Methods and compositions for treating systemic mastocytosis

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.

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; 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 SEO ID NO:61, (ii) HVR-H2 comprising the amino acid sequence of SEO ID NO:62, and (iii) HVR-H3 comprising the amino acid sequence of SEO ID NO:63; and wherein the light chain variable region comprises (i) HVR-L1 comprising the amino acid sequence of SEO ID NO:64, (ii) HVR-L2 comprising the amino acid sequence of SEO ID NO:65, and (iii) HVR-L3 comprising the amino acid sequence of SEO ID NO:66. 
     
     
         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  claim 1 , 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  claim 1 , wherein the individual has a KIT D816V mutation. 
     
     
         7 - 10 . (canceled) 
     
     
         11 . The method of  claim 1 , 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  claim 1 , wherein the individual is diagnosed with advanced systemic mastocytosis before administration of the antibody. 
     
     
         13 - 14 . (canceled) 
     
     
         15 . The method of  claim 1 , 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 or human IgG4 Fc region. 
     
     
         17 - 26 . (canceled) 
     
     
         27 . The method of  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         28 . The method of  claim 1 , wherein the antibody is an IgG1 antibody. 
     
     
         29 . The method of  claim 1 , 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  claim 1 , wherein at least one or two of the heavy chains of the antibody is non-fucosylated. 
     
     
         32 . The method of  claim 1 , wherein the antibody is a humanized antibody or a chimeric antibody. 
     
     
         33 . (canceled) 
     
     
         34 . The method of  claim 1 , 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 - 68 . (canceled) 
     
     
         69 . The method of  claim 1 , wherein the individual is a human. 
     
     
         70 . The method of  claim 1 , wherein the antibody is in a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier. 
     
     
         71 - 93 . (canceled)