US2020181270A1PendingUtilityA1
Methods and compositions for treating systemic mastocytosis

Assignee: ALLAKOS INCPriority: Oct 22, 2015Filed: Feb 20, 2020Published: Jun 11, 2020
Est. expiryOct 22, 2035(~9.3 yrs left)· nominal 20-yr term from priority
Inventors:Christopher R. Bebbington Nenad Tomasevic Rustom Falahati
A61K 45/06A61K 39/3955C07K 16/2851C07K 2317/73A61K 2039/507A61P 35/00C07K 16/2803C07K 2317/41C07K 2317/24A61P 37/00C07K 2317/732A61K 2039/505
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References
Claims
Abstract

The invention provides methods and compositions for the prevention and treatment of advanced systemic mastocytosis such as systemic mastocytosis with an associated hematologic non-mast-cell lineage disease (SM-AHNMD). In particular, the invention provides methods for the prevention and treatment of advanced systemic mastocytosis through administration of antibodies or agonists that bind to human Siglec-8 or compositions comprising said antibodies or agonists. The invention also provides articles of manufacture or kits comprising antibodies or agonists that bind to human Siglec-8 for the prevention and treatment of advanced systemic mastocytosis such as SM-AHNMD.
Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method for treating or preventing advanced systemic mastocytosis in an individual comprising administering to the individual an effective amount of an antibody that binds to human Siglec-8. 
     
     
         2 . The method of  claim 1 , wherein the advanced systemic mastocytosis is selected from the group consisting of: aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and systemic mastocytosis with an associated hematologic non-mast-cell lineage disease (SM-AHNMD). 
     
     
         3 . The method of  claim 2 , wherein the SM-AHNMD is selected from the group consisting of: SM-myelodysplastic syndrome (SM-MDS), SM-myeloproliferative neoplasm (SM-MPN), SM-chronic myelomonocytic leukemia (SM-CMML), SM-chronic eosinophilic leukemia (SM-CEL), and SM-acute myeloid leukemia (SM-AML). 
     
     
         4 . The method of  claim 1 , wherein the advanced systemic mastocytosis is associated with eosinophilia. 
     
     
         5 . The method of any one of  claims 1 - 4 , wherein the advanced systemic mastocytosis is not adequately controlled by cladribine, interferon-α, a corticosteroid, a tyrosine kinase inhibitor or a combination thereof. 
     
     
         6 . The method of any one of  claims 1 - 5 , wherein the individual has a KIT D816V mutation. 
     
     
         7 . The method of any one of  claims 1 - 6 , wherein the antibody depletes at least about 20% of the mast cells expressing Siglec-8 in a sample obtained from the individual as compared to a baseline level before administration of the antibody. 
     
     
         8 . The method of  claim 7 , wherein the sample is a tissue sample or a biological fluid sample. 
     
     
         9 . The method of  claim 8 , wherein the biological fluid sample is a blood sample. 
     
     
         10 . The method of  claim 8 , wherein the tissue sample is a bone marrow sample, a skin sample, a spleen sample, a lymph node sample, a liver sample or a gastrointestinal tract sample. 
     
     
         11 . The method of any one of  claims 1 - 10 , wherein one or more symptom in the individual with advanced systemic mastocytosis is reduced as compared to a baseline level before administration of the antibody. 
     
     
         12 . The method of any one of  claims 1 - 11 , wherein the individual is diagnosed with advanced systemic mastocytosis before administration of the antibody. 
     
     
         13 . The method of any one of  claims 1 - 12 , 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/or 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. 
     
     
         14 . The method of any one of  claims 1 - 12 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:6; and/or a light chain variable region comprising the amino acid sequence selected from SEQ ID NOs:16 or 21. 
     
     
         15 . The method of any one of  claims 1 - 14 , wherein the antibody comprises a heavy chain Fc region comprising a human IgG Fc region. 
     
