Treatment regimens using anti-nkg2a antibodies

Abstract

The present invention relates to methods for the treatment of disease, notably cancer, using antibodies that specifically bind and inhibit human NKG2A. Included are therapeutic regimens that provide improved efficacy of anti-NKG2A antibodies.

We claim: 
     
         1 . A method of treating an individual having a cancer with an anti-NKG2A antibody that binds and neutralizes the inhibitory activity of NKG2A, wherein antibody competes with HLA-E for binding to NKG2A, the treatment comprising administering to the individual the antibody for at least one administration cycle in which the anti-NKG2A antibody is administered at least twice and in amounts effective to maintain between two successive administrations of the anti-NKG2A antibody, a blood concentration of anti-NKG2A antibody of at least 10 μg/ml. 
     
     
         2 . The method of  claim 1 , wherein the anti-NKG2A antibody is administered at least twice and in amounts effective to maintain a continuous blood concentration of the anti-NKG2A antibody of at least 10 μg/ml throughout the administration cycle. 
     
     
         3 . The method of  claim 1 , wherein the antibody is administered to maintain a continuous blood concentration of anti-NKG2A antibody of at least 10 μg/ml throughout the administration cycle. 
     
     
         4 . The method of  claim 1 , wherein the antibody is administered to achieve a peak blood concentration of anti-NKG2A antibody of at least 100 μg/ml upon administration. 
     
     
         5 . The method of  claim 1 , wherein the antibody is administered in an amount effective to provide a continuous (minimal) blood concentration of the anti-NKG2A antibody of at least about 100 μg/ml for at least one week following administration of the anti-NKG2A antibody. 
     
     
         6 . The method of  claim 1 , wherein the antibody is administered to maintain a continuous (minimal) blood concentration of the anti-NKG2A antibody of at least about 100 μg/ml between two successive administrations of the anti-NKG2A antibody. 
     
     
         7 . The method of  claim 1 , wherein the antibody is administered to maintain a continuous blood concentration of the anti-NKG2A antibody of at least 100 μg/ml between two successive administrations of the anti-NKG2A antibody, optionally throughout the administration cycle. 
     
     
         8 . The method of  claim 1 , wherein the antibody is administered 2 times per month. 
     
     
         9 . The method of  claim 1 , wherein the antibody is administered intravenously two times per month and the amount of anti-NKG2A antibody administered is between 2-10 mg/kg body weight. 
     
     
         10 . The method of  claim 1 , wherein the antibody is administered intravenously two times per month and the amount of anti-NKG2A antibody administered is between 4-10 mg/kg body weight. 
     
     
         11 . The method of  claim 10 , wherein the treatment comprises a loading period in which the antibody is administered at least once at an initial dose effective to maintain a blood concentration of at least 100 μg/ml until the next successive administration of the anti-NKG2A antibody, followed by a maintenance period in which the antibody is administered at least twice in a second dose and at a frequency effective to maintain a continuous blood concentration of the anti-NKG2A antibody of at least 100 μg/ml between successive administrations of the anti-NKG2A antibody. 
     
     
         12 . The method of  claim 11 , wherein the antibody is administered intravenously, and wherein the loading period comprises administering the antibody once at a dose of between 8-10 mg/kg, and the maintenance period comprises administering the antibody at least twice, at an interval of about two weeks at dose of between 2-6 mg/kg body weight. 
     
     
         13 . The method of  claim 1 , wherein the individual has a hematological tumor. 
     
     
         14 . The method of  claim 1 , wherein the individual has a solid tumor. 
     
     
         15 . The method of  claim 14 , wherein the individual has a head and neck squamous cell carcinoma (HNSCC). 
     
     
         16 . The method of  claim 1 , wherein antibody has an EC50 for binding to NKG2A-expressing cells of between 1-10 ng/ml. 
     
     
         17 . The method of  claim 1 , wherein antibody has KD of between 10-10 M and 10-12 M for binding to a recombinant soluble NKG2A polypeptide, as assessed by surface plasmon resonance. 
     
     
         18 . The method of  claim 1 , wherein the antibody comprises a human IgG4 constant region, wherein the antibody comprises an Fc-engineered constant region comprising an amino acid modification that reduces binding to a human Fcγ receptor, or wherein the antibody fragment lacks an Fc domain. 
     
     
         19 . The method of  claim 1 , wherein the antibody comprises a heavy chain comprising an amino acid sequence of any one of SEQ ID NO: 2-6 and a light chain comprising the amino acid sequence of SEQ ID NO: 7. 
     
     
         20 . A method for the treatment or prevention of a cancer in an individual with an antibody that binds and neutralizes the inhibitory activity of NKG2A, comprising:
 a) determining the HLA-E polypeptide status of malignant cells within the individual having a cancer, and   b) upon a determination that the patient has HLA-E polypeptides prominently expressed on the surface of malignant cells, administering to the individual the in an amount effective to achieve a blood (serum) concentration of the anti-NKG2A antibody that corresponds to at least the EC50, optionally the EC100, for NKG2A+ NK cell response.