies and antigen binding fragments that specifically bind to the extracellular domain of interleukin 7 receptor alpha chain (IL-7Rα). These antibodies include the 4A10 and 2B8 antibodies, their chimeric forms including human IgG constant regions (such as human IgG1), and variants thereof. The antibodies and fragments are useful for targeting IL-7Rα on cell surfaces, including T cell acute lymphoblastic leukemia (T-ALL) cells or B cell acute lymphoblastic leukemia (B-ALL) cells. The invention further encompasses nucleic acids encoding these antibodies or fragments, expression vectors, host cells, conjugates with effector molecules or detectable markers, and chimeric antigen receptors (CARs) incorporating these antibodies.
The invention addresses the problem that current therapeutic strategies for ALL, especially T-ALL and B-ALL, are associated with toxicity and limited efficacy, with about 20% of cases not cured. ALL is a leading cause of death in children and treatment can cause serious side effects including cognitive impairments. Adult ALL prognosis is even less favorable. There is a need for targeted therapies that provide effective treatment but reduce cytotoxic effects. IL-7Rα is frequently expressed and mutated in ALL, with gain-of-function mutations leading to uncontrolled lymphocyte proliferation. Prior art had identified these mutations and the IL-7 pathway’s role in ALL, but effective antibodies targeting IL-7Rα with therapeutic efficacy had not been described.
The core innovation, thus, is the identification and development of monoclonal antibodies (4A10 and 2B8) that specifically bind to distinct, non-overlapping epitopes of the IL-7Rα extracellular domain, including mutant forms associated with ALL. These antibodies mediate antibody-dependent cell cytotoxicity (ADCC) against IL-7Rα-positive cells and can inhibit IL-7 signaling. In in vivo models, the antibodies reduce proliferation of leukemic cells and prolong survival. The antibodies can be used alone or in combination therapy, for example with CXCR4 antagonists like AMD3100, with synergistic effects against ALL. Furthermore, the antibodies and fragments can be used for diagnostic purposes, to detect IL-7Rα expression and to identify or confirm ALL in subjects. Additionally, IL-7Rα-specific antibodies can be used for treatment or prevention of autoimmune diseases associated with IL-7Rα polymorphisms.
Claims Coverage
The independent claims cover monoclonal antibodies or antigen binding fragments specifically binding the extracellular domain of IL-7Rα, nucleic acids encoding them, expression vectors and host cells expressing them, and methods of treatment using these antibodies and compositions.
Monoclonal antibody specifically binding IL-7Rα extracellular domain
An isolated monoclonal antibody comprising heavy chain variable region (VH) with HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 1 and light chain variable region (VL) with LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 2 (4A10), or VH with HCDR1, HCDR2, HCDR3 of SEQ ID NO: 3 and VL with LCDR1, LCDR2, LCDR3 of SEQ ID NO: 4 (2B8).
Specific complementarity determining regions
Antibody including HCDRs and LCDRs comprising amino acid sequences of SEQ ID NOs: 5-10 for 4A10 or SEQ ID NOs: 11-16 for 2B8 antibodies.
Complete VH and VL sequences
Antibody including VH and VL amino acid sequences as set forth in SEQ ID NOs: 1 and 2, or SEQ ID NOs: 3 and 4, respectively.
Humanized or chimeric antibodies
Antibody comprising human framework regions and/or constant regions, and antibodies of IgG, IgM, or IgA isotype.
Antibodies with enhanced FC region
Antibodies including constant region modifications that increase binding to neonatal Fc receptor and/or antibody-dependent cell cytotoxicity (ADCC).
Functional activities of antibody
Antibodies mediating ADCC killing of IL-7Rα positive cells and/or inhibiting IL-7 signaling in IL-7Rα positive cells, such as T-ALL cells.
Antigen binding fragments and bispecific antibodies
Fragments such as Fv, Fab, F(ab')2, scFv, scFv2 that specifically bind IL-7Rα, and bispecific antibodies that specifically bind both IL-7Rα and CD3.
Conjugates and antibody-drug conjugates
Antibodies or fragments linked to effector molecules or detectable markers, including antibody-drug conjugates with chemotherapeutic agents, optionally conjugated by cleavable peptide linkers.
Nucleic acid molecules, expression vectors, and host cells
Isolated nucleic acids encoding the VH and/or VL of the antibodies or antigen binding fragments, expression vectors containing such nucleic acids, and host cells transformed to express the antibodies or fragments, including T cells or other immune cells.
Therapeutic compositions and methods
Pharmaceutical compositions containing the antibodies, fragments, bispecific antibodies, or conjugates, and methods of treating IL-7Rα-positive cancers (such as ALL) or autoimmune diseases by administering therapeutically effective amounts, optionally combined with a CXCR4 antagonist such as AMD3100.
The claims broadly cover IL-7Rα-specific monoclonal antibodies including 4A10 and 2B8 and their antigen binding fragments, humanized or chimeric forms, conjugates, nucleic acids encoding them, host cells expressing them, diagnostic and therapeutic methods, and combination therapies. The inventive features address specific binding to non-overlapping epitopes of IL-7Rα, functional properties including ADCC and inhibition of IL-7 signaling, and treatment of cancers and autoimmune diseases.
Stated Advantages
The disclosed antibodies effectively reduce proliferation of IL-7Rα-positive leukemic cells and prolong survival in in vivo models of ALL.
The antibodies mediate antibody-dependent cellular cytotoxicity (ADCC) targeting IL-7Rα-positive cells, thereby providing an immune-mediated killing mechanism.
Combination therapy with CXCR4 antagonists and IL-7Rα antibodies synergistically depletes T-ALL cells from bone marrow, enhancing therapeutic efficacy.
The antibodies can specifically bind non-overlapping epitopes of IL-7Rα including wild type and mutant forms, allowing for potential combination antibody therapies.
Antibodies and related molecules can inhibit IL-7 signaling, potentially lowering leukemic cell survival signals without NK cell involvement.
Documented Applications
Treatment or prevention of cancers expressing IL-7Rα, including acute lymphoblastic leukemia such as T-ALL and B-ALL.
Diagnostic detection of IL-7Rα expression in biological samples to identify or confirm IL-7Rα-positive cancers.
Combination therapies using IL-7Rα-specific antibodies and CXCR4 antagonists (e.g., AMD3100) for synergistic depletion of T-ALL cells from bone marrow.
Treatment or prevention of autoimmune diseases including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, sarcoidosis, atopic dermatitis, inhalation allergy, primary biliary cirrhosis, inflammatory bowel disease, and graft versus host disease.
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