     
         16 . The method of  claim 15 , wherein the human IgG Fc region comprises a human IgG1. 
     
     
         17 . The method of any one of  claims 1 - 12 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:75; and/or a light chain comprising the amino acid sequence selected from SEQ ID NOs:76 or 77. 
     
     
         18 . The method of any one of  claims 1 - 12 , 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 selected from SEQ ID NOs:67-70; and/or 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:71. 
     
     
         19 . The method of any one of  claims 1 - 12 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence selected from SEQ ID NOs:11-14; and/or a light chain variable region comprising the amino acid sequence selected from SEQ ID NOs:23-24. 
     
     
         20 . The method of any one of  claims 1 - 12 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence selected from SEQ ID NOs:2-14; and/or a light chain variable region comprising the amino acid sequence selected from SEQ ID NOs:16-24. 
     
     
         21 . The method of any one of  claims 1 - 12 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence selected from SEQ ID NOs:2-10; and/or a light chain variable region comprising the amino acid sequence selected from SEQ ID NOs:16-22. 
     
     
         22 . The method of any one of  claims 1 - 12 , wherein the antibody comprises:
 (a) heavy chain variable region comprising:   (1) an HC-FR1 comprising the amino acid sequence selected from SEQ ID NOs:26-29;   (2) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:61;   (3) an HC-FR2 comprising the amino acid sequence selected from SEQ ID NOs:31-36;   (4) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:62;   (5) an HC-FR3 comprising the amino acid sequence selected from SEQ ID NOs:38-43;   (6) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; and   (7) an HC-FR4 comprising the amino acid sequence selected from SEQ ID NOs:45-46,   and/or   (b) a light chain variable region comprising:   (1) an LC-FR1 comprising the amino acid sequence selected from SEQ ID NOs:48-49;   (2) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:64;   (3) an LC-FR2 comprising the amino acid sequence selected from SEQ ID NOs:51-53;   (4) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:65;   (5) an LC-FR3 comprising the amino acid sequence selected from SEQ ID NOs:55-58;   (6) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:66; and   (7) an LC-FR4 comprising the amino acid sequence of SEQ ID NO:60.   
     
     
         23 . The method of any one of  claims 1 - 12 , wherein the antibody comprises:
 (a) heavy chain variable region comprising:   (1) an HC-FR1 comprising the amino acid sequence of SEQ ID NO:26;   (2) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:61;   (3) an HC-FR2 comprising the amino acid sequence of SEQ ID NO:34;   (4) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:62;   (5) an HC-FR3 comprising the amino acid sequence of SEQ ID NO:38;   (6) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; and   (7) an HC-FR4 comprising the amino acid sequence of SEQ ID NOs:45;   and/or   (b) a light chain variable region comprising:   (1) an LC-FR1 comprising the amino acid sequence of SEQ ID NO:48;   (2) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:64;   (3) an LC-FR2 comprising the amino acid sequence of SEQ ID NO:51;   (4) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:65;   (5) an LC-FR3 comprising the amino acid sequence of SEQ ID NO:55;   (6) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:66; and   (7) an LC-FR4 comprising the amino acid sequence of SEQ ID NO:60.   
     
     
         24 . The method of any one of  claims 1 - 12 , wherein the antibody comprises:
 (a) heavy chain variable region comprising:   (1) an HC-FR1 comprising the amino acid sequence of SEQ ID NO:26;   (2) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:61;   (3) an HC-FR2 comprising the amino acid sequence of SEQ ID NO:34;   (4) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:62;   (5) an HC-FR3 comprising the amino acid sequence of SEQ ID NO:38;   (6) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; and   (7) an HC-FR4 comprising the amino acid sequence of SEQ ID NOs:45;   and/or   (b) a light chain variable region comprising:   (1) an LC-FR1 comprising the amino acid sequence of SEQ ID NO:48;   (2) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:64;   (3) an LC-FR2 comprising the amino acid sequence of SEQ ID NO:51;   (4) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:65;   (5) an LC-FR3 comprising the amino acid sequence of SEQ ID NO:58;   (6) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:66; and   (7) an LC-FR4 comprising the amino acid sequence of SEQ ID NO:60.   
     
