Combined use of fc gamma riib (cd32b) and cd20 specific antibodies

Abstract

The invention provides a method of treating a patient having target cells that express FcγRIIb, the method comprising administering (i) an antibody molecule that specifically binds a surface antigen of the target cell, which antibody molecule has an Fc domain capable of binding FcγRIIb; in combination with (ii) an agent that prevents or reduces binding between the Fc domain of the antibody molecule and FcγRIIb; characterized in that the patient is selected on the basis that their target cells express an elevated level of FcγRIIb.

What is claimed is: 
     
         1 . A composition comprising;
 (i) an antibody molecule that specifically binds a cell surface antigen of a target cell, which antibody has a Fc domain capable of binding FcγRIIb; in combination with   (ii) an agent that prevents or reduces FcγRIIb binding to the Fc domain of the antibody molecule wherein the agent is selected from the group consisting of an antibody;   a chimeric antibody; a single chain antibody; a Fab; a F(ab′)2; an scFv; and a dAb antibody fragment; and   characterized in that the composition is for use in the treatment of a patient with target cells having an elevated level of FcγRIIb expression.   
     
     
         2 . A method of treating a patient having target cells that express FcγRIIb, the method comprising administering (i) an antibody molecule that specifically binds a surface antigen of the target cell, which antibody molecule has an Fc domain capable of binding FcγRIIb; in combination with (ii) an agent that prevents or reduces binding between the Fc domain of the antibody molecule and FcγRIIb wherein the agent is selected from the group consisting of an antibody; a chimeric antibody; a single chain antibody; a Fab; a F(ab′)2; an scFv; and a dAb antibody fragment;
 characterized in that the patient is selected on the basis that their target cells express an elevated level of FcγRIIb. 
 
     
     
         3 . A method for predicting the response of target cells of a patient to treatment with an antibody molecule that specifically binds a target cell surface antigen and has an Fc domain capable of binding FcγRIIb; characterized in that the method comprises determining the level of expression of FcγRIIb on the target cells, whereby elevated levels of FcγRIIb are predictive of a reduction in, or the absence of, a response to treatment with the antibody molecule. 
     
     
         4 . The method according to  claim 2  wherein the agent prevents or reduces FcγRIIb present on the target cell from binding to the Fc domain of the antibody molecule. 
     
     
         5 . The method according to  claim 2  wherein the antibody molecule that specifically binds a cell surface antigen of a target cell, which antibody has a Fc domain capable of binding FcγRIIb, is capable of being internalized into the target cell in an FcγRIIb-dependent manner. 
     
     
         6 . The method according to  claim 2  wherein the agent that prevents or reduces FcγRIIb binding to the Fc domain of the antibody molecule additionally prevents or reduces internalization of the antibody molecule into the target cell. 
     
     
         7 . The method as claimed in  claim 2  wherein the target cell is a cancer cell. 
     
     
         8 . The method as claimed in  claim 2  wherein the target cell is a B cell. 
     
     
         9 . The method as claimed in  claim 2  wherein the patient to be treated is a cancer patient and the treatment is cancer treatment. 
     
     
         10 . The method as claimed in  claim 9  wherein the cancer treatment is for a cancer selected from the group consisting of non-Hodgkin lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, and chronic lymphocytic leukaemia. 
     
     
         11 . The method as claimed in  claim 2  wherein the agent specifically binds FcγRIIb. 
     
     
         12 . The method as claimed in  claim 11  wherein the agent does not include a domain capable of recruiting an effector cell. 
     
     
         13 . The method as claimed in  claim 12  wherein the agent is one or more monoclonal antibody molecules. 
     
