Apoptotic anti-ige antibodies

Abstract

The present application relates to apoptotic anti-IgE antibodies, nucleic acid encoding the same, therapeutic compositions thereof, and their use in the treatment of IgE-mediated disorders.

What is claimed is: 
     
         1 . An anti-IgE/M1′ antibody that specifically binds the M1′ segment of IgE and which induces apoptosis in IgE-expressing B-cells. 
     
     
         2 . The antibody of  claim 1 , wherein the antibody binds IgE that is of human, rhesus monkey and cynomolgus monkey in origin. 
     
     
         3 . An anti-IgE/M1′ antibody that specifically binds the M1′ segment of IgE and specifically depletes IgE-producing B-cells when a therapeutically effective amount is administered in vivo to a mammal. 
     
     
         4 . The antibody of  claim 3  that reduces total serum IgE. 
     
     
         5 . The antibody of  claim 4  that reduces free serum IgE. 
     
     
         6 . The antibody of  claim 4 , wherein the IgE is allergen-specific. 
     
     
         7 . The antibody of  claim 3  that is chimeric. 
     
     
         8 . The antibody of  claim 3  that is humanized. 
     
     
         9 . The antibody of  claim 3  that is human. 
     
     
         10 . An anti-IgE/M1′ antibody that specifically binds to the same epitope as one bound by an antibody selected from the group consisting of: 47H4, 7A6, 26A11, 47H4v5, 7A6v1 and 26A11 v6. 
     
     
         11 . The antibody of  claim 10  wherein the epitope corresponds to a peptide selected from the group consisting of: peptide 4 (SEQ ID NO:8), peptide 5 (SEQ ID NO:9), peptide 7 (SEQ ID NO:11) or peptide 8 (SEQ ID NO:12). 
     
     
         12 . The antibody of  claim 11 , wherein the epitope corresponds to peptide 4 (SEQ ID NO:8). 
     
     
         13 . A peptide selected from the group consisting of: peptide 4 (SEQ ID NO:8), peptide 5 (SEQ ID NO:9), peptide 7 (SEQ ID NO:11) or peptide 8 (SEQ ID NO:12). 
     
     
         14 . An anti-IgE/M1′ antibody that specifically binds to an M1′ segment of IgE with a Scatchard binding affinity that is equivalent to that of the murine anti-IgE/M1′ antibody 47H4. 
     
     
         15 . The antibody of  claim 14 , wherein the affinity is between 0.30 and 0.83 nm. 
     
     
         16 . An anti-IgE/M1′ antibody that specifically binds to an M1′ segment of IgE with a Scatchard binding affinity that is equivalent to that of humanized anti-IgE/M1′ antibody 47H4v5. 
     
     
         17 . The antibody of  claim 16 , wherein the affinity is about 1.5 nm. 
     
     
         18 . An anti-IgE/M1′ antibody comprising the heavy chain and light chain HVRs of an antibody or antigen-binding fragment thereof selected from the group consisting of: 26A11, 26A11 v.1-16, 7A6, 7A6v1, 47H4, 47H4v1-6. 
     
     
         19 . The antibody of  claim 18  comprising variable regions of the heavy and light chains of the antibody or antigen-binding fragment thereof selected from the group consisting of: 26A11, 26A11 v.1-16, 7A6, 7A6v1, 47H4, 47H4v1-6. 
     
     
         20 . The antibody of  claim 18 , comprising the heavy and light chain HVRs or an antibody or antigen-binding fragment thereof of 47H4v1-6. 
     
     
         21 . The antibody of  claim 18  that is afucosylated. 
     
     
         22 . A composition comprising the antibody of any of  claims 1 - 21  in combination with at least one pharmaceutically acceptable carrier. 
     
     
         23 . A composition comprising the antibody of any of  claims 1 - 21  in combination with at least one pharmaceutically acceptable carrier and one or more drugs selected from the group consisting of: anti-IgE antibody, antihistamine, bronchodilator, glucocorticoid, NSAID, TNF-antagonist, integrin antagonist, immunosuppressive agent, IL-4 antagonist, IL-13 antagonist, dual IL-4/IL-13 antagonist, DMARD, antibody that binds to a B-cell surface marker and BAFF antagonist. 
     
     
         24 . An isolated nucleic that encodes an antibody or antigen-binding fragment thereof comprising the heavy and light chain HVRs of an apoptotic anti-IgE/M1′ antibody or antigen-binding fragment thereof selected from the group consisting of: 26A11, 26A11 v1-16, 7A6, 7A6v1, 47H4, 47H4v1-6. 
     
     
         25 . The nucleic acid of  claim 24 , further comprising nucleic acid encoding the variable regions of the heavy and light chains of the antibody sequence selected from the group consisting of: 26A11, 26A11v1-16, 7A6, 7A6v1, 47H4, 47H4v1-6. 
     
     
         26 . The nucleic acid of  claim 25 , wherein the encoded antibody is afucosylated. 
     
     
         27 . A vector in which the nucleic acid of  claim 25  is operably linked. 
     
     
         28 . A host cell comprising the vector of  claim 27 . 
     
     
         29 . The host cell of  claim 28  that is mammalian. 
     
     
         30 . The host cell of  claim 29  that is Chinese Hamster Ovary. 
     
     
         31 . A process for producing an apoptotic anti-IgE/M1′ antibody or functional fragment comprising culturing the host cell of  claim 28  under conditions suitable for expression of the antibody or fragment, and recovering the antibody or fragment. 
     