     
         25 . The method of any one of  claims 1 - 12 , wherein the antibody comprises:
 (a) a heavy chain variable region comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:88, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:91, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:94; and/or a light chain variable region comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:97, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:100, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO:103.   (b) 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.   (c) 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.   
     
     
         26 . The method of  claim 25 , wherein the antibody comprises:
 a. a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:106; and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:109.   b. a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:107; and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:110.   c. a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:108; and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:111.   
     
     
         27 . The method of any one of  claims 1 - 26 , wherein the antibody is a monoclonal antibody. 
     
     
         28 . The method of any one of  claims 1 - 27 , wherein the antibody is an IgG1 antibody. 
     
     
         29 . The method of any one of  claims 1 - 28 , wherein the antibody has been engineered to improve antibody-dependent cell-mediated cytotoxicity (ADCC) activity. 
     
     
         30 . The method of  claim 29 , wherein the antibody comprises at least one amino acid substitution in the Fc region that improves ADCC activity. 
     
     
         31 . The method of any one of  claims 1 - 30 , wherein at least one or two of the heavy chains of the antibody is non-fucosylated. 
     
     
         32 . The method of any one of  claims 1 - 25  and  27 - 31 , wherein the antibody is a human antibody, a humanized antibody or a chimeric antibody. 
     
     
         33 . The method of  claim 1 - 32 , wherein the antibody comprises an antibody fragment selected from the group consisting of Fab, Fab′-SH, Fv, scFv, and (Fab′) 2  fragments. 
     
     
         34 . The method of any one of  claims 1 - 33 , wherein the antibody is administered in combination with one or more additional therapeutic agent selected from the group consisting of: a cytotoxic agent, a cytokine, a growth inhibitory agent, a protein kinase inhibitor, a corticosteroid, an antibody, or an anti-cancer agent. 
     
     
         35 . A method of depleting mast cells expressing Siglec-8 in an individual with advanced systemic mastocytosis comprising administering to the individual an effective amount of an antibody that binds to human Siglec-8, wherein the antibody kills mast cells expressing Siglec-8 by ADCC activity. 
     
     
         36 . The method of  claim 35 , wherein the advanced systemic mastocytosis is selected from the group consisting of: aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and systemic mastocytosis with an associated hematologic non-mast-cell lineage disease (SM-AHNMD). 
     
     
         37 . The method of  claim 36 , wherein the SM-AHNMD is selected from the group consisting of: SM-myelodysplastic syndrome (SM-MDS), SM-myeloproliferative neoplasm (SM-MPN), SM-chronic myelomonocytic leukemia (SM-CMML), SM-chronic eosinophilic leukemia (SM-CEL), and SM-acute myeloid leukemia (SM-AML). 
     
     
         38 . The method of  claim 35 , wherein the advanced systemic mastocytosis is associated with eosinophilia. 
     
     
         39 . The method of any one of  claims 35 - 38 , wherein the advanced systemic mastocytosis is not adequately controlled by cladribine, interferon-α, a corticosteroid, a tyrosine kinase inhibitor or a combination thereof. 
     
     
         40 . The method of any one of  claims 35 - 39 , wherein the individual has a KIT D816V mutation. 
     
     
         41 . The method of any one of  claims 35 - 40 , wherein the antibody depletes at least about 20% of the mast cells expressing Siglec-8 in a sample obtained from the individual as compared to a baseline level before administration of the antibody. 
     
     
         42 . The method of  claim 41 , wherein the sample is a tissue sample or a biological fluid sample. 
     
     
         43 . The method of  claim 42 , wherein the biological fluid sample is a blood sample. 
     
