Methods for diagnosis and treatment of proliferative disorders mediated by cd40 signaling

Abstract

Methods for identifying subjects having a cancer or pre-malignant condition that will benefit from anti-CD40 therapeutic agents that modulate CD40L-mediated CD40 signaling are provided. The methods comprise the use of biomarkers of cellular apoptosis, cell proliferation and survival, and CD40 signaling pathways to monitor ex vivo response to one or more anti-CD40 therapeutic agents of interest that modulate CD40 signaling on CD40-expressing neoplastic cells. The ex vivo prognostic assays can be used alone or in conjunction with other prognostic assays to identify candidate subjects who will benefit from treatment with anti-CD40 therapeutic agents. Methods of the invention also comprise the use of these biomarkers to monitor in vivo efficacy of treatment with an anti-CD40 therapeutic agent.

That which is claimed: 
     
         1 . A method for identifying a subject having a cancer or pre-malignant condition that is responsive to treatment with an anti-CD40 therapeutic agent, said method comprising:
 a) providing a test biological sample and a control biological sample from said subject, wherein said test biological sample and said control biological sample comprise CD40-expressing neoplastic cells that have been stimulated with a CD40 ligand;   b) contacting said test biological sample with an effective amount of said anti-CD40 therapeutic agent;   c) detecting the level of at least one biomarker in said test biological sample, wherein said biomarker is selected from the group consisting of a biomarker of cellular apoptosis, a biomarker of a CD40L-mediated CD40 signaling pathway, and a biomarker of cell survival; and   d) comparing the level of said at least one biomarker in said test biological sample to the level of said at least one biomarker detected in said control biological sample, wherein said control biological sample has not been contacted with said anti-CD40 therapeutic agent.   
     
     
         2 . The method of  claim 1 , wherein said CD40-expressing neoplastic cells were stimulated ex vivo with a ligand of CD40 prior to said contacting step. 
     
     
         3 . The method of  claim 2 , wherein said ligand of CD40 is selected from the group consisting of soluble CD40L and membrane-bound CD40L. 
     
     
         4 . The method of  claim 1 , wherein said anti-CD40 therapeutic agent is an antagonist anti-CD40 monoclonal antibody that is capable of specifically binding to a human CD40 antigen expressed on the surface of a human B cell, said monoclonal antibody being free of significant agonist activity when bound to the CD40 antigen expressed on the surface of said B cell. 
     
     
         5 . The method of  claim 4 , wherein said antagonist anti-CD40 monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 or CHIR-12.12;   b) the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   c) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:6, the sequence shown in SEQ ID NO:7, the sequence shown in SEQ ID NO:8, both the sequence shown in SEQ ID NO:6 and SEQ ID NO:7, and both the sequence shown in SEQ ID NO:6 and SEQ ID NO:8;   d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:2, the sequence shown in SEQ ID NO:4, the sequence shown in SEQ ID NO:5, both the sequence shown in SEQ ID NO:2 and SEQ ID NO:4, and both the sequence shown in SEQ ID NO:2 and SEQ ID NO:5;   e) a monoclonal antibody having an amino acid sequence encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of the sequence shown in SEQ ID NO:1, the sequence shown in SEQ ID NO:3, and both the sequence shown in SEQ ID NO:1 and SEQ ID NO:3;   f) a monoclonal antibody that binds to an epitope capable of binding the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   g) a monoclonal antibody that binds to an epitope comprising residues 82-87 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   h) a monoclonal antibody that binds to an epitope comprising residues 82-89 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   i) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay;   j) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-i), wherein said antibody is recombinantly produced; and   k) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-j), wherein said fragment retains the capability of specifically binding to said human CD40 antigen.   
     
     
         6 . The method of  claim 5 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
         7 . The method of  claim 1 , wherein said anti-CD40 therapeutic agent is a CD40 ligand (CD40L) antagonist that inhibits CD40/CD40L interaction or CD40L-mediated CD40 signaling. 
     
     
         8 . The method of  claim 7 , wherein said CD40L antagonist is selected from the group consisting of an anti-CD40L monoclonal antibody that specifically binds to CD40L, a soluble form of CD40, a soluble form of a fusion protein comprising CD40, and a pharmaceutical agent. 
     
     
         9 . The method of  claim 1 , wherein said biomarker of apoptosis is selected from the group consisting of a cleaved Caspase protein, cleaved poly ADP-ribose polymerase (PARP), cell surface expression of phosphotidylserine (PS), genomic DNA fragmentation, and any combinations thereof. 
     
     
         10 . The method of  claim 9 , wherein said cleaved Caspase protein is selected from the group consisting of cleaved Caspase-3, cleaved Caspase-7, and cleaved Caspase-9. 
     
     
         11 . The method of  claim 9 , wherein cell surface PS is detected by annexin V staining and wherein genomic DNA fragmentation is detected by TUNEL staining. 
     
     
         12 . The method of  claim 9 , wherein an increase in the level of at least one of said biomarkers of apoptosis within said test biological sample relative to said control biological sample is indicative of a subject who would benefit from treatment with said anti-CD40 therapeutic agent. 
     
     
         13 . The method of  claim 1 , wherein said CD40L-mediated CD40 signaling pathway is selected from the group consisting of the AKT signaling pathway, the NF-κB signaling pathway, and a mitogen-activated protein kinase (MAPK) signaling pathway. 
     
