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-11111306-B2
Publication Date
2021-09-07
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 disclosure provides monoclonal antibodies and antigen binding fragments that specifically bind to the extracellular domain of the interleukin 7 receptor alpha chain (IL-7Rα). These antibodies include the 4A10 and 2B8 antibodies, which were isolated from mouse hybridoma cell lines and can be expressed in chimeric forms containing human IgG constant regions. The antibodies specifically bind to non-overlapping epitopes on IL-7Rα and can mediate antibody-dependent cellular cytotoxicity (ADCC) against IL-7Rα-expressing cells.
The antibodies and antigen binding fragments are particularly useful for treating or preventing acute lymphoblastic leukemia (ALL), including T cell ALL (T-ALL) and B cell ALL (B-ALL), by targeting IL-7Rα expressed on leukemic cells. Methods include administering therapeutically effective amounts of the antibodies, antigen binding fragments, nucleic acid molecules encoding the antibodies, or compositions thereof. Combination therapies with additional agents such as CXCR4 antagonists are also disclosed for treating IL-7Rα-positive cancers.
The problem being solved is the need for new targeted therapies for ALL, especially therapies that have reduced cytotoxicity compared to existing treatments. Current treatments for ALL, particularly in pediatric patients, can be highly toxic and cause severe side effects such as cognitive impairment. Moreover, about 20% of ALL cases remain uncured. Adult ALL has an even less favorable prognosis. Therefore, there is a demand for therapies targeting mechanisms involved in ALL pathogenesis, such as IL-7Rα, to provide effective and less toxic treatment options.
Claims Coverage
The patent describes three main inventive features related to monoclonal antibodies and related compositions for treating IL-7Rα positive cancers and autoimmune diseases, their molecular structures and modifications, and methods of combination therapy with additional agents.
Monoclonal antibodies with specific variable regions targeting IL-7Rα
A monoclonal antibody specifically binding to the extracellular domain of IL-7Rα, comprising heavy chain variable regions with HCDR1, HCDR2, HCDR3 as per SEQ ID NO: 1 (4A10 VH) or SEQ ID NO: 3 (2B8 VH), and light chain variable regions with LCDR1, LCDR2, LCDR3 as per SEQ ID NO: 2 (4A10 VL) or SEQ ID NO: 4 (2B8 VL), including antigen binding fragments or bispecific antibodies containing such sequences.
Antibody modifications enhancing activity and therapeutic use
Monoclonal antibodies may comprise human framework and constant regions, be of IgG, IgM, or IgA isotypes (notably IgG1), contain modifications increasing binding to the neonatal Fc receptor and antibody-dependent cellular cytotoxicity (ADCC), and possess Fc domains with variable glycosylation patterns (including reduced fucosylation or presence of galactose and biantennary oligosaccharides). They mediate ADCC of IL-7Rα positive cells and can inhibit IL-7 signaling in these cells.
Methods of treating IL-7Rα positive cancers or autoimmune diseases with combination therapies
Methods include administering a therapeutically effective amount of the specified monoclonal antibody (or fragment or bispecific form) together with an additional agent such as chemotherapeutic agents, alkylating agents, antimetabolites, vinca alkaloids, epipodophyllotoxins, antibiotics, adrenocorticosteroids (e.g., prednisone), or CXCR4 antagonists to treat IL-7Rα-positive cancers (including acute lymphoblastic leukemia types) or autoimmune diseases.
The claims cover monoclonal antibodies with defined variable region sequences targeting IL-7Rα, their structural and functional modifications, and therapeutic methods using these antibodies alone or in combination with other agents to treat IL-7Rα positive cancers and autoimmune diseases.
Stated Advantages
The disclosed antibodies are surprisingly effective for treatment of acute lymphoblastic leukemia (ALL), including T-ALL and B-ALL.
The chimeric antibodies mediate ADCC killing of IL-7Rα-positive cancer cells, including leukemic cells.
The antibodies can inhibit IL-7-induced signaling in IL-7Rα-positive cells, potentially reducing survival signals.
The disclosed combination therapy with IL-7Rα-specific antibodies and CXCR4 antagonists synergistically depletes leukemia cells from bone marrow, enhancing therapeutic efficacy.
Documented Applications
Treatment or prevention of acute lymphoblastic leukemia (ALL), including T cell ALL (T-ALL) and B cell ALL (B-ALL) expressing IL-7Rα.
Treatment or prevention of autoimmune diseases such as rheumatoid arthritis, type I diabetes, atopic dermatitis, multiple sclerosis, primary biliary cirrhosis, inflammatory bowel disease, sarcoidosis, and graft versus host disease using IL-7Rα-specific antibodies.
Detection and diagnosis of cancers that express IL-7Rα in biological samples from subjects using the disclosed antibodies or antigen binding fragments.
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