Human Rhinovirus (HRV) Antibodies

Abstract

The invention provides isolated fully human monoclonal anti-HRV antibodies, as well as method of making and using these antibodies. Anti-HRV antibodies of the invention prevent or treat subjects having HRV-infections, and related diseases, including, but not limited to, the common cold, nasopharyngitis, croup, pneumonia, bronchiolitis, asthma, chronic obstructive pulmonary disease (COPD), sinusitis, bacterial superinfection, and cystic fibrosis.

What is claimed is: 
     
         1 . An isolated fully human monoclonal antibody, wherein said monoclonal antibody has the following characteristics
 a) binds to an epitope in the rhinovirus capsid protein selected from the group consisting of VP1, VP2, VP3, and VP4;   b) binds to rhinovirus inside infected cells; and   c) binds to rhinovirus.   
     
     
         2 . The antibody of  claim 1 , wherein the antibody binds to an epitope comprising a portion of two or more rhinovirus capsid proteins selected from the group consisting of VP1, VP2, VP3, and VP4. 
     
     
         3 . The antibody of  claim 1 , wherein the antibody binds to rhinovirus serotypes from one or more clades selected from the group consisting of clade A (major group), clade A (minor group), clade B, and clade D. 
     
     
         4 . The antibody of  claim 1 , wherein the antibody cross-neutralizes multiple rhinovirus serotypes from the group consisting of clade A (major group), clade A (minor group), clade B, and clade D. 
     
     
         5 . The antibody of  claim 1 , wherein the antibody neutralizes at least 40% of HRV serotypes selected from the group consisting of HRV-12, HRV-13, HRV-16, HRV-21, HRV-23, HRV-24, HRV-28, HRV-34, HRV-36, HRV-38, HRV-40, HRV-51, HRV-54, HRV-61, HRV-63, HRV-64, HRV-67, HRV-74, HRV-75, HRV-76, HRV-88, HRV-89, HRV-29, HRV-31, HRV-49, HRV-62, HRV-14, HRV-26, HRV-37, HRV-48, HRV-52, HRV-70, HRV-83, HRV-84, HRV-86, HRV-93, HRV-08, and HRV-45. 
     
     
         6 . The antibody of  claim 1 , wherein the antibody binds to at least 90% of the HRV serotypes. 
     
     
         7 . The antibody of  claim 3 , wherein the antibody neutralizes the HRV serotypes with an median IC50 value of equal to or less than 100 ng/ml. 
     
     
         8 . The antibody of  claim 1 , wherein the antibody is isolated from a B-cell from a human donor. 
     
     
         9 . The antibody of  claim 1 , wherein said epitope is non-linear. 
     