     
         14 . The method as claimed in  claim 2  wherein the agent comprises a variable heavy chain (VH) comprising the following CDRs:
 (i) SEQ ID NO: 29 and SEQ ID NO: 30 and SEQ ID NO: 31; or 
 (ii) SEQ ID NO: 35 and SEQ ID NO: 36 and SEQ ID NO: 37; or 
 (iii) SEQ ID NO: 41 and SEQ ID NO: 42 and SEQ ID NO: 43; or 
 (iv) SEQ ID NO: 47 and SEQ ID NO: 48 and SEQ ID NO: 49; or 
 (v) SEQ ID NO: 53 and SEQ ID NO: 54 and SEQ ID NO: 55; or 
 (vi) SEQ ID NO: 59 and SEQ ID NO: 60 and SEQ ID NO: 61; or 
 (vii) SEQ ID NO: 65 and SEQ ID NO: 66 and SEQ ID NO: 67; or 
 (viii) SEQ ID NO: 71 and SEQ ID NO: 72 and SEQ ID NO: 73; or 
 (ix) SEQ ID NO: 77 and SEQ ID NO: 78 and SEQ ID NO: 79; or 
 (x) SEQ ID NO: 83 and SEQ ID NO: 84 and SEQ ID NO: 85; or 
 (xi) SEQ ID NO: 89 and SEQ ID NO: 90 and SEQ ID NO: 91; or 
 (xii) SEQ ID NO: 95 and SEQ ID NO: 96 and SEQ ID NO: 97; or 
 (xiii) SEQ ID NO: 101 and SEQ ID NO: 102 and SEQ ID NO: 103. 
 
     
     
         15 . The method as claimed in  claim 2  wherein the agent comprises a variable light chain (VL) comprising the following CDRs:
 (i) SEQ ID NO: 32 and SEQ ID NO: 33 and SEQ ID NO: 34; or 
 (ii) SEQ ID NO: 38 and SEQ ID NO: 39 and SEQ ID NO: 40; or 
 (iii) SEQ ID NO: 44 and SEQ ID NO: 45 and SEQ ID NO: 46; or 
 (iv) SEQ ID NO: 50 and SEQ ID NO: 51 and SEQ ID NO: 52; or 
 (v) SEQ ID NO: 56 and SEQ ID NO: 57 and SEQ ID NO: 58; or 
 (vi) SEQ ID NO: 62 and SEQ ID NO: 63 and SEQ ID NO: 64; or 
 (vii) SEQ ID NO: 68 and SEQ ID NO: 69 and SEQ ID NO: 70; or 
 (viii) SEQ ID NO: 74 and SEQ ID NO: 75 and SEQ ID NO: 76; or 
 (ix) SEQ ID NO: 80 and SEQ ID NO: 81 and SEQ ID NO: 82; or 
 (x) SEQ ID NO: 86 and SEQ ID NO: 87 and SEQ ID NO: 88; or 
 (xi) SEQ ID NO: 92 and SEQ ID NO: 93 and SEQ ID NO: 94; or 
 (xii) SEQ ID NO: 98 and SEQ ID NO: 99 and SEQ ID NO: 100; or 
 (xiii) SEQ ID NO: 104 and SEQ ID NO: 105 and SEQ ID NO: 106. 
 
     
     
         16 . The method as claimed in  claim 2  wherein the agent comprises a variable heavy chain (VH) amino acid sequence selected from the group consisting of: SEQ ID NO: 3; SEQ ID NO: 4; SEQ ID NO: 5, SEQ ID NO: 6; SEQ ID NO: 7; SEQ ID NO: 8;
 SEQ ID NO: 9; SEQ ID NO: 10; SEQ ID NO: 11; SEQ ID NO: 12; SEQ ID NO: 13; SEQ ID NO: 14; and SEQ ID NO: 15. 
 
     
     
         17 . The method as claimed in  claim 2  wherein the agent comprises a variable light chain (VL) amino acid sequence selected from the group consisting of: SEQ ID NO:
 16; SEQ ID NO: 17; SEQ ID NO: 18; SEQ ID NO: 19; SEQ ID NO: 20; SEQ ID NO: 21; 
 SEQ ID NO: 22; SEQ ID NO:23; SEQ ID NO: 24; SEQ ID NO: 25; SEQ ID NO: 26; 
 SEQ ID NO: 27; and SEQ ID NO: 28. 
 
