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 - 29 . (canceled) 
     
     
         30 . A composition comprising an antibody that specifically binds to human Siglec-8, wherein the antibody comprises a Fc region and N-glycoside-linked carbohydrate chains linked to the Fc region, wherein less than 50% of the N-glycoside-linked carbohydrate chains contain a fucose residue. 
     
     
         31 . The composition of  claim 30 , wherein substantially none of the N-glycoside-linked carbohydrate chains contain a fucose residue. 
     
     
         32 . The composition of  claim 30 , wherein the antibody is a humanized antibody, a chimeric antibody or a human antibody. 
     
     
         33 - 60 . (canceled) 
     
     
         61 . An antibody that binds to a human Siglec-8 and a non-human primate Siglec-8. 
     
     
         62 . The antibody of  claim 61 , wherein the non-human primate is a baboon. 
     
     
         63 . The antibody of  claim 61 , wherein the antibody comprises:
 (a) a heavy chain variable region comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:89, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:92, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:95; and/or a light chain variable region comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:98, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:101, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO:104.   (b) a heavy chain variable region comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:90, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:93, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:96; and/or a light chain variable region comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:99, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:102, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO:105.   
     
     
         64 . The antibody of  claim 61 , wherein the antibody binds to an epitope in Domain 1 of human Siglec-8, wherein Domain 1 comprises the amino acid sequence of SEQ ID NO:112. 
     
     
         65 . The antibody of  claim 61 , wherein the antibody binds to an epitope in Domain 3 of human Siglec-8, wherein Domain 3 comprises the amino acid sequence of SEQ ID NO:114. 
     
     
         66 . The antibody of  claim 61 , wherein the antibody is a humanized antibody, a chimeric antibody or a human antibody. 
     
     
         67 . The antibody of  claim 61 , wherein the antibody is a murine antibody. 
     
     
         68 . The antibody of  claim 61 , wherein the antibody is an IgG1 antibody. 
     
     
         69 . (canceled) 
     
     
         70 . A nucleic acid encoding the antibody of  claim 61 . 
     
     
         71 . A vector comprising the nucleic acid of  claim 70 . 
     
     
         72 . The vector of  claim 71 , which is an expression vector. 
     
     
         73 . A host cell comprising the nucleic acid of  claim 70 . 
     
     
         74 . A method of producing an antibody comprising culturing the host cell of  claim 73  under a condition that produces the antibody. 
     
     
         75 . The method of  claim 74 , further comprising recovering the antibody produced by the host cell. 
     
     
         76 . An anti-Siglec-8 antibody produced by the method of  claim 74 . 
     
     
         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 the composition of  claim 30 . 
     
     
         78 . The method of  claim 77 , wherein the disease is an eosinophil mediated-disease. 
     
     
         79 . The method of  claim 77 , wherein the disease is a mast cell mediated-disease. 
     
     
         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 - 107 . (canceled) 
     
     
         108 . A pharmaceutical composition comprising the antibody of  claim 61  and a pharmaceutically acceptable carrier. 
     
     
         109 . (canceled) 
     
     
         110 . An antibody that binds to an epitope in Domain 2 or Domain 3 of human Siglec-8. 
     
     
         111 . The antibody of  claim 110 , wherein Domain 2 comprises the amino acid sequence of SEQ ID NO:113. 
     
     
         112 . The antibody of  claim 110 , wherein the antibody binds to the same epitope as antibody 1C3. 
     
     
         113 . The antibody of  claim 110 , wherein Domain 3 comprises the amino acid sequence of SEQ ID NO:114. 
     
     
         114 . The antibody of  claim 110 , wherein the antibody binds to the same epitope as antibody 1H10. 
     
     
         115 . The antibody of  claim 110 , wherein the antibody is a humanized antibody, a chimeric antibody or a human antibody. 
     
     
         116 . The antibody of  claim 110 , wherein the antibody is a murine antibody. 
     
     
         117 . The antibody of  claim 110 , wherein the antibody is an IgG1 antibody. 
     
     
         118 . The antibody of  claim 61 , wherein the antibody binds to the same epitope as antibody 4F11. 
     
     
         119 . The antibody of  claim 61 , wherein the antibody has been engineered to improve antibody-dependent cell-mediated cytotoxicity (ADCC) activity. 
     
     
         120 . The antibody of  claim 61 , wherein at least one or two of the heavy chains of the antibody is non-fucosylated. 
     
     
         121 . The antibody of  claim 110 , wherein the antibody has been engineered to improve antibody-dependent cell-mediated cytotoxicity (ADCC) activity. 
     
     
         122 . The antibody of  claim 110 , wherein at least one or two of the heavy chains of the antibody is non-fucosylated. 
     
     
         123 . An antibody that binds to an epitope in Domain 1 of human Siglec-8 and competes with antibody 4F11 for binding to Siglec-8. 
     
     
         124 . The antibody of  claim 123 , wherein the antibody does not compete with antibody 2E2 for binding to Siglec-8. 
     
     
         125 . The antibody of  claim 124 , wherein the antibody is not antibody 2E2. 
     
     
         126 . The antibody of  claim 123 , wherein the antibody has been engineered to improve antibody-dependent cell-mediated cytotoxicity (ADCC) activity. 
     
     
         127 . The antibody of  claim 123 , wherein at least one or two of the heavy chains of the antibody is non-fucosylated. 
     
     
         128 . The antibody of  claim 123 , wherein Domain 1 comprises the amino acid sequence of SEQ ID NO:112.