     
         10 . The antibody of  claim 1 , wherein the antibody comprises a combination of complementarity determining regions (CDRs) selected from the group consisting of:
 (a) a VH CDR1 region comprising the amino acid sequence of DFYWT (SEQ ID NO: 5); a VH CDR2 region comprising the amino acid sequence of EIDRDGATYYNPSLKS (SEQ ID NO: 6); a VH CDR3 region comprising the amino acid sequence of RPMLRGVWGNFRSNWFDP (SEQ ID NO: 7); a VL CDR1 region comprising the amino acid sequence of SGSSSNIGYSYVS (SEQ ID NO: 14); a VL CDR2 region comprising the amino acid sequence of ENNKRPS (SEQ ID NO: 15); and a VL CDR3 region comprising the amino acid sequence of GTWDTRLFGGV (SEQ ID NO: 16);   (b) a VH CDR1 region comprising the amino acid sequence of DFAMH (SEQ ID NO: 21); a VH CDR2 region comprising the amino acid sequence of SISRDGSTKYSGDSVKG (SEQ ID NO: 22); a VH CDR3 region comprising the amino acid sequence of DSPYYLDIVGYRYFHHYGMDV (SEQ ID NO: 23); a VL CDR1 region comprising the amino acid sequence of RASQILHSYNLA (SEQ ID NO: 30); a VL CDR2 region comprising the amino acid sequence of GAYNRAS (SEQ ID NO: 31); and a VL CDR3 region comprising the amino acid sequence of QQYGDSPSPGLT (SEQ ID NO: 32);   (c) a VH CDR1 region comprising the amino acid sequence of QNDYHWA (SEQ ID NO: 37); a VH CDR2 region comprising the amino acid sequence of SVHYRQKSYYSPSLKS (SEQ ID NO: 38); a VH CDR3 region comprising the amino acid sequence of HNREDYYDSNAYFDE (SEQ ID NO: 39); a VL CDR1 region comprising the amino acid sequence of SGDDLENTLVC (SEQ ID NO: 46); a VL CDR2 region comprising the amino acid sequence of QDSKRPS (SEQ ID NO: 47); and a VL CDR3 region comprising the amino acid sequence of QTWHRSTAQYV (SEQ ID NO: 48);   (d) a VH CDR1 region comprising the amino acid sequence of SNDQYWA (SEQ ID NO: 53); a VH CDR2 region comprising the amino acid sequence of SVHYRRRNYYSPSLES (SEQ ID NO: 54); a VH CDR3 region comprising the amino acid sequence of HNWEDYYESNAYFDY (SEQ ID NO: 55); a VL CDR1 region comprising the amino acid sequence of SGDQLENTFVC (SEQ ID NO: 62); a VL CDR2 region comprising the amino acid sequence of QGSKRPS (SEQ ID NO: 63); and a VL CDR3 region comprising the amino acid sequence of QAWDRSTAHYV (SEQ ID NO: 64).   
     
     
         11 . An isolated anti-HRV antibody, wherein said antibody a combination of complementarity determining regions (CDRs) selected from the group consisting of:
 (a) a VH CDR1 region comprising the amino acid sequence of DFYWT (SEQ ID NO: 5); a VH CDR2 region comprising the amino acid sequence of EIDRDGATYYNPSLKS (SEQ ID NO: 6); a VH CDR3 region comprising the amino acid sequence of RPMLRGVWGNFRSNWFDP (SEQ ID NO: 7); a VL CDR1 region comprising the amino acid sequence of SGSSSNIGYSYVS (SEQ ID NO: 14); a VL CDR2 region comprising the amino acid sequence of ENNKRPS (SEQ ID NO: 15); and a VL CDR3 region comprising the amino acid sequence of GTWDTRLFGGV (SEQ ID NO: 16);   (b) a VH CDR1 region comprising the amino acid sequence of DFAMH (SEQ ID NO: 21); a VH CDR2 region comprising the amino acid sequence of SISRDGSTKYSGDSVKG (SEQ ID NO: 22); a VH CDR3 region comprising the amino acid sequence of DSPYYLDIVGYRYFHHYGMDV (SEQ ID NO: 23); a VL CDR1 region comprising the amino acid sequence of RASQILHSYNLA (SEQ ID NO: 30); a VL CDR2 region comprising the amino acid sequence of GAYNRAS (SEQ ID NO: 31); and a VL CDR3 region comprising the amino acid sequence of QQYGDSPSPGLT (SEQ ID NO: 32);   (c) a VH CDR1 region comprising the amino acid sequence of QNDYHWA (SEQ ID NO: 37); a VH CDR2 region comprising the amino acid sequence of SVHYRQKSYYSPSLKS (SEQ ID NO: 38); a VH CDR3 region comprising the amino acid sequence of HNREDYYDSNAYFDE (SEQ ID NO: 39); a VL CDR1 region comprising the amino acid sequence of SGDDLENTLVC (SEQ ID NO: 46); a VL CDR2 region comprising the amino acid sequence of QDSKRPS (SEQ ID NO: 47); and a VL CDR3 region comprising the amino acid sequence of QTWHRSTAQYV (SEQ ID NO: 48); and   (d) a VH CDR1 region comprising the amino acid sequence of SNDQYWA (SEQ ID NO: 53); a VH CDR2 region comprising the amino acid sequence of SVHYRRRNYYSPSLES (SEQ ID NO: 54); a VH CDR3 region comprising the amino acid sequence of HNWEDYYESNAYFDY (SEQ ID NO: 55); a VL CDR1 region comprising the amino acid sequence of SGDQLENTFVC (SEQ ID NO: 62); a VL CDR2 region comprising the amino acid sequence of QGSKRPS (SEQ ID NO: 63); and a VL CDR3 region comprising the amino acid sequence of QAWDRSTAHYV (SEQ ID NO: 64).   
     
