Anti-kir antibodies, formulations, and uses thereof

Abstract

A novel IgG4 isotype anti-KIR antibody, novel formulations of this and other IgG4 anti-KIR antibodies, and methods of using such formulations are provided. Also described are compositions, formulations, dosages, and administration regimens suitable for NK cell activation and therapeutic applications of anti-KIR antibodies, as well as kits comprising one or more anti-KIR antibodies with instructions for use in treating cancer.

1 - 15 . (canceled) 
     
     
         16 . A method of modulating NK cell activity in a patient in need thereof, comprising administering to the patient an antibody which binds at least one human inhibitory Killer Ig-like Receptor (KIR) at a dose of at least about 0.0003 mg/kg, wherein the antibody potentiates the cytotoxic activity of NK cells. 
     
     
         17 . The method of  claim 16 , wherein the dose is selected from about 0.0003, about 0.003, about 0.015, about 0.075, about 0.3, about 1, or about 3 mg/kg. 
     
     
         18 . The method of  claim 16 , comprising repeating the administration at least once. 
     
     
         19 . The method of  claim 16 , wherein the antibody comprises the variable heavy (SEQ ID NO:3) and variable light (SEQ ID NO:2) region sequences of antibody 1-7F9. 
     
     
         20 . The method of  claim 16 , resulting in at least about 50% KIR occupancy on NK cells by said antibody. 
     
     
         21 . The method of  claim 16 , wherein the patient has increased CD107a levels on NK cells in a blood sample taken about 24 hrs after the first dose. 
     
     
         22 . A method of treating cancer in a patient, comprising administering an antibody which binds at least one human inhibitory KIR at a dose and a dosing frequency achieving at least about 95% KIR occupancy on NK cells in plasma for at least about three months, wherein the antibody potentiates the cytotoxic activity of NK cells. 
     
     
         23 . The method of  claim 22 , wherein a dose of from about 0.075 to about 0.3 mg/kg is administered from about 2 times per week to about once per month. 
     
     
         24 . The method of  claim 22 , wherein a dose of from about 0.3 to about 1 mg/kg is administered from about once to about twice per month. 
     
     
         25 . The method of  claim 22 , wherein a dose of from about 1 to about 3 mg/kg is administered from about once per month to about once per 2 months. 
     
     
         26 . The method of  claim 22 , wherein the dose and dosing frequency are selected from any one of the following combinations: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Dose (mg/kg) 
                   Dosing regimen 
                 
                     
                     
                 
                     
                   About 0.003 
                   1-2 times per day; 
                 
                     
                   About 0.015 
                   3-5 times per week; 
                 
                     
                   About 0.075 
                   1-2 times per week; 
                 
                     
                   About 0.3 
                   1-2 times per month; 
                 
                     
                   About 1 
                   About 1 time per month; or 
                 
                     
                   About 3 
                   1-2 times per 2-month period. 
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         27 . The method of  claim 22 , wherein the cancer is acute myeloid leukemia (AML), chronic myeloid leukemia (CML), multiple myeloma (MMy), non-Hodgkin's lymphoma (NHL), colorectal cancer, renal cancer, ovarian cancer, lung cancer, breast cancer, or malignant melanoma. 
     
     
         28 . The method of  claim 22 , wherein the antibody comprises the variable heavy (SEQ ID NO:3) and variable light (SEQ ID NO:2) region sequences of antibody 1-7F9. 
     
     
         29 . An article of manufacture comprising:
 (a) a container comprising an anti-KIR antibody; and   (b) a package insert with instructions for treating cancer in a patient, wherein the instructions indicate that a dose of the anti-KIR antibody of about 0.075 to about 3 mg/kg is administered to the patient at a frequency of from about twice per week to about once every 2 months.   
     
     
         30 . A pharmaceutically acceptable and active formulation comprising: (a) about 0.05 mg/mL to about 10 mg/mL of an IgG4 antibody; (b) about 10-50 mM sodium phosphate; (c) about 160-250 mM sucrose or about 100 mM NaCl; and (d) polysorbate 80, at a pH of about 7.