     
         14 . The method of  claim 13 , wherein said MAPK signaling pathway is selected from the group consisting of the MEK/ERK signaling pathway and the MEK/p38 signaling pathway. 
     
     
         15 . The method of  claim 13 , wherein said biomarker of said CD40L-mediated CD40 signaling pathway is selected from the group consisting of phospho-PI3K, phospho-PDK1, phospho-AKT, phospho-MEK, phospho-ERK, phospho-p38, phospho-IKKα/β, phospho-IκB protein, and activated NF-κB. 
     
     
         16 . The method of  claim 15 , wherein a reduction in the level of at least one of said biomarkers of at least one of said CD40L-mediated CD40 signaling pathways within said test biological sample relative to said control biological sample is indicative of a subject who would benefit from treatment with said anti-CD40 therapeutic agent. 
     
     
         17 . The method of  claim 1 , wherein said biomarker of cell survival is selected from the group consisting of an anti-apoptotic protein that is a Bcl-2 family member, an IAP apoptosis inhibitor protein, and TNF receptor-associated factor-1 (TRAF-1). 
     
     
         18 . The method of  claim 17 , wherein said Bcl-2 family member is selected from the group consisting of Bcl-xl and Mcl-1. 
     
     
         19 . The method of  claim 17 , wherein said IAP apoptosis inhibitor protein is selected from the group consisting of survivin, XIAP, and cIAP1. 
     
     
         20 . The method of  claim 17 , wherein a reduction in the level of at least one of said biomarkers of cell survival in said test biological sample relative to said control biological sample is indicative of a subject who would benefit from treatment with said anti-CD40 therapeutic agent. 
     
     
         21 . The method of  claim 1 , further comprising detecting in said test biological sample and said control biological sample the level of at least one cytokine marker of CD40 signaling. 
     
     
         22 . The method of  claim 21 , wherein said cytokine marker is selected from the group consisting of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, IL-10, granulocyte monocyte colony-stimulating factor (GM-CSF), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1β (MIP-1β). 
     
     
         23 . The method of  claim 21 , wherein a reduction in the level of at least one of said cytokine markers in said test biological sample relative to said control biological sample is indicative of a subject who would benefit from treatment with said anti-CD40 therapeutic agent. 
     
     
         24 . The method of  claim 1 , wherein said anti-CD40 therapeutic agent is an anti-CD40 monoclonal antibody that specifically binds to a human CD40 antigen expressed on the surface of a CD40-expressing cell, thereby modulating antibody-dependent cell-mediated cytotoxity (ADCC) activity, and wherein said biomarker is a biomarker of apoptosis. 
     
     
         25 . The method of  claim 24 , wherein said anti-CD40 monoclonal antibody is an antagonist anti-CD40 monoclonal antibody selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 or CHIR-12.12;   b) the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   c) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:6, the sequence shown in SEQ ID NO:7, the sequence shown in SEQ ID NO:8, both the sequence shown in SEQ ID NO:6 and SEQ ID NO:7, and both the sequence shown in SEQ ID NO:6 and SEQ ID NO:8;   d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:2, the sequence shown in SEQ ID NO:4, the sequence shown in SEQ ID NO:5, both the sequence shown in SEQ ID NO:2 and SEQ ID NO:4, and both the sequence shown in SEQ ID NO:2 and SEQ ID NO:5;   e) a monoclonal antibody having an amino acid sequence encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of the sequence shown in SEQ ID NO:1, the sequence shown in SEQ ID NO:3, and both the sequence shown in SEQ ID NO:1 and SEQ ID NO:3;   f) a monoclonal antibody that binds to an epitope capable of binding the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   g) a monoclonal antibody that binds to an epitope comprising residues 82-87 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   h) a monoclonal antibody that binds to an epitope comprising residues 82-89 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   i) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay; and   j) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-i), wherein said antibody is recombinantly produced.   
     
     
         26 . The method of  claim 24 , wherein said biomarker of apoptosis is selected from the group consisting of a cleaved caspase protein, cleaved poly ADP-ribose polymerase (PARP), cell surface expression of phosphotidylserine (PS), genomic DNA fragmentation, and any combinations thereof. 
     
     
         27 . The method of  claim 26 , wherein said cleaved caspase protein is selected from the group consisting of cleaved Caspase-3, cleaved Caspase-7, and cleaved Caspase-9. 
     
     
         28 . The method of  claim 26 , wherein cell surface PS is detected by annexin V staining and wherein genomic DNA fragmentation is detected by TUNEL staining. 
     
     
         29 . The method of  claim 24 , wherein an increase in the level of at least one of said biomarkers of apoptosis within said test biological sample relative to said control biological sample is indicative of a subject who would benefit from treatment with said anti-CD40 antibody. 
     
     
         30 . The method of  claim 1 , wherein said cancer is characterized by neoplastic B cell growth. 
     
     
         31 . The method of  claim 30 , wherein said cancer is selected from the group consisting of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, multiple myeloma, B cell lymphoma, high-grade B cell lymphoma, intermediate-grade B cell lymphoma, low-grade B cell lymphoma, B cell acute lympohoblastic leukemia, Hodgkin's disease, plasmacytoma, follicular lymphoma, follicular small cleaved lymphoma, follicular large cell lymphoma, follicular mixed small cleaved lymphoma, diffuse small cleaved cell lymphoma, diffuse small lymphocytic lymphoma, prolymphocytic leukemia, lymphoplasmacytic lymphoma, marginal zone lymphoma, mucosal associated lymphoid tissue lymphoma, monocytoid B cell lymphoma, splenic lymphoma, hairy cell leukemia, diffuse large cell lymphoma, mediastinal large B cell lymphoma, lymphomatoid granulomatosis, intravascular lymphomatosis, diffuse mixed cell lymphoma, diffuse large cell lymphoma, immunoblastic lymphoma, Burkitt's lymphoma, AIDS-related lymphoma, Waldenstrom's Macroglobulinemia, mantle cell lymphoma, and heavy chain disease. 
     