     
         12 . An antibody that binds the same epitope as an antibody selected from the group consisting of the antibodies of  claim 11 . 
     
     
         13 . The antibody of  claim 11  further comprising,
 a) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 4 and a light chain sequence comprising amino acid sequence SEQ ID NO: 13, or 
 b) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 20 and a light chain sequence comprising amino acid sequence SEQ ID NO: 29, or 
 c) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 36 and a light chain sequence comprising amino acid sequence SEQ ID NO: 45, or 
 d) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 52 and a light chain sequence comprising amino acid sequence SEQ ID NO: 61. 
 
     
     
         14 . A nucleic acid molecule encoding the antibody of  claim 11 . 
     
     
         15 . A vector comprising the nucleic acid molecule of  claim 18 . 
     
     
         16 . A cell comprising the vector of  claim 15 . 
     
     
         17 . An isolated B cell clone or immortalized B-cell clone expressing the antibody of  claim 11 . 
     
     
         18 . An isolated epitope which binds to the antibody of  claim 11 . 
     
     
         19 . An immunogenic polypeptide or glycopeptide comprising the epitope of  claim 18 . 
     
     
         20 . A pharmaceutical composition comprising the antibody of  claim 11 , and a pharmaceutically acceptable carrier. 
     
     
         21 . The composition of  claim 20 , further comprising a second therapeutic agent. 
     
     
         22 . The composition of  claim 21 , wherein the second therapeutic agent is a second antibody, an antiviral drug, an antibiotic, a bronchodilator, a leukotriene blocker, a steroid, an anti-inflammatory drug, or an oxygen therapy. 
     