     
         44 . The method of  claim 42 , wherein the tissue sample is a bone marrow sample, a skin sample, a spleen sample, a lymph node sample, a liver sample or a gastrointestinal tract sample. 
     
     
         45 . The method of any one of  claims 35 - 44 , wherein one or more symptom in the individual with advanced systemic mastocytosis is reduced as compared to a baseline level before administration of the antibody. 
     
     
         46 . The method of any one of  claims 35 - 45 , wherein the individual is diagnosed with advanced systemic mastocytosis before administration of the antibody. 
     
     
         47 . The method of any one of  claims 35 - 46 , 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/or 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. 
     
     
         48 . The method of any one of  claims 35 - 46 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:6; and/or a light chain variable region comprising the amino acid sequence selected from SEQ ID NOs:16 or 21. 
     
     
         49 . The method of any one of  claims 35 - 48 , wherein the antibody comprises a heavy chain Fc region comprising a human IgG Fc region. 
     
     
         50 . The method of  claim 49 , wherein the human IgG Fc region comprises a human IgG1. 
     
     
         51 . The method of any one of  claims 35 - 46 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:75; and/or a light chain comprising the amino acid sequence selected from SEQ ID NOs:76 or 77. 
     
     
         52 . The method of any one of  claims 35 - 46 , 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 selected from SEQ ID NOs:67-70; and/or 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:71. 
     
     
         53 . The method of any one of  claims 35 - 46 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence selected from SEQ ID NOs:11-14; and/or a light chain variable region comprising the amino acid sequence selected from SEQ ID NOs:23-24. 
     
     
         54 . The method of any one of  claims 35 - 46 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence selected from SEQ ID NOs:2-14; and/or a light chain variable region comprising the amino acid sequence selected from SEQ ID NOs:16-24. 
     
     
         55 . The method of any one of  claims 35 - 46 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence selected from SEQ ID NOs:2-10; and/or a light chain variable region comprising the amino acid sequence selected from SEQ ID NOs:16-22. 
     
     
         56 . The method of any one of  claims 35 - 46 , wherein the antibody comprises:
 (a) heavy chain variable region comprising:   (1) an HC-FR1 comprising the amino acid sequence selected from SEQ ID NOs:26-29;   (2) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:61;   (3) an HC-FR2 comprising the amino acid sequence selected from SEQ ID NOs:31-36;   (4) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:62;   (5) an HC-FR3 comprising the amino acid sequence selected from SEQ ID NOs:38-43;   (6) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; and   (7) an HC-FR4 comprising the amino acid sequence selected from SEQ ID NOs:45-46,   and/or   (b) a light chain variable region comprising:   (1) an LC-FR1 comprising the amino acid sequence selected from SEQ ID NOs:48-49;   (2) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:64;   (3) an LC-FR2 comprising the amino acid sequence selected from SEQ ID NOs:51-53;   (4) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:65;   (5) an LC-FR3 comprising the amino acid sequence selected from SEQ ID NOs:55-58;   (6) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:66; and   (7) an LC-FR4 comprising the amino acid sequence of SEQ ID NO:60.   
     
     
         57 . The method of any one of  claims 35 - 46 , wherein the antibody comprises:
 (a) heavy chain variable region comprising:   (1) an HC-FR1 comprising the amino acid sequence of SEQ ID NO:26;   (2) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:61;   (3) an HC-FR2 comprising the amino acid sequence of SEQ ID NO:34;   (4) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:62;   (5) an HC-FR3 comprising the amino acid sequence of SEQ ID NO:38;   (6) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; and   (7) an HC-FR4 comprising the amino acid sequence of SEQ ID NOs:45;   and/or   (b) a light chain variable region comprising:   (1) an LC-FR1 comprising the amino acid sequence of SEQ ID NO:48;   (2) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:64;   (3) an LC-FR2 comprising the amino acid sequence of SEQ ID NO:51;   (4) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:65;   (5) an LC-FR3 comprising the amino acid sequence of SEQ ID NO:55;   (6) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:66; and   (7) an LC-FR4 comprising the amino acid sequence of SEQ ID NO:60.   
     
