Method to inhibit airway hyperresponsiveness using aerosolized t cell receptor antibodies

Abstract

Disclosed is a method to reduce airway hyperresponsivesness in an animal by the direct delivery to the lungs of aerosolized antibodies against T cell receptors. The method is particularly useful for treating airway hyperresponsiveness associated with allergic inflammation, is effective at extremely low doses of antibody, and does not have a substantial effect on the peripheral immune system.

1 . A method to reduce airway hyperresponsiveness in a mammal that has, or is at risk of developing, airway hyperresponsiveness, comprising administering to the lungs of said mammal an aerosolized antibody formulation comprising antibodies that selectively bind to a CD3 T cell receptor. 
     
     
         2 .- 8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein said antibody is a humanized monoclonal antibody. 
     
     
         10 . The method of  claim 1 , wherein said antibody does not stimulate T cell activation. 
     
     
         11 . The method of  claim 1 , wherein said antibody is a monovalent antibody. 
     
     
         12 . The method of  claim 1 , wherein said antibody is a neutralizing antibody. 
     
     
         13 . The method of  claim 1 , wherein said aerosolized antibody formulation is administered at a dose of less than about 500 μg antibody per milliliter of formulation. 
     
     
         14 . The method of  claim 1 , wherein said aerosolized antibody formulation is administered at a dose of less than about 100 μg antibody per milliliter of formulation. 
     
     
         15 . The method of  claim 1 , wherein said aerosolized antibody formulation is administered at a dose of less than about 50 μg antibody per milliliter of formulation. 
     
     
         16 . The method of  claim 1 , wherein said aerosolized antibody formulation is administered at a dose of between about 5 μg antibody and about 10 μg antibody per milliliter of formulation. 
     
     
         17 . The method of  claim 1 , wherein said aerosolized antibody formulation comprises less than 35% by weight of said antibody. 
     
     
         18 . The method of  claim 1 , wherein said aerosolized antibody formulation is administered at a dose of less than about 400 μg×kilogram −1  body weight of said mammal. 
     
     
         19 . The method of  claim 1 , wherein said aerosolized antibody formulation is administered at a dose of less than about 40 μg×kilogram −1  body weight of said mammal. 
     
     
         20 . The method of  claim 1 , wherein said aerosolized antibody formulation is administered at a dose of less than about 1 μg×kilogram −1  body weight of said mammal. 
     
     
         21 . The method of  claim 1 , wherein said aerosolized antibody formulation is administered at a dose of less than about 0.5 μg×kilogram −1  body weight of said mammal. 
     
     
         22 . The method of  claim 1 , wherein said aerosolized antibody formulation is administered at a dose of less than about 0.1 μg×kilogram −1  body weight of said mammal. 
     
     
         23 . The method of  claim 1 , wherein said aerosolized antibody formulation is administered at a dose of less than about 20 ng×kilogram −1  body weight of said mammal. 
     
     
         24 . The method of  claim 1 , wherein said aerosolized antibody formulation comprises a pharmaceutically acceptable carrier. 
     
     
         25 . The method of  claim 24 , wherein said pharmaceutically acceptable carrier is selected from the group consisting of: a dry, dispersible powder; small capsules;
 liposomes; and a nebulized spray.   
     
     
         26 . The method of  claim 1 , wherein said aerosolized antibody formulation is administered to said mammal in conjunction with another agent that supports the treatment of AHR selected from the group consisting of: corticosteroids, (oral, inhaled and injected), β-agonists (long or short acting), leukotriene modifiers (inhibitors or receptor antagonists), antihistamines, phosphodiesterase inhibitors, sodium cromoglycate, nedocrimal, and theophylline. 
     
     
         27 . The method of  claim 1 , wherein said mammal has been sensitized to an allergen and has been exposed to, or is at risk of being exposed to, an amount of said allergen that is sufficient to induce airway hyperresponsiveness (AHR) in said mammal in the absence of said aerosolized antibody formulation. 
     
     
         28 . The method of  claim 1 , wherein said aerosolized antibody formulation is administered within a time period of between 48 hours or less prior to exposure to an AHR provoking stimulus that is sufficient to induce AHR, and within 48 hours or less after the detection of the first symptoms of AHR. 
     
     
         29 . The method of  claim 1 , wherein said aerosolized antibody formulation is administered upon the detection of the first symptoms of acute onset AHR. 
     
     
         30 . The method of  claim 1 , wherein said aerosolized antibody formulation is administered within 1 hour after the detection of the first symptoms of acute onset AHR. 
     
     
         31 . The method of  claim 1 , wherein said aerosolized antibody formulation is administered within 12 hours or less prior to exposure to a AHR provoking stimulus that is sufficient to induce acute onset AHR. 
     
     
         32 . The method of  claim 1 , wherein said aerosolized antibody formulation is administered within 2 hours or less prior to exposure to a AHR provoking stimulus that is sufficient to induce acute onset AHR. 
     
     
         33 . The method of  claim 1 , wherein administration of said aerosolized antibody formulation does not substantially affect peripheral immune function in said mammal. 
     
     
         34 . The method of  claim 1 , wherein administration of said aerosolized antibody formulation reduces the airway hyperresponsiveness of said mammal such that the FEV 1  value of said mammal is improved by at least about 5%. 
     
     
         35 . The method of  claim 1 , wherein said mammal is a human.