     
         23 . The composition of  claim 21 , wherein the second agent is selected from the group consisting of:
 (a) a second antibody that is specific for human rhinovirus, influenza, parainfluenza, coronavirus, adenovirus, respiratory syncytical virus, picornavirus, metapneumovirus, or anti-IgE antibody;   (b) an anti-viral drug selected from the group consisting of an entry inhibitor, a fusion inhibitor, an integrase inhibitor, a nucleoside analog, a protease inhibitor, and a reverse transcriptase inhibitor;   (c) an anti-viral drug selected from the group consisting of Abacavir, Acicolvir, Acyclovir, Adefovir, Amantadine, Amprenavir, Ampligen, Arbidol, Atazanavir, Atripla, Boceprevir, Cidofovir, Combivir, Darunavir, Delavirdine, Didanosine, Docosanol, Edoxudine, Efavirenz, Emtricitabine, Enfuvirtide, Entecavir, Famciclovir, Fomivirsen, Fosamprenavir, Foscarnet, Fosfonet, Ganciclovir, Ibacitabine, Imunovir, Idoxuridine, Imiquimod, Indinavir, Inosine, Interferon (Type I, II, or III), Lamivudine, Lopinavir, Loviride, Maraviroc, Moroxydine, Methisazone, Nelfinavir, Nevirapine, Nexavir, Oseltamivir, Peginterferon alpha-2a, Pencicolvir, Peramivir, Pleconaril, Podophyllotoxin, Raltegravir, Ribavirin, Rimantadine, Ritonavir, Pyramidine, Saquinavir, Stavudine, Tea tree oil, Tenofovir, Tenofovir disoproxil, Tipranavir, Trifluridine, Trizivir, Tromantadine, Truvada, Valaciclovir, Valganciclovir, Vicriviroc, Vidarabine, Viramidine, Zalcitabine, Zanamivir, and Zidovudine;   (d) an antibiotic selected from the group consisting of an Aminoglycoside, a Carbapenem, a Cephalosporin, a Lincosamide, a Macrolide, a Penicillin, and a Quinolone;   (e) an antibiotic selected from the group consisting of Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmycin, Tobramycin, Paromycin, Geldanamycin, Ertapenem, Dorpenem, Imipenem/Cilastatin, Meropenem, Cefadroxil, Cefazolin, Cefalotin, Cefalothin, Cefalexin, Cefaclor, Ceamandole, Cefoxitin, Cefprozil, Cefurozime, Cefixime, Cefdinir, Defditoren, Cefoperazone, Cefotaxime, Cefazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftobiprole, Teicoplanin, Vancomycin, Telavancin, Clindamycin, Lincomycin, Daptomycin, Azithromyzin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Spectinomycin, Aztreonam, Furazolidone, Nitofurantoin, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Temocillin, Ticarcillin, Amoxicillin/clavulanate, Ampicillin/sulbactam, Piperacillin/tazobactam, Ticarcillin/clavulanate, Bacitracin, Colistin, Polymyxin B, Ciprofloxacin, Enoxacin, Gatifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, Temafloxacin, Mafenide, Sulfonamidochrysoidine, Sulfacetamide, Sulfadiazine, Silver sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim, Trimethoprim-Sulfamethoxazole (Co-trumoxazole), Demeclocycline, Docycline, Minocycline, Oxytetracycline, Tetracycline, Clofazimine, Dapsone, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Pyrazinamide, Rifampicin, Rifampin, Rifabutin, Rifapentin, Stretomycin, Arsphenamine, Choramphenicol, Fosfomycin, Fusidic acid, Linezolid, Metonidazole, Mupirocin, Platensimycin, Quinupristin/Dalfopristin, Rifaximin, Thamphenicol, Tigecycline, and Tinidazole;   (f) a short-acting bronchodilator or a long-acting bronchodilator;   (g) a short-acting bronchodilator comprising a β2-agonist or an anticholinergic;   (h) an long-acting bronchodilator comprising a β2-agonist or a theophylline;   (i) a corticosteroid;   (j) corticosteroid selected from the group consisting of hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, and fluprednidene acetate;   (k) an anti-inflammatory drug comprising an antihistamine or a histamine receptor blocker; and   (l) oxygen therapy comprising supplemental oxygen gas, and wherein the arterial blood oxygen saturation of the subject following treatment is greater than or equal to 85%.   
     
     
         24 . A method of immunizing a subject against human rhinovirus (HRV) infection, comprising administering to the subject the composition of  claim 20 . 
     
     
         25 . A method of preventing or treating a human rhinovirus infection, comprising administering to a subject the composition of  claim 20 . 
     
     
         26 . The method  claim 25 , wherein the human rhinovirus infection causes or exacerbates the common cold, nasopharyngitis, croup, pneumonia, bronchiolitis, asthma, chronic obstructive pulmonary disease (COPD), sinusitis, bacterial superinfection, or cystic fibrosis. 
     
     
         27 . A method of preventing or treating a human rhinovirus (HRV)-related disease, comprising administering to a subject the composition of  claim 20 . 
     
     
         28 . The method  claim 27 , wherein the human rhinovirus (HRV)-related disease is the common cold, nasopharyngitis, croup, pneumonia, bronchiolitis, asthma, chronic obstructive pulmonary disease (COPD), sinusitis, bacterial superinfection, or cystic fibrosis. 
     
     
         29 . A vaccine comprising an epitope which specifically binds to the isolated anti-HRV antibody of  claim 11 . 
     
     
         30 . A vaccine comprising the isolated anti-HRV antibody of  claim 11 .