     
         32 . The method of  claim 31 , wherein said subject has chronic lymphocytic leukemia. 
     
     
         33 . The method of  claim 32 , further comprising assaying a biological sample from said subject for at least one clinically useful prognostic marker selected from the group consisting of ZAP-70 expression level, CD38 expression level, β2 microglobulin expression level, p53 mutational status, ATM mutational status, chromosome 17p deletion, and chromosome 11q deletion. 
     
     
         34 . The method of  claim 1 , wherein said cancer is a non-B cell hematological malignancy. 
     
     
         35 . The method of  claim 34 , wherein said malignancy is selected from the group consisting of acute leukemias, myeloblastic leukemias, acute myelocytic leukemias, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, erythroleukemia, chronic myelocytic leukemia, and polycythemia vera. 
     
     
         36 . The method of  claim 1 , wherein said cancer is a solid tumor comprising neoplastic cells expressing CD40 antigen. 
     
     
         37 . The method of  claim 36 , wherein said solid tumor is selected from the group consisting of lung carcinoma, breast carcinoma, ovarian carcinoma, skin carcinoma, colon carcinoma, urinary bladder carcinoma, liver carcinoma, gastric carcinoma, prostate cancer, renal cell carcinoma, nasopharyngeal carcinoma, squamous cell carcinoma, thyroid papillary carcinoma, cervical carcinoma, and sarcomas. 
     
     
         38 . The method of  claim 1 , wherein said pre-malignant condition is monoclonal gammopathy of undetermined significance (MGUS). 
     
     
         39 . The method of  claim 1 , further comprising detecting in a biological sample of said subject the level of expression of cell-surface CD40, the level of expression of cell-surface CD40L, or both, on CD40-expressing neoplastic cells within said biological sample. 
     
     
         40 . The method of  claim 1 , further comprising detecting the level of circulating soluble CD40 or circulating soluble CD40L in a biological sample collected from subject. 
     
     
         41 . The method of  claim 1 , wherein detecting the level of said biomarker comprises using an antibody to detect biomarker protein expression. 
     
     
         42 . The method of  claim 1 , wherein detecting the level of said biomarker comprises nucleic acid hybridization. 
     
     
         43 . The method of  claim 1 , wherein detecting the level of said biomarker comprises performing quantitative RT-PCR. 
     
     
         44 . A method of treating a subject with a cancer or pre-malignant condition that is associated with CD40-expressing cells, said method comprising screening said patient with a method according to any one of  claims 1  through  43 , and then treating said subject with said anti-CD40 therapeutic agent when said method according to any one of  claims 1  through  43  generates a result that is indicative of a positive treatment outcome with said anti-CD40 therapeutic agent. 
     
     
         45 . A method for identifying a subject having a cancer or pre-malignant condition that is responsive to treatment with an anti-CD40 therapeutic agent, said method comprising:
 a) providing a biological sample from said subject, wherein said biological sample comprises CD40-expressing neoplastic cells;   b) detecting the level of at least one CD40-related factor in said biological sample, wherein said CD40-related factor is selected from the group consisting of cell-surface CD40 on said CD40-expressing neoplastic cells and cell-surface CD40L on said CD40-expressing neoplastic cells; and   c) comparing the level of said at least one CD40-related factor in said biological sample to the level of said at least one CD40-related factor in a reference standard;   
       wherein an increase in the level of said at least one CD40-related factor in said biological sample relative to the level of said at least one CD40-related factor in said reference standard is indicative of a positive treatment outcome with said anti-CD40 therapeutic agent. 
     
     
         46 . The method of  claim 45 , wherein said detecting comprises use of flow cytometry, immunohistochemistry, Western Blot, immunoprecipitation, magnetic bead selection, quantification of neoplastic cells expressing cell-surface CD40, quantification of neoplastic cells expressing cell-surface CD40L, or any combination thereof. 
     
     
         47 . A method for identifying a subject having a cancer or pre-malignant condition that is responsive to treatment with an anti-CD40 therapeutic agent, said method comprising:
 a) providing a sample of blood or a blood component from said subject;   b) detecting the level of at least one CD40-related factor in said sample, wherein said CD40-related factor is selected from the group consisting of circulating level of CD40 and circulating level of CD40L; and   c) comparing the level of said at least one CD40-related factor in said sample to the level of said at least one CD40-related factor in a reference standard;   
       wherein an increase in the level of said at least one CD40-related factor in said sample relative to the level of said at least one CD40-related factor in said reference standard is indicative of a positive treatment outcome with said anti-CD40 therapeutic agent. 
     
     
         48 . The method of  claim 47 , wherein said detecting uses ELISA, RIA, ECL, multiplexing technologies, or any combination thereof. 
     