     
         32 . An article of manufacture enclosing the composition of  claim 22  and a package insert indicating use for the treatment of an IgE-mediated disorder. 
     
     
         33 . The article of  claim 32  that is a vial. 
     
     
         34 . The article of  claim 32  that is a pre-filled syringe. 
     
     
         35 . The article of  claim 34 , further comprising an injection device. 
     
     
         36 . The article of  claim 35  that is an auto-injector. 
     
     
         37 . A method for specifically depleting IgE-producing B-cells, comprising administering to a mammal a therapeutically effective amount of an anti-IgE/M1′ antibody that specifically binds to the M1′ segment of IgE and induces apoptosis in IgE-expressing B-cells. 
     
     
         38 . The method of  claim 37 , wherein the antibody comprises the heavy and light chain HVRs of the antibody selected from the group consisting of: 26A11, 26A11 v1-16, 7A6, 7A6v1, 47H4, 47H4v1-6. 
     
     
         39 . The method of  claim 38 , further comprising the reduction of total serum IgE. 
     
     
         40 . The method of  claim 39 , further comprising the reduction of free serum IgE. 
     
     
         41 . The method of  claim 39 , wherein the IgE is allergen-specific. 
     
     
         42 . The method of  claim 38 , wherein the antibody has ADCC activity. 
     
     
         43 . A method of treating an IgE-mediated disorder comprising administering a therapeutically effective amount of an anti-IgE/M1′ antibody that specifically binds to the M1′ segment of IgE induces apoptosis of IgE-expressing B-cells. 
     
     
         44 . The method of  claim 43 , wherein the antibody specifically depletes IgE-expressing B-cells. 
     
     
         45 . The method of  claim 43 , wherein the antibody reduces total serum IgE. 
     
     
         46 . The method of  claim 45 , wherein the antibody reduce free serum IgE. 
     
     
         47 . The method of  claim 45 , wherein the IgE is allergen-specific. 
     
     
         48 . The method of  claim 43 , wherein the antibody comprises the heavy and light chain HVRs or an antibody selected from the group consisting of 26A11, 26A11v1-16, 7A6, 7A6v1, 47H4, 47H4v1-6. 
     
     
         49 . The method of  claim 43  wherein the IgE-mediated disorder is selected from the group consisting of: allergic rhinitis, allergic asthma, non-allergic asthma, atopic dermatitis, allergic gastroenteropathy, anaphylaxis, urticaria, food allergies, allergic bronchopulmonary aspergillosis, parasitic diseases, interstitial cystitis, hyper-IgE syndrome, ataxia-telangiectasia, Wiskott-Aldrich syndrome, athymic lymphoplasia, IgE myeloma, graft-versus-host reaction and allergic purpura. 
     
     
         50 . A method of treating an IgE-mediated disorder comprising a therapeutically effective amount of an anti-IgE/M1′ antibody that specifically binds to the M1′ segment of IgE and that induces apoptosis of IgE-expressing B-cells in combination with a therapeutically effective amount of at least one drug selected from the group consisting of: anti-IgE antibody, antihistamine, bronchodilator, glucocorticoid, NSAID, decongestant, cough suppressant, analgesic, TNF-antagonist, integrin antagonist, immunosuppressive agent, IL-4 antagonist, IL-13 antagonist, dual IL-4/IL-13 antagonist, DMARD, antibody that binds to a B-cell surface marker and BAFF antagonist. In a specific aspect, the antibody specifically depletes IgE-producing B-cells. 
     
     
         51 . A method of treating an IgE-mediated disorder comprising a combined treatment regimen of administering a therapeutically effective amount of an anti-IgE/M1′ antibody that specifically binds to the M1′ segment of IgE and that induces apoptosis of IgE-expressing B-cells prior to, simultaneous with or after the administration of a known method of treatment for allergic disorders. 
     
     
         52 . The method of  claim 51 , wherein the known treatment for allergic disorder comprises the administration of an anti-IgE antibody antihistamine, a bronchodilator, a glucocorticoid, a non-steroidal anti-inflammatory drug, an immunosuppressant, a IL-4 antagonist, a IL-13 antagonist, a dual IL-4/IL-13 antagonist, a decongestant, a cough suppressant or an analgesic. 
     
     
         53 . The method of  claim 51 , wherein the known treatment for allergic disorder comprises a treatment regimen of allergen densitization. 
     
     
         54 . A method for preventing allergen-induced IgE production, comprising administering a therapeutically effective amount of an anti-IgE/M1′ antibody that that specifically binds to the M1′ segment of IgE and induces apoptosis of IgE-expressing B-cells. 
     
     
         55 . A method for reducing allergen-induced IgE production, comprising administering a therapeutically effective amount of an anti-IgE/M1′ antibody that that specifically binds to the M1′ segment of IgE and induces apoptosis of IgE-expressing B-cells. 
     
     
         56 . A murine hybridoma deposited at the ATCC on Mar. 21, 2007 selected from the group consisting of: PTA-8260, PTA-8261, PTA-8262, PTA-8263, PTA-8264, PTA-8265, PTA-8266, PTA-8267, PTA-8268, PTA-8269, PTA-8270. 
     
     
         57 . An antibody that is secreted by the hybridoma of  claim 52 . 
     
     
         58 . A transgenic animal that expresses the human M1′ segment of IgE.