     
         58 . The method of any one of  claims 35 - 46 , wherein the antibody comprises:
 (a) heavy chain variable region comprising:   (1) an HC-FR1 comprising the amino acid sequence of SEQ ID NO:26;   (2) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:61;   (3) an HC-FR2 comprising the amino acid sequence of SEQ ID NO:34;   (4) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:62;   (5) an HC-FR3 comprising the amino acid sequence of SEQ ID NO:38;   (6) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; and   (7) an HC-FR4 comprising the amino acid sequence of SEQ ID NOs:45;   and/or   (b) a light chain variable region comprising:   (1) an LC-FR1 comprising the amino acid sequence of SEQ ID NO:48;   (2) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:64;   (3) an LC-FR2 comprising the amino acid sequence of SEQ ID NO:51;   (4) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:65;   (5) an LC-FR3 comprising the amino acid sequence of SEQ ID NO:58;   (6) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:66; and   (7) an LC-FR4 comprising the amino acid sequence of SEQ ID NO:60.   
     
     
         59 . The method of any one of  claims 35 - 46 , wherein the antibody comprises:
 (a) a heavy chain variable region comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:88, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:91, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:94; and/or a light chain variable region comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:97, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:100, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO:103.   (b) 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.   (c) 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.   
     
     
         60 . The method of  claim 59 , wherein the antibody comprises:
 (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:106; and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:109.   (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:107; and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:110.   (c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:108; and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:111.   
     
     
         61 . The method of any one of  claims 35 - 60 , wherein the antibody is a monoclonal antibody. 
     
     
         62 . The method of any one of  claims 35 - 61 , wherein the antibody is an IgG1 antibody. 
     
     
         63 . The method of any one of  claims 35 - 62 , wherein the antibody has been engineered to improve antibody-dependent cell-mediated cytotoxicity (ADCC) activity. 
     
     
         64 . The method of  claim 63 , wherein the antibody comprises at least one amino acid substitution in the Fc region that improves ADCC activity. 
     
     
         65 . The method of any one of  claims 35 - 64 , wherein at least one or two of the heavy chains of the antibody is non-fucosylated. 
     
     
         66 . The method of any one of  claims 35 - 59  and  61 - 65 , wherein the antibody is a human antibody, a humanized antibody or a chimeric antibody. 
     
     
         67 . The method of  claim 35 - 66 , wherein the antibody comprises an antibody fragment selected from the group consisting of Fab, Fab′-SH, Fv, scFv, and (Fab′) 2  fragments. 
     
     
         68 . The method of any one of  claims 35 - 67 , wherein the antibody is administered in combination with one or more additional therapeutic agent selected from the group consisting of: a cytotoxic agent, a cytokine, a growth inhibitory agent, a protein kinase inhibitor, a corticosteroid, an antibody, or an anti-cancer agent. 
     
     
         69 . The method of any one of  claims 1 - 68 , wherein the individual is a human. 
     
     
         70 . The method of any one of  claims 1 - 69 , wherein the antibody is in a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier. 
     
     
         71 . A composition comprising an antibody that binds to human Siglec-8 for use in treating or preventing advanced systemic mastocytosis in an individual. 
     
     
         72 . The composition of  claim 71 , 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. 
     
     
         73 . The composition of  claim 72 , wherein substantially none of the N-glycoside-linked carbohydrate chains contain a fucose residue. 
     
     
         74 . The composition of any one of  claims 71 - 73 , wherein the antibody depletes at least about 20% of the mast cells expressing Siglec-8 in a sample obtained from the individual as compared to a baseline level before administration of the antibody. 
     
     
         75 . The composition of  claim 74 , wherein the sample is a tissue sample or a biological fluid sample. 
     