     
         49 . The method of  claim 45 , wherein said anti-CD40 therapeutic agent is an antagonist anti-CD40 monoclonal antibody that is capable of specifically binding to a human CD40 antigen expressed on the surface of a human B cell, said monoclonal antibody being free of significant agonist activity when bound to the CD40 antigen expressed on the surface of said B cell. 
     
     
         50 . The method of  claim 49 , wherein said antagonist anti-CD40 monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 or CHIR-12.12;   b) the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   c) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:6, the sequence shown in SEQ ID NO:7, the sequence shown in SEQ ID NO:8, both the sequence shown in SEQ ID NO:6 and SEQ ID NO:7, and both the sequence shown in SEQ ID NO:6 and SEQ ID NO:8;   d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:2, the sequence shown in SEQ ID NO:4, the sequence shown in SEQ ID NO:5, both the sequence shown in SEQ ID NO:2 and SEQ ID NO:4, and both the sequence shown in SEQ ID NO:2 and SEQ ID NO:5;   e) a monoclonal antibody having an amino acid sequence encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of the sequence shown in SEQ ID NO:1, the sequence shown in SEQ ID NO:3, and both the sequence shown in SEQ ID NO:1 and SEQ ID NO:3;   f) a monoclonal antibody that binds to an epitope capable of binding the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   g) a monoclonal antibody that binds to an epitope comprising residues 82-87 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   h) a monoclonal antibody that binds to an epitope comprising residues 82-89 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   i) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay;   j) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-i), wherein said antibody is recombinantly produced; and   k) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-j), wherein said fragment retains the capability of specifically binding to said human CD40 antigen.   
     
     
         51 . The method of  claim 50 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
         52 . The method of  claim 45 , wherein said anti-CD40 therapeutic agent is a CD40 ligand (CD40L) antagonist that inhibits CD40/CD40L interaction or CD40L-mediated CD40 signaling. 
     
     
         53 . The method of  claim 52 , wherein said CD40L antagonist is selected from the group consisting of an anti-CD40L monoclonal antibody that specifically binds to CD40L, a soluble form of CD40, a soluble form of a fusion protein comprising CD40, and a pharmaceutical agent. 
     
     
         54 . The method of  claim 45 , wherein said anti-CD40 therapeutic agent is an anti-CD40 monoclonal antibody that specifically binds to a human CD40 antigen expressed on the surface of a CD40-expressing cell, thereby modulating ADCC activity. 
     
     
         55 . The method of  claim 54 , wherein said anti-CD40 monoclonal antibody is an antagonist anti-CD40 monoclonal antibody selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 or CHIR-12.12;   b) the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   c) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:6, the sequence shown in SEQ ID NO:7, the sequence shown in SEQ ID NO:8, both the sequence shown in SEQ ID NO:6 and SEQ ID NO:7, and both the sequence shown in SEQ ID NO:6 and SEQ ID NO:8;   d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:2, the sequence shown in SEQ ID NO:4, the sequence shown in SEQ ID NO:5, both the sequence shown in SEQ ID NO:2 and SEQ ID NO:4, and both the sequence shown in SEQ ID NO:2 and SEQ ID NO:5;   e) a monoclonal antibody having an amino acid sequence encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of the sequence shown in SEQ ID NO:1, the sequence shown in SEQ ID NO:3, and both the sequence shown in SEQ ID NO:1 and SEQ ID NO:3;   f) a monoclonal antibody that binds to an epitope capable of binding the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   g) a monoclonal antibody that binds to an epitope comprising residues 82-87 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   h) a monoclonal antibody that binds to an epitope comprising residues 82-89 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   i) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay; and   j) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-i), wherein said antibody is recombinantly produced.   
     
     
         56 . The method of  claim 45 , wherein said cancer is characterized by neoplastic B cell growth. 
     
     
         57 . The method of  claim 56 , wherein said cancer is selected from the group consisting of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, multiple myeloma, B cell lymphoma, high-grade B cell lymphoma, intermediate-grade B cell lymphoma, low-grade B cell lymphoma, B cell acute lymphoblastic leukemia, Hodgkin's disease, plasmacytoma, follicular lymphoma, follicular small cleaved lymphoma, follicular large cell lymphoma, follicular mixed small cleaved lymphoma, diffuse small cleaved cell lymphoma, diffuse small lymphocytic lymphoma, prolymphocytic leukemia, lymphoplasmacytic lymphoma, marginal zone lymphoma, mucosal associated lymphoid tissue lymphoma, monocytoid B cell lymphoma, splenic lymphoma, hairy cell leukemia, diffuse large cell lymphoma, mediastinal large B cell lymphoma, lymphomatoid granulomatosis, intravascular lymphomatosis, diffuse mixed cell lymphoma, diffuse large cell lymphoma, immunoblastic lymphoma, Burkitt's lymphoma, AIDS-related lymphoma, Waldenstrom's Macroglobulinemia, and mantle cell lymphoma. 
     
     
         58 . The method of  claim 57 , wherein said subject has chronic lymphocytic leukemia. 
     
     
         59 . The method of  claim 58 , further comprising assaying a biological sample from said subject for at least one clinically useful prognostic marker selected from the group consisting of ZAP-70 expression level, CD38 expression level, β2 microglobulin expression level, p53 mutational status, ATM mutational status, chromosome 17p deletion, and chromosome 11q deletion. 
     
     
         60 . The method of  claim 45 , wherein said pre-malignant condition is monoclonal gammopathy of undetermined significance (MGUS). 
     