     
     
         18 . The method as claimed in  claim 2  wherein the agent comprises the following CDR amino acid sequences:
 (i) SEQ ID NO: 29 and SEQ ID NO: 30 and SEQ ID NO: 31 and SEQ ID NO: 32 and SEQ ID NO: 33 and SEQ ID NO: 34; or 
 (ii) SEQ ID NO: 35 and SEQ ID NO: 36 and SEQ ID NO: 37 and SEQ ID NO: 38 and SEQ ID NO: 39 and SEQ ID NO: 40; or 
 (iii) SEQ ID NO: 41 and SEQ ID NO: 42 and SEQ ID NO: 43 and SEQ ID NO: 44 and SEQ ID NO: 45 and SEQ ID NO: 46; or 
 (iv) SEQ ID NO: 47 and SEQ ID NO: 48 and SEQ ID NO: 49 and SEQ ID NO: 50 and SEQ ID NO: 51 and SEQ ID NO: 52; or 
 (v) SEQ ID NO: 53 and SEQ ID NO: 54 and SEQ ID NO: 55 and SEQ ID NO: 56 and SEQ ID NO: 57 and SEQ ID NO: 58; or 
 (vi) SEQ ID NO: 59 and SEQ ID NO: 60 and SEQ ID NO: 61 and SEQ ID NO: 62 and SEQ ID NO: 63 and SEQ ID NO: 64; or 
 (vii) SEQ ID NO: 65 and SEQ ID NO: 66 and SEQ ID NO: 67 and SEQ ID NO: 68 and SEQ ID NO: 69 and SEQ ID NO: 70; or 
 (viii) SEQ ID NO: 71 and SEQ ID NO: 72 and SEQ ID NO: 73 and SEQ ID NO: 74 and SEQ ID NO: 75 and SEQ ID NO: 76; or 
 (ix) SEQ ID NO: 77 and SEQ ID NO: 78 and SEQ ID NO: 79 and SEQ ID NO: 80 and SEQ ID NO: 81 and SEQ ID NO: 82; or 
 (x) SEQ ID NO: 83 and SEQ ID NO: 84 and SEQ ID NO: 85 and SEQ ID NO: 86 and SEQ ID NO: 87 and SEQ ID NO: 88; or 
 (xi) SEQ ID NO: 89 and SEQ ID NO: 90 and SEQ ID NO: 91 and SEQ ID NO: 92 and SEQ ID NO: 93 and SEQ ID NO: 94; or 
 (xii) SEQ ID NO: 95 and SEQ ID NO: 96 and SEQ ID NO: 97 and SEQ ID NO: 98 and SEQ ID NO: 99 and SEQ ID NO: 100; or 
 (xiii) SEQ ID NO: 101 and SEQ ID NO: 102 and SEQ ID NO: 103 and SEQ ID NO: 104 and SEQ ID NO: 105 and SEQ ID NO: 106. 
 
     
     
         19 . The method as claimed in  claim 2  wherein the agent comprises the following amino acid sequences:
 (i) SEQ ID NO: 3 and SEQ ID NO: 16; or 
 (ii) SEQ IS NO: 4 and SEQ ID NO: 17; or 
 (iii) SEQ IS NO: 5 and SEQ ID NO: 18; or 
 (iv) SEQ ID NO: 6 and SEQ ID NO: 19; or 
 (v) SEQ ID NO: 7 and SEQ ID NO: 20; or 
 (vi) SEQ ID NO: 8 and SEQ ID NO: 21; or 
 (vii) SEQ ID NO: 9 and SEQ ID NO: 22; or 
 (viii) SEQ ID NO: 10 and SEQ ID NO: 23; or 
 (ix) SEQ ID NO: 11 and SEQ ID NO: 24; or 
 (x) SEQ ID NO: 12 and SEQ ID NO: 25; or 
 (xi) SEQ ID NO: 13 and SEQ ID NO: 26; or 
 (xii) SEQ ID NO: 14 and SEQ ID NO: 27; or 
 (xiii) SEQ ID NO: 15 and SEQ ID NO: 28. 
 
     
     
         20 . The method as claimed in  claim 2  wherein the agent prevents or reduces FcγRIIb signalling. 
     
     
         21 . The method as claimed in  claim 2  wherein the cell surface antigen is CD19, CD20 or CD40. 
     
     
         22 . The method as claimed in  claim 21  wherein the antibody molecule is a Type I CD20 antibody. 
     
     
         23 . The method as claimed in  claim 2  where elevated FcγRIIb expression on the target cells is determined relative to a control, and the control is the normal level of FcγRIIb expression in cells of the same type as the target cells.