Anti-siglec-8 antibodies and methods of use thereof

Abstract

The invention provides humanized anti-Siglec-8 antibodies and their use in treating and preventing eosinophil-mediated disorders and/or mast cell-mediated disorders, as well as compositions and kits comprising the humanized anti-Siglec-8 antibodies.

1 - 76 . (canceled) 
     
     
         77 . A method of treating or preventing a disease mediated by cells expressing Siglec-8 in a subject, the method comprising administering to the subject an effective amount of a humanized antibody that binds to a human Siglec-8, wherein the antibody comprises a human IgG1 Fc region, and wherein at least one or two of the heavy chains of the antibody is/are non-fucosylated. 
     
     
         78 . The method of  claim 77 , wherein the disease is an eosinophil mediated-disease or a mast cell mediated-disease. 
     
     
         79 . (canceled) 
     
     
         80 . The method of  claim 77 , wherein the antibody inhibits one or more symptoms of an allergic reaction. 
     
     
         81 . The method of  claim 80 , wherein the allergic reaction is a Type I hypersensitivity reaction. 
     
     
         82 . The method of  claim 77 , wherein the disease is selected from the group consisting of: asthma, allergic rhinitis, nasal polyposis, atopic dermatitis, chronic urticaria, mastocytosis, eosinophilic leukemia, and hypereosinophilic syndrome. 
     
     
         83 . The method of  claim 77 , wherein the disease is selected from the group consisting of: pauci granulocytic asthma, acute or chronic airway hypersensitivity, eosinophilic esophagitis, Churg-Strauss syndrome, inflammation associated with a cytokine, inflammation associated with cells expressing Siglec-8, malignancy associated with cells expressing Siglec-8, physical urticaria, cold urticaria, pressure-urticaria, bullous pemphigoid, food allergy, and allergic bronchopulmonary aspergillosis (ABPA). 
     
     
         84 . The method of  claim 77 , wherein the subject is suffering from asthma that is not adequately controlled by an inhaled corticosteroid, a short acting β2 agonist, a long acting β2 agonist, or a combination thereof. 
     
     
         85 - 91 . (canceled) 
     
     
         92 . The method of  claim 77 , wherein the antibody is produced in a cell line having a alpha1,6-fucosyltransferase (Fut8) knockout. 
     
     
         93 . The method of  claim 77 , wherein the antibody is produced in a cell line overexpressing β1,4-N-acetylglycosminyltransferase III (GnT-III). 
     
     
         94 . The method of  claim 93 , wherein the cell line additionally overexpresses Golgi μ-mannosidase II (ManII). 
     
     
         95 - 109 . (canceled) 
     
     
         110 . The method of  claim 77 , wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:61, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:62, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; and wherein the light chain variable region comprises (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:65, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO:66. 
     
     
         111 . The method of  claim 77 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:6; and a light chain variable region comprising the amino acid sequence of SEQ ID NO:16 or 21. 
     
     
         112 . The method of  claim 77 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:75 and a light chain comprising the amino acid sequence of SEQ ID NO:76 or 77, or a heavy chain comprising the amino acid sequence of SEQ ID NO:87 and a light chain comprising the amino acid sequence of SEQ ID NO:76. 
     
     
         113 . The method of  claim 77 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence selected from SEQ ID NOs:2-14; and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:16-24. 
     
     
         114 . The method of  claim 77 , wherein the binding affinity or avidity of the antibody to a human Siglec-8 is higher than the binding affinity or avidity of antibody 2E2 or 2C4 to the human Siglec-8. 
     
     
         115 . The method of  claim 77 , wherein the antibody is administered to the subject in a composition comprising the antibody and a pharmaceutically acceptable carrier. 
     
     
         116 . The method of  claim 115 , wherein the antibody comprises N-glycoside-linked carbohydrate chains linked to the Fc region, and wherein substantially none of the N-glycoside-linked carbohydrate chains contain a fucose residue. 
     
     
         117 . The method of  claim 92 , wherein the cell line is a mammalian cell line. 
     
     
         118 . The method of  claim 93 , wherein the cell line is a mammalian cell line. 
     
     
         119 . The method of  claim 77 , wherein the subject is a human.