     
         61 . A method of treating a subject with a cancer or pre-malignant condition that is associated with CD40-expressing cells, said method comprising screening said patient with a method according to any one of  claims 45  through  60 , and then treating said subject with said anti-CD40 therapeutic agent when said method according to any one of  claims 46  through  62  generates a result that is indicative of a positive treatment outcome with said anti-CD40 therapeutic agent. 
     
     
         62 . A method for monitoring efficacy of an anti-CD40 therapeutic agent in treatment of a subject for a cancer or pre-malignant condition that is associated with CD40-expressing neoplastic cells, said method comprising:
 a) obtaining a baseline biological sample from said subject prior to administering a dose of said anti-CD40 therapeutic agent, wherein said baseline biological sample comprises CD40-expressing neoplastic cells;   b) detecting the level of at least one biomarker in said baseline biological sample, wherein said biomarker is selected from the group consisting of a biomarker of cellular apoptosis, a biomarker of a CD40L-mediated CD40 signaling pathway, and a biomarker of cell survival;   c) administering said anti-CD40 therapeutic agent to said subject;   d) obtaining from said subject at least one subsequent biological sample;   e) detecting the level of said at least one biomarker in said at least one subsequent sample; and   f) comparing the level of said at least one biomarker in said at least one subsequent sample with the level of said at least one biomarker in said baseline biological sample, and correlating a change in the level of said at least one biomarker with treatment efficacy.   
     
     
         63 . The method of  claim 62 , wherein a single dose of said anti-CD40 therapeutic agent is administered to said subject. 
     
     
         64 . The method of  claim 62 , wherein multiple doses of said anti-CD40 therapeutic agent are administered to said subject. 
     
     
         65 . The method of  claim 62 , wherein said anti-CD40 therapeutic agent is an antagonist anti-CD40 monoclonal antibody that is capable of specifically binding to a human CD40 antigen expressed on the surface of a human B cell, said monoclonal antibody being free of significant agonist activity when bound to the CD40 antigen expressed on the surface of said B cell. 
     
     
         66 . The method of  claim 65 , wherein said antagonist anti-CD40 monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 or CHIR-12.12;   b) the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   c) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:6, the sequence shown in SEQ ID NO:7, the sequence shown in SEQ ID NO:8, both the sequence shown in SEQ ID NO:6 and SEQ ID NO:7, and both the sequence shown in SEQ ID NO:6 and SEQ ID NO:8;   d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:2, the sequence shown in SEQ ID NO:4, the sequence shown in SEQ ID NO:5, both the sequence shown in SEQ ID NO:2 and SEQ ID NO:4, and both the sequence shown in SEQ ID NO:2 and SEQ ID NO:5;   e) a monoclonal antibody having an amino acid sequence encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of the sequence shown in SEQ ID NO:1, the sequence shown in SEQ ID NO:3, and both the sequence shown in SEQ ID NO:1 and SEQ ID NO:3;   f) a monoclonal antibody that binds to an epitope capable of binding the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   g) a monoclonal antibody that binds to an epitope comprising residues 82-87 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   h) a monoclonal antibody that binds to an epitope comprising residues 82-89 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   i) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay;   j) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-i), wherein said antibody is recombinantly produced; and   k) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-j), wherein said fragment retains the capability of specifically binding to said human CD40 antigen.   
     
     
         67 . The method of  claim 66 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
         68 . The method of  claim 62 , wherein said anti-CD40 therapeutic agent is a CD40 ligand (CD40L) antagonist that inhibits CD40/CD40L interaction or CD40L-mediated CD40 signaling. 
     
     
         69 . The method of  claim 68 , wherein said CD40L antagonist is selected from the group consisting of an anti-CD40L monoclonal antibody that specifically binds to CD40L, a soluble form of CD40, a soluble form of a fusion protein comprising CD40, and a pharmaceutical agent. 
     
     
         70 . The method of  claim 62 , wherein said biomarker of apoptosis is selected from the group consisting of a cleaved Caspase protein, cleaved poly ADP-ribose polymerase (PARP), cell surface expression of phosphotidylserine (PS), genomic DNA fragmentation, and any combinations thereof. 
     
     
         71 . The method of  claim 70 , wherein said cleaved Caspase protein is selected from the group consisting of cleaved Caspase-3, cleaved Caspase-7, and cleaved Caspase-9. 
     
     
         72 . The method of  claim 70 , wherein cell surface PS is detected by annexin V staining and wherein genomic DNA fragmentation is detected by TUNEL staining. 
     
     
         73 . The method of  claim 70 , wherein an increase in the level of at least one of said biomarkers of apoptosis within said subsequent biological sample relative to said baseline biological sample is indicative of efficacy of treatment with said anti-CD40 therapeutic agent. 
     
     
         74 . The method of  claim 62 , wherein said CD40L-mediated CD40 signaling pathway is selected from the group consisting of the AKT signaling pathway, the NF-κB signaling pathway, and a mitogen-activated protein kinase (MAPK) signaling pathway. 
     
     
         75 . The method of  claim 74 , wherein said MAPK signaling pathway is selected from the group consisting of the MEK/ERK signaling pathway and the MEK/p38 signaling pathway. 
     
     
         76 . The method of  claim 74 , wherein said biomarker of said CD40L-mediated CD40 signaling pathway is selected from the group consisting of phospho-PI3K, phospho-PDK1, phospho-AKT, phospho-MEK, phospho-ERK, phospho-p38, phospho-IKKα/β, phospho-IκB protein, and activated NF-κB. 
     
