METHODS FOR IMPROVING THE BIOACTIVITY OF THERAPEUTIC IgE ANTIBODIES FOR THE TREATMENT OF DISEASE

Abstract

The invention provides a method for increasing the bioactivity (e.g. the biosafety and efficacy) of a therapeutic IgE antibody of the invention in the treatment of a patient. Methods of the invention include: i) administering to the patient a therapeutic IgE antibody in combination with at least one bioactivity-enhancing agent, ii) strategic treatment regimens and protocols for the dosing and administration of a therapeutic IgE antibody of the invention, and iii) the use of a therapeutic IgE antibody having a variable region comprising at least one antigen binding region specific for binding an epitope of an antigen wherein the epitope is not highly repetitive or is non-repetitive.

1 . A method for increasing the bioactivity of a therapeutic IgE antibody in a patient comprising administering to the patient a therapeutic IgE antibody in combination with at least one bioactivity-enhancing agent selected from the group consisting of: immunostimulatory compounds; chemotherapeutic agents; immunosuppressive agents; and any combination thereof, in an amount effective to increase the bioactivity of the therapeutic IgE antibody as compared to the administration of the therapeutic IgE antibody alone. 
     
     
         2 . The method of  claim 1  wherein the IgE antibody is a monoclonal antibody comprising human Fc epsilon (ε) constant regions. 
     
     
         3 . The method of  claim 1  wherein the IgE antibody is a monoclonal antibody comprising human Fc epsilon (ε) constant regions and a variable region comprising at least one antigen binding region specific for a cancer antigen. 
     
     
         4 . The method of  claim 2  wherein the IgE antibody is a chimeric antibody, a humanized antibody or a fully human antibody. 
     
     
         5 . The method of  claim 1  wherein the immunostimulatory compound is a TLR3 agonist or a TLR4 agonist. 
     
     
         6 . The method of  claim 1  wherein the immunosuppressive agent is a corticosteroid. 
     
     
         7 . The method of  claim 1  wherein the chemotherapeutic agent is gemcitabine, cyclophosphamide, topotecan, or doxorubicin. 
     
     
         8 . The method of  claim 1  wherein the IgE antibody is a monoclonal antibody comprising human Fc epsilon (ε) constant regions and a variable region comprising at least one antigen binding region specific for binding an epitope of an antigen wherein the epitope is not highly repetitive or is non-repetitive. 
     
     
         9 . The method of  claim 1  wherein the bioactivity-enhancing agent is administered to the patient at least 30 minutes prior to administration of the therapeutic IgE antibody. 
     
     
         10 . The method of  claim 1  wherein the bioactivity-enhancing agent is administered to the patient about 30 minutes to about 8 hours prior to administration of the therapeutic IgE antibody. 
     
     
         11 . The method of  claim 1  wherein increased bioactivity is the reduction or elimination of systemic hypersensitivity in the patient to the therapeutic IgE antibody. 
     
     
         12 . The method of  claim 1  wherein increased bioactivity is the enhancement of the patient's Th1-type immune response to the antigen. 
     
     
         13 . The method of  claim 1  wherein increased bioactivity is the enhancement of the cytotoxic T-lymphocyte response to the antigen. 
     
     
         14 . The method of  claim 1  wherein increased bioactivity is the inhibition of non-IgE mediated factors in the participation of a systemic allergic response to the therapeutic IgE antibody. 
     
     
         15 . The method of  claim 1  wherein increased bioactivity is the reduction of the dosage of the therapeutic IgE antibody or reduction in the frequency of treatment with the antibody. 
     
     
         16 . A method for increasing the bioactivity of a therapeutic IgE antibody toward a tumor in a patient comprising administering to the patient a therapeutic IgE antibody specific for an antigen associated with the tumor in combination with at least one bioactivity-enhancing agent selected from the group consisting of: immunostimulatory compounds, chemotherapeutic agents, immunosuppressive agents, and any combination thereof, in an amount effective to increase the bioactivity of the therapeutic IgE antibody as compared to the administration of the therapeutic IgE antibody alone. 
     
     
         17 . The method of  claim 16  wherein the therapeutic IgE antibody is a monoclonal antibody is a monoclonal antibody comprising human Fc epsilon (ε) constant regions selected from: a chimeric antibody; a humanized antibody, and a fully human antibody. 
     
     
         18 . The method of  claim 16  wherein increased bioactivity is selected from: inducing local hypersensitivity reactions at the site of the tumor or in the tumor microenvironment; reduction in the dosage of the antibody; reduction in allergic responses to the therapeutic IgE antibody; reduction or inhibition of non-IgE mediated factors that participate in allergic responses to the therapeutic IgE antibody; reduction of the dosage of the therapeutic IgE antibody; and reduction in the frequency of treatment with the IgE antibody. 
     
     
         19 . A method of increasing the biosafety of a therapeutic IgE monoclonal antibody in a patient comprising administering a therapeutic IgE monoclonal antibody wherein the IgE antibody comprises a variable region comprising at least one antigen binding region specific for binding an epitope of an antigen wherein the epitope is not highly repetitive or is non-repetitive optionally in combination with a bioactivity enhancing agent in an amount effective to increase the biosafety of the IgE monoclonal antibody as compared to the biosafety of the IgE antibody when administered alone. 
     
     
         20 . The method of  claim 19  wherein increased biosafety is selected from: (i) reduction of the dosage of the antibody, (ii) reduction in the frequency of treatment with the antibody, (iii) reduction or elimination of the occurrence of systemic hypersensitivity in a patient, (iv) induce shifting the dominant immune response in a patient from a Th2 to Th1 immune response; and (v) reduction or inhibition of non-IgE mediated factors that participate in allergic responses to the therapeutic IgE antibody. 
     
     
         21 . The method of  claim 19  wherein the IgE antibody is a monoclonal antibody selected from: a chimeric antibody; a humanized antibody; and a fully human antibody. 
     
     
         22 . The method of  claim 19  wherein the bioactivity-enhancing agent is administered to the patient at least 30 minutes prior to administration of the therapeutic IgE antibody. 
     
     
         23 . The method of  claim 19  wherein the bioactivity-enhancing agent is administered to the patient about 30 minutes to about 8 hours prior to administration of the therapeutic IgE antibody. 
     
     
         24 . A method of increasing the bioactivity of a therapeutic IgE antibody comprising the step of administering an IgE antibody to a patient in an amount effective to induce direct IgE antibody mediated toxicity against the antigen and diseased cells and induce antigen processing and cross presentation to induce Tc1 T-cell mediated cellular immune response to the antigen in a patient capable of mounting such responses.