     
         76 . The composition of  claim 75 , wherein the biological fluid sample is a blood sample. 
     
     
         77 . The composition of  claim 75 , wherein the tissue sample is a bone marrow sample, a skin sample, a spleen sample, a lymph node sample, a liver sample or a gastrointestinal tract sample. 
     
     
         78 . The composition of any one of  claims 71 - 77 , wherein one or more symptom in the individual with advanced systemic mastocytosis is reduced as compared to a baseline level before administration of the antibody. 
     
     
         79 . The composition of any one of  claims 71 - 78 , wherein the antibody is administered in combination with one or more additional therapeutic agent selected from the group consisting of: a cytotoxic agent, a cytokine, a growth inhibitory agent, a protein kinase inhibitor, a corticosteroid, an antibody, or an anti-cancer agent. 
     
     
         80 . An article of manufacture comprising a medicament comprising an antibody that binds to human Siglec-8 and a package insert comprising instructions for administration of the medicament in an individual in need thereof to treat or prevent advanced systemic mastocytosis. 
     
     
         81 . The article of manufacture of  claim 80 , wherein the advanced systemic mastocytosis is selected from the group consisting of: aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and systemic mastocytosis with an associated hematologic non-mast-cell lineage disease (SM-AHNMD). 
     
     
         82 . The article of manufacture of  claim 81 , wherein the SM-AHNMD is selected from the group consisting of: SM-myelodysplastic syndrome (SM-MDS), SM-myeloproliferative neoplasm (SM-MPN), SM-chronic myelomonocytic leukemia (SM-CMML), SM-chronic eosinophilic leukemia (SM-CEL), and SM-acute myeloid leukemia (SM-AML). 
     
     
         83 . The article of manufacture of  claim 80 , wherein the advanced systemic mastocytosis is associated with eosinophilia. 
     
     
         84 . The article of manufacture of any one of  claims 80 - 83 , wherein the advanced systemic mastocytosis is not adequately controlled by cladribine, interferon-α, a corticosteroid, a tyrosine kinase inhibitor or a combination thereof. 
     
     
         85 . The article of manufacture of any one of  claims 80 - 84 , wherein the individual has a KIT D816V mutation. 
     
     
         86 . The article of manufacture of any one of  claims 80 - 85 , wherein the package insert further indicates that the treatment is effective in depleting at least about 20% of the mast cells expressing Siglec-8 in a sample obtained from the individual as compared to a baseline level before administration of the medicament comprising the antibody. 
     
     
         87 . The article of manufacture of  claim 86 , wherein the sample is a tissue sample or a biological fluid sample. 
     
     
         88 . The article of manufacture of  claim 87 , wherein the biological fluid sample is a blood sample. 
     
     
         89 . The article of manufacture of  claim 87 , wherein the tissue sample is a bone marrow sample, a skin sample, a spleen sample, a lymph node sample, a liver sample or a gastrointestinal tract sample. 
     
     
         90 . The article of manufacture of any one of  claims 80 - 89 , wherein the package insert further indicates that the treatment is effective in reducing one or more symptom in the individual with advanced systemic mastocytosis as compared to a baseline level before administration of the medicament comprising the antibody. 
     
     
         91 . The article of manufacture of any one of  claims 80 - 90 , further comprising one or more additional medicament and wherein the package insert further comprises instructions for simultaneous or sequential administration of the one or more additional medicament in combination with the medicament comprising the antibody that binds to Siglec-8. 
     
     
         92 . The article of manufacture of  claim 91 , wherein the one or more additional medicament comprises a therapeutic agent selected from the group consisting of: a cytotoxic agent, a cytokine, a growth inhibitory agent, a protein kinase inhibitor, a corticosteroid, an antibody, or an anti-cancer agent. 
     
     
         93 . The article of manufacture of any one of  claims 80 - 92 , wherein the individual is a human.
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