     
         77 . The method of  claim 76 , wherein a reduction in the level of at least one of said biomarkers of at least one of said CD40L-mediated CD40 signaling pathways within said subsequent biological sample relative to said baseline biological sample is indicative of efficacy of treatment with said anti-CD40 therapeutic agent. 
     
     
         78 . The method of  claim 62 , wherein said biomarker of cell survival is selected from the group consisting of an anti-apoptotic protein that is a Bcl-2 family member, an IAP apoptosis inhibitor protein, and TNF receptor-associated factor-1 (TRAF-1). 
     
     
         79 . The method of  claim 78 , wherein said Bcl-2 family member is selected from the group consisting of Bcl-xl and Mcl-1. 
     
     
         80 . The method of  claim 78 , wherein said IAP apoptosis inhibitor protein is selected from the group consisting of survivin, XIAP, and cIAP1. 
     
     
         81 . The method of  claim 78 , wherein a reduction in the level of at least one of said biomarkers of cell survival in said subsequent biological sample relative to said baseline biological sample is indicative of efficacy of treatment with said anti-CD40 therapeutic agent. 
     
     
         82 . The method of  claim 62 , further comprising detecting in said subsequent biological sample and said baseline biological sample the level of at least one cytokine marker of CD40 signaling. 
     
     
         83 . The method of  claim 82 , wherein said cytokine marker is selected from the group consisting of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, IL-10, granulocyte monocyte colony-stimulating factor (GM-CSF), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1β (MIP-1β). 
     
     
         84 . The method of  claim 82 , wherein a reduction in the level of at least one of said cytokine markers in said subsequent biological sample relative to said baseline biological sample is indicative of efficacy of treatment with said anti-CD40 therapeutic agent. 
     
     
         85 . The method of  claim 62 , wherein said anti-CD40 therapeutic agent is an anti-CD40 monoclonal antibody that specifically binds to a human CD40 antigen expressed on the surface of a CD40-expressing cell, thereby modulating antibody-dependent cell-mediated cytotoxity (ADCC), and wherein said biomarker is a biomarker of apoptosis. 
     
     
         86 . The method of  claim 85 , wherein said anti-CD40 monoclonal antibody is an antagonist anti-CD40 monoclonal antibody selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 or CHIR-12.12;   b) the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   c) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:6, the sequence shown in SEQ ID NO:7, the sequence shown in SEQ ID NO:8, both the sequence shown in SEQ ID NO:6 and SEQ ID NO:7, and both the sequence shown in SEQ ID NO:6 and SEQ ID NO:8;   d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:2, the sequence shown in SEQ ID NO:4, the sequence shown in SEQ ID NO:5, both the sequence shown in SEQ ID NO:2 and SEQ ID NO:4, and both the sequence shown in SEQ ID NO:2 and SEQ ID NO:5;   e) a monoclonal antibody having an amino acid sequence encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of the sequence shown in SEQ ID NO:1, the sequence shown in SEQ ID NO:3, and both the sequence shown in SEQ ID NO:1 and SEQ ID NO:3;   f) a monoclonal antibody that binds to an epitope capable of binding the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   g) a monoclonal antibody that binds to an epitope comprising residues 82-87 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   h) a monoclonal antibody that binds to an epitope comprising residues 82-89 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   i) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay; and   j) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-i), wherein said antibody is recombinantly produced.   
     
     
         87 . The method of  claim 85 , wherein said biomarker of apoptosis is selected from the group consisting of a cleaved caspase protein, cleaved poly ADP-ribose polymerase (PARP), cell surface expression of phosphotidylserine (PS), genomic DNA fragmentation, and any combinations thereof. 
     
     
         88 . The method of  claim 87 , wherein said cleaved caspase protein is selected from the group consisting of cleaved Caspase-3, cleaved Caspase-7, and cleaved Caspase-9. 
     
     
         89 . The method of  claim 87 , wherein cell surface PS is detected by annexin V staining and wherein genomic DNA fragmentation is detected by TUNEL staining. 
     
     
         90 . The method of  claim 85 , wherein an increase in the level of at least one of said biomarkers of apoptosis within said subsequent biological sample relative to said baseline biological sample is indicative of efficacy of treatment with said anti-CD40 therapeutic agent. 
     
     
         91 . The method of  claim 62 , wherein said cancer is characterized by neoplastic B cell growth. 
     
     
         92 . The method of  claim 91 , wherein said cancer is selected from the group consisting of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, multiple myeloma, B cell lymphoma, high-grade B cell lymphoma, intermediate-grade B cell lymphoma, low-grade B cell lymphoma, B cell acute lymphoblastic leukemia, Hodgkin's disease, plasmacytoma, follicular lymphoma, follicular small cleaved lymphoma, follicular large cell lymphoma, follicular mixed small cleaved lymphoma, diffuse small cleaved cell lymphoma, diffuse small lymphocytic lymphoma, prolymphocytic leukemia, lymphoplasmacytic lymphoma, marginal zone lymphoma, mucosal associated lymphoid tissue lymphoma, monocytoid B cell lymphoma, splenic lymphoma, hairy cell leukemia, diffuse large cell lymphoma, mediastinal large B cell lymphoma, lymphomatoid granulomatosis, intravascular lymphomatosis, diffuse mixed cell lymphoma, diffuse large cell lymphoma, immunoblastic lymphoma, Burkitt's lymphoma, AIDS-related lymphoma, Waldenstrom's Macroglobulinemia, mantle cell lymphoma, and heavy chain disease. 
     
