Anti-ms4a6a antibodies and methods of use thereof

Abstract

The present disclosure is generally directed to compositions that include antibodies, e.g., monoclonal, antibodies, antibody fragments, etc., that specifically bind a MS4A6A polypeptide, e.g., a mammalian MS4A6A or human MS4A6A, and use of such compositions in preventing, reducing risk, or treating an individual in need thereof.

1 . An isolated antibody that binds to human MS4A6A, wherein the antibody (i) increases cell surface levels of MS4A6A or increases intracellular levels of MS4A6A or (ii) increases MS4A6A activity. 
     
     
         2 - 3 . (canceled) 
     
     
         4 . An isolated antibody that binds to human MS4A6A, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises:
 an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:4-16;   an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:17-31; and   an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:32-45; and   the light chain variable region comprises:   an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:46-60;   an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:61-76; and   an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:77-90.   
     
     
         5 . The antibody of  claim 4 , wherein the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:91-108. 
     
     
         6 . The antibody of  claim 4 , wherein the light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 109-126. 
     
     
         7 . An isolated antibody that binds to human MS4A6A, wherein the antibody (i) competes with the antibody of  claim 4  for binding to human MS4A6A or (ii) binds essentially the same or overlapping MS4A6A epitope as the antibody of claim  3 . 
     
     
         8 - 11 . (canceled) 
     
     
         12 . The antibody of  claim 29 , wherein the antibody is a monoclonal antibody. 
     
     
         13 . The antibody of  claim 29 , wherein the antibody is of the IgG class, the IgMclass, or the IgA class. 
     
     
         14 . The antibody of  claim 13 , wherein the antibody is of the IgG class and has an IgG1, IgG2, or IgG4 isotype. 
     
     
         15 . The antibody of claim  3 , wherein the antibody is an antibody fragment. 
     
     
         16 . The antibody of  claim 15 , wherein the fragment is a Fab, Fab′, Fab′-SH, F(ab′)2, Fv or scFv fragment. 
     
     
         17 . The antibody of  claim 29 , wherein the antibody further comprises:
 (a) an antigen facilitating transport across the blood-brain-barrier;   (b) an antigen facilitating transport across the blood-brain-barrier selected from the group consisting of transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor related proteins 1 and 2(LPR-1 and 2), diphtheria toxin receptor, CRM197, a llama single domain antibody, TMEM 30(A), a protein transduction domain, TAT, Syn-B, penetratin, a polyargininepeptide, an angiopeptide, and ANG1005;   (c) a disease-causing agent selected from the group consisting of disease-causing peptides or proteins or, disease-causing nucleic acids, wherein the disease-causing nucleic acids are antisense GGCCCC (G2C4) repeat-expansion RNA, the diseasecausing proteins are selected from the group consisting of amy loid beta, oligomeric amy loid beta, amy loid beta plaques, amy loid precursor protein or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amy loid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, SIBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-praline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, praline-alanine (PA) repeat peptides, ubiquitin, and praline-arginine (PR) repeat peptides;   (d) ligands and/or proteins expressed on immune cells, wherein the ligands and/or proteins selected from the group consisting of CD40, OX40, ICOS, CD28, CD137/4-1BB, CD27, GITR, PD-L1, CTLA-4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GALS, TIM3, A2AR, LAG-3, and phosphatidylserine; and   (e) a protein, lipid, polysaccharide, or glycolipid expressed on one or more tumor cells.   
     
     
         18 . An isolated nucleic acid comprising a nucleic acid sequence encoding the antibody of  claim 29 . 
     
     
         19 . A vector comprising the nucleic acid of  claim 18 . 
     
     
         20 . An isolated host cell comprising the vector of  claim 19 . 
     
     
         21 . A method of producing an antibody that binds to human MS4A6A, comprising culturing the cell of  claim 20  so that the antibody is produced. 
     
     
         22 . (canceled) 
     
     
         23 . A pharmaceutical composition comprising the antibody of  claim 29  and a pharmaceutically acceptable carrier. 
     
     
         24 . A method of preventing, reducing risk, or treating an individual having a disease, disorder, or injury selected from the group consisting of Alzheimer's disease, late onset Alzheimer's disease, and cognitive impairment comprising administering to the individual in need thereof a therapeutically effective amount of the antibody of  claim 29 . 
     
     
         25 . A method of preventing, reducing risk, or treating an individual having a disease, disorder, condition, or injury caused by or associated with (i) reduced activity or expression of MS4A6A or (ii) loss of function of MS4A6A, the method comprising administering to the individual in need thereof a therapeutically effective amount of the antibody of  claim 1 . 
     
     
         26 . (canceled) 
     
     
         27 . A method of preventing, reducing the risk, or treating a neurodegenerative disease, disorder, condition, or injury in an individual having at least one genetic allele associated with Alzheimer's disease risk or susceptibility, the method comprising administering to the individual in need thereof a therapeutically effective amount of the antibody of  claim 29 . 
     
     
         28 . (canceled) 
     
     
         29 . An isolated antibody that binds to human MS4A6A, wherein the antibody (i) reduces cell surface levels of MS4A6A or total cellular protein levels of MS4A6A or (ii) reduce MS4A6A activity.