Combination of Anti-CD20 Antibody and PI3 Kinase Selective Inhibitor

Abstract

Highly effective combinations of a compound of formula A (a PI3Kδ selective inhibitor) and anti-CD20 antibodies are provided herein for the treatment and amelioration of PI3Kδ and/or CD20 mediated diseases and disorders. In particular, the combination can be used to treat cancers and autoimmune diseases. More particularly, the invention provides for a combination of a compound of formula A, or stereoisomers thereof, and ublituximab for the treatment and/or amerioration of hematological malignancies such as leukemia and lymphoma. The invention also provides for a combination of a compound of formula A, or stereoisomers thereof, and anti-CD20 antibodies, including ublituximab for the treatment and/or amelioration of multiple scelrosis.

What is claimed is: 
     
         1 . A method of treating multiple sclerosis which comprises administering to a subject an effective amount of a combination of
 (i) a compound selected from the group consisting of (RS)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one, or a pharmaceutically acceptable salt, solvate, or prodrug of said compound; and   (ii) an anti-CD20 antibody or antigen-binding fragment thereof.   
     
     
         2 . The method of  claim 1 , wherein said anti-CD20 antibody or fragment thereof is selected from the group consisting of antibodies and fragments that are or bind the same epitope as ublituximab, rituximab, ofatumumab, ocrelizumab, veltuzumab, obinutuzumab, ocaratuzumab, PRO131921 and tositumomab. 
     
     
         3 . The method of  claim 1 , wherein said antibody or fragment thereof comprises the VH CDR1, CDR2 and CDR3 region of sequences SEQ ID NO:1, 2, and 3, and the VL CDR1, CDR2 and CDR3 region of sequences SEQ ID NO:6, 7, and 8. 
     
     
         4 . The method of  claim 3 , wherein said antibody or fragment thereof comprises a VH of SEQ ID NO:4 and a VL of SEQ ID NO:9. 
     
     
         5 . The method of  claim 2 , wherein and said anti-CD20 antibody is ublituximab or an anti-CD20 antibody that binds to the same epitope as ublituximab. 
     
     
         6 . The method of  claim 5 , wherein said anti-CD20 antibody is ublituximab. 
     
     
         7 . The method of any one of  claims 1 - 6 , wherein said compound is (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one. 
     
     
         8 . The method of  claim 1 , wherein said compound is the p-toluenesulfonate salt of (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and said anti-CD20 antibody is ublituximab. 
     
     
         9 . The method of  claim 1  or  8 , wherein said compound and said anti-CD20 antibody or fragment are administered to the subject sequentially or simultaneously. 
     
     
         10 . The method of  claim 1  or  8 , wherein said compound and said anti-CD20 antibody or fragment are contained in the same or separate pharmaceutical compositions. 
     
     
         11 . The method of  claim 1 , further comprising administering to the subject at least one additional therapeutic agent. 
     
     
         12 . The method of  claim 11 , wherein said additional therapeutic agent is a steroidal anti-inflammatory drug, a non-steroidal anti-inflammatory drug or an immune-selective anti-inflammatory drug.