     
         93 . The method of  claim 62 , wherein said cancer is a non-B cell hematological malignancy. 
     
     
         94 . The method of  claim 93 , wherein said malignancy is selected from the group consisting of acute leukemias, myeloblastic leukemias, acute myelocytic leukemias, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, erythroleukemia, chronic myelocytic leukemia, and polycythemia vera. 
     
     
         95 . The method of  claim 62 , wherein said cancer is a solid tumor comprising neoplastic cells expressing CD40 antigen. 
     
     
         96 . The method of  claim 95 , wherein said solid tumor is selected from the group consisting of lung carcinoma, breast carcinoma, ovarian carcinoma, skin carcinoma, colon carcinoma, urinary bladder carcinoma, liver carcinoma, gastric carcinoma, prostate cancer, renal cell carcinoma, nasopharyngeal carcinoma, squamous cell carcinoma, thyroid papillary carcinoma, cervical carcinoma, and sarcomas. 
     
     
         97 . The method of  claim 62 , wherein said pre-malignant condition is monoclonal gammopathy of undetermined significance (MGUS). 
     
     
         98 . The method of  claim 62 , further comprising detecting in said subsequent biological sample and said baseline biological sample the level of expression of at least one CD40-related factor selected from the group consisting of cell-surface CD40, cell-surface CD40L, and both cell-surface CD40 and cell-surface CD40L on CD40-expressing neoplastic cells within said subsequent and baseline biological samples, wherein a reduction in the level of expression of at least one of said CD40-related factors within said subsequent biological sample relative to said baseline biological sample is indicative of efficacy of treatment with said anti-CD40 therapeutic agent. 
     
     
         99 . The method of  claim 62 , further comprising collecting from said subject a baseline sample of blood or a blood component and a subsequent sample of blood or said blood component, and detecting the level of circulating soluble CD40 or circulating soluble CD40L in said baseline sample and said subsequent sample, wherein a reduction in the level of expression of at least one of said circulating soluble CD40 or circulating soluble CD40L within said subsequent sample relative to said baseline sample is indicative of efficacy of treatment with said anti-CD40 therapeutic agent. 
     
     
         100 . A method for monitoring efficacy of an anti-CD40 therapeutic agent in treatment of a subject for a cancer or pre-malignant condition that is associated with CD40-expressing neoplastic cells, said method comprising:
 a) obtaining a baseline biological sample from said subject prior to administering a dose of said anti-CD40 therapeutic agent, wherein said baseline biological sample comprises CD40-expressing neoplastic cells;   b) detecting the level of at least one CD40-related factor in said baseline biological sample, wherein said CD40-related factor is selected from the group consisting of cell-surface CD40 on said CD40-expressing neoplastic cells and cell-surface CD40L on said CD40-expressing neoplastic cells;   c) administering said anti-CD40 therapeutic agent to said subject;   d) obtaining from said subject at least one subsequent biological sample;   e) detecting the level of said at least one CD40-related factor in said at least one subsequent sample; and   f) comparing the level of said at least one CD40-related factor in said at least one subsequent sample with the level of said at least one CD40-related factor in said baseline biological sample, wherein a reduction in the level of expression of at least one of said CD40-related factors within said subsequent biological sample relative to said baseline biological sample is indicative of efficacy of treatment with said anti-CD40 therapeutic agent.   
     
     
         101 . A method for monitoring efficacy of an anti-CD40 therapeutic agent in treatment of a subject for a cancer or pre-malignant condition that is associated with CD40-expressing neoplastic cells, said method comprising:
 a) obtaining a baseline sample of blood or a blood component from said subject prior to administering a dose of said anti-CD40 therapeutic agent;   b) detecting the level of at least one CD40-related factor in said baseline sample, wherein said CD40-related factor is selected from the group consisting of circulating level of CD40 and circulating level of CD40L;   c) administering said anti-CD40 therapeutic agent to said subject;   d) obtaining from said subject at least one subsequent sample of blood or said blood component;   e) detecting the level of said at least one CD40-related factor in said at least one subsequent sample; and   f) comparing the level of said at least one CD40-related factor in said at least one subsequent sample with the level of said at least one CD40-related factor in said baseline sample, wherein a reduction in the level of expression of at least one of said CD40-related factors within said subsequent sample relative to said baseline sample is indicative of efficacy of treatment with said anti-CD40 therapeutic agent.   
     
     
         102 . The method of  claim 100 , wherein a single dose of said anti-CD40 therapeutic agent is administered to said subject. 
     
     
         103 . The method of  claim 100 , wherein multiple doses of said anti-CD40 therapeutic agent are administered to said subject. 
     
     
         104 . The method of  claim 100 , wherein said anti-CD40 therapeutic agent is an antagonist anti-CD40 monoclonal antibody that is capable of specifically binding to a human CD40 antigen expressed on the surface of a human B cell, said monoclonal antibody being free of significant agonist activity when bound to the CD40 antigen expressed on the surface of said B cell. 
     
