Camptothecin Conjugates of Anti-CD22 Antibodies for Treatment of B Cell Diseases

Abstract

Disclosed herein are compositions and methods of use comprising combinations of anti-CD22 antibodies with a therapeutic agent. The therapeutic agent may be attached to the anti-CD22 antibody or may be separately administered, either before, simultaneously with or after the anti-CD22 antibody. In preferred embodiments, the therapeutic agent is an antibody or fragment thereof that binds to an antigen different from CD22, such as CD19, CD20, CD21, CD22, CD23, CD37, CD40, CD40L, CD52, CD80 and HLA-DR. However, the therapeutic agent may an immunomodulator, a cytokine, a toxin or other therapeutic agent known in the art. More preferably, the anti-CD22 antibody is part of a DNL complex, such as a hexavalent DNL complex. Most preferably, combination therapy with the anti-CD22 antibody or fragment and the therapeutic agent is more effective than the antibody alone, the therapeutic agent alone, or the combination of anti-CD22 antibody and therapeutic agent that are not conjugated to each other. Administration of the anti-CD22 antibody and therapeutic agent induces apoptosis and cell death of target cells in diseases such as B-cell lymphomas or leukemias, autoimmune disease or immune dysfunction disease.

1 - 24 . (canceled) 
     
     
         25 . A method of treating a B cell lymphoma or B cell leukemia comprising administering to a human with a B cell lymphoma or B cell leukemia, an immunoconjugate consisting of (i) an anti-CD22 antibody or antigen binding fragment thereof; and (ii) at least one therapeutic agent attached by a chelating agent to the anti-CD22 antibody or fragment thereof, wherein the therapeutic agent is an alpha-emitting radionuclide, wherein the anti-CD22 antibody or fragment thereof comprises the light chain complementarity determining region (CDR) sequences CDR1 (KSSQSVLYSANHKYLA, SEQ ID NO:1), CDR2 (WASTRES, SEQ ID NO:12), and CDR3 (HQYLSSWTF, SEQ ID NO:3) and the heavy chain CDR sequences CDR1 (SYWLH, SEQ ID NO:4), CDR2 (YINPRNDYTEYNQNFKD, SEQ ID NO:5), and CDR3 (RDITTFY, SEQ ID NO:6). 
     
     
         26 . The method of  claim 25 , wherein the radionuclide is Th-227. 
     
     
         27 . The method of  claim 25 , wherein the radionuclide has a decay energy in the range of 2,000 to 10,000 keV. 
     
     
         28 . The method of  claim 25 , wherein the radionuclide has a decay energy in the range of 3,000 to 8,000 keV. 
     
     
         29 . The method of  claim 25 , wherein the radionuclide has a decay energy in the range of 4,000 to 7,000 keV. 
     
     
         30 . The method of  claim 25 , wherein the anti-CD22 antibody or fragment thereof is epratuzumab. 
     
     
         31 . The method of  claim 25 , further comprising administering to said individual an anti-B cell antibody or antigen-binding fragment thereof that binds to an antigen selected from the group consisting of CD19, CD20, CD21, CD22, CD23, CD37, CD40, CD40L, CD52, CD80 and HLA-DR. 
     
     
         32 . The method of  claim 31 , wherein the anti-B cell antibody or fragment thereof binds to CD20. 
     
     
         33 . The method of  claim 32 , wherein the anti-B cell antibody is selected from the group consisting of GA101, BCX-301, DXL 625, L26, B-Ly1, MEM-97, LT20, 2H7, AT80, B-H20, HI20a, HI47, 13.6E12, 4f11, 5c11, 7d1, rituximab and veltuzumab. 
     
     
         34 . The method of  claim 32 , wherein the anti-B cell antibody is rituximab or veltuzumab. 
     
     
         35 . The method of  claim 32 , wherein the anti-B cell antibody or fragment thereof comprises the light chain complementarity-determining region (CDR) sequences CDR1 (RASSSVSYIH; SEQ ID NO:7), CDR2 (ATSNLAS; SEQ ID NO:8), and CDR3 (QQWTSNPPT; SEQ ID NO:9) and the heavy chain variable region CDR sequences CDR1 (SYNMH; SEQ ID NO:10), CDR2 (A1YPGNGDTSYNQKFKG; SEQ ID NO:11), and CDR3 (STYYGGDWYFDV; SEQ ID NO:12). 
     
     
         36 . The method of  claim 30 , wherein the B cell lymphoma or leukemia is selected from the group consisting of mantle cell lymphoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B cell lymphoma, Burkitt lymphoma, follicular lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia and hairy cell leukemia. 
     
     
         37 . The method of  claim 36 , wherein the disease is mantle cell lymphoma. 
     
     
         38 . The method of  claim 25 , further comprising killing B cells by a mechanism selected from the group consisting of homotypic adhesion, loss of mitochondrial membrane potential, production of reactive oxygen species, increased phosphorylation of ERKs and JNK, downregulation of pAkt and Bcl-xL, and enlargement of lysosomes. 
     
     
         39 . The method of  claim 25 , wherein the anti-CD22 antibody is a G1m3 allotype. 
     
     
         40 . The method of  claim 25 , wherein the anti-CD22 antibody is a chimeric, humanized or human antibody. 
     
     
         41 . The method of  claim 25 , wherein the anti-CD22 antibody or fragment thereof comprises human IgG1, IgG2, IgG3, or IgG4 constant regions. 
     
     
         42 . The method of  claim 30 , further comprising storing the immunoconjugate prior to administration at a pH in the range of 5.5 to 7.5 in a solution comprising a buffer selected from the group consisting of 2-(N-morpholino)ethanesulfonic acid (MES), N-(2-acetamido)-2-iminodiacetic acid (ADA), 1,4-piperazinediethanesulfonic acid (PIPES), N-(2-acetamido)-2-aminoethanesulfonic acid (ACES), N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES), and N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) or HEPES. 
     
     
         43 . The method of  claim 42 , wherein the buffer is 25 mM MES, pH 6.5. 
     
     
         44 . The method of  claim 42 , wherein the solution further comprises trehalose and polysorbate 80. 
     
     
         45 . The method of  claim 44 , further comprising lyophilizing the solution and storing the lyophilized antibody at 2-8° C. 
     
     
         46 . The method of  claim 30 , wherein the B cell lymphoma or leukemia is selected from the group consisting of mantle cell lymphoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B cell lymphoma, Burkitt lymphoma, follicular lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia and hairy cell leukemia, and wherein the method further comprises administering veltuzumab. 
     
     
         47 . The method of  claim 25 , wherein the chelating agent is selected from the group consisting of NOTA, DOTA, TETA. 
     
     
         48 . The method of  claim 30 , wherein the chelating agent is selected from the group consisting of NOTA, DOTA, TETA.