     
         105 . The method of  claim 104 , wherein said antagonist anti-CD40 monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 or CHIR-12.12;   b) the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   c) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:6, the sequence shown in SEQ ID NO:7, the sequence shown in SEQ ID NO:8, both the sequence shown in SEQ ID NO:6 and SEQ ID NO:7, and both the sequence shown in SEQ ID NO:6 and SEQ ID NO:8;   d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:2, the sequence shown in SEQ ID NO:4, the sequence shown in SEQ ID NO:5, both the sequence shown in SEQ ID NO:2 and SEQ ID NO:4, and both the sequence shown in SEQ ID NO:2 and SEQ ID NO:5;   e) a monoclonal antibody having an amino acid sequence encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of the sequence shown in SEQ ID NO:1, the sequence shown in SEQ ID NO:3, and both the sequence shown in SEQ ID NO:1 and SEQ ID NO:3;   f) a monoclonal antibody that binds to an epitope capable of binding the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   g) a monoclonal antibody that binds to an epitope comprising residues 82-87 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   h) a monoclonal antibody that binds to an epitope comprising residues 82-89 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   i) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay;   j) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-i), wherein said antibody is recombinantly produced; and   k) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-j), wherein said fragment retains the capability of specifically binding to said human CD40 antigen.   
     
     
         106 . The method of  claim 105 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
         107 . The method of  claim 100 , wherein said anti-CD40 therapeutic agent is a CD40 ligand (CD40L) antagonist that inhibits CD40/CD40L interaction or CD40L-mediated CD40 signaling. 
     
     
         108 . The method of  claim 107 , wherein said CD40L antagonist is selected from the group consisting of an anti-CD40L monoclonal antibody that specifically binds to CD40L, a soluble form of CD40, a soluble form of a fusion protein comprising CD40, and a pharmaceutical agent. 
     
     
         109 . The method of  claim 100 , wherein said anti-CD40 therapeutic agent is an anti-CD40 monoclonal antibody that specifically binds to a human CD40 antigen expressed on the surface of a CD40-expressing cell, thereby modulating ADCC activity. 
     
     
         110 . The method of  claim 109 , wherein said anti-CD40 monoclonal antibody is an antagonist anti-CD40 monoclonal antibody selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 or CHIR-12.12;   b) the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   c) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:6, the sequence shown in SEQ ID NO:7, the sequence shown in SEQ ID NO:8, both the sequence shown in SEQ ID NO:6 and SEQ ID NO:7, and both the sequence shown in SEQ ID NO:6 and SEQ ID NO:8;   d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:2, the sequence shown in SEQ ID NO:4, the sequence shown in SEQ ID NO:5, both the sequence shown in SEQ ID NO:2 and SEQ ID NO:4, and both the sequence shown in SEQ ID NO:2 and SEQ ID NO:5;   e) a monoclonal antibody having an amino acid sequence encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of the sequence shown in SEQ ID NO:1, the sequence shown in SEQ ID NO:3, and both the sequence shown in SEQ ID NO:1 and SEQ ID NO:3;   f) a monoclonal antibody that binds to an epitope capable of binding the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   g) a monoclonal antibody that binds to an epitope comprising residues 82-87 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   h) a monoclonal antibody that binds to an epitope comprising residues 82-89 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   i) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay; and   j) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-i), wherein said antibody is recombinantly produced.   
     
     
         111 . The method of  claim 100 , wherein said cancer is characterized by neoplastic B cell growth. 
     
     
         112 . The method of  claim 111 , wherein said cancer is selected from the group consisting of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, multiple myeloma, B cell lymphoma, high-grade B cell lymphoma, intermediate-grade B cell lymphoma, low-grade B cell lymphoma, B cell acute lymphoblastic leukemia, Hodgkin's disease, plasmacytoma, follicular lymphoma, follicular small cleaved lymphoma, follicular large cell lymphoma, follicular mixed small cleaved lymphoma, diffuse small cleaved cell lymphoma, diffuse small lymphocytic lymphoma, prolymphocytic leukemia, lymphoplasmacytic lymphoma, marginal zone lymphoma, mucosal associated lymphoid tissue lymphoma, monocytoid B cell lymphoma, splenic lymphoma, hairy cell leukemia, diffuse large cell lymphoma, mediastinal large B cell lymphoma, lymphomatoid granulomatosis, intravascular lymphomatosis, diffuse mixed cell lymphoma, diffuse large cell lymphoma, immunoblastic lymphoma, Burkitt's lymphoma, AIDS-related lymphoma, Waldenstrom's Macroglobulinemia, mantle cell lymphoma, and heavy chain disease. 
     
     
         113 . The method of  claim 100 , wherein said pre-malignant condition is monoclonal gammopathy of undetermined significance (MGUS). 
     
     
         114 . A method of treating a subject for monoclonal gammopathy of undetermined significance (MGUS) in order to block progression of said MGUS to multiple myeloma in said subject, said method comprising administering to said subject an antagonist anti-CD40 monoclonal antibody that is capable of specifically binding to a human CD40 antigen expressed on the surface of a human B cell, said monoclonal antibody being free of significant agonist activity when bound to the CD40 antigen expressed on the surface of said B cell. 
     
     
         115 . The method of  claim 114 , wherein said antagonist anti-CD40 monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 or CHIR-12.12;   b) the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   c) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:6, the sequence shown in SEQ ID NO:7, the sequence shown in SEQ ID NO:8, both the sequence shown in SEQ ID NO:6 and SEQ ID NO:7, and both the sequence shown in SEQ ID NO:6 and SEQ ID NO:8;   d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:2, the sequence shown in SEQ ID NO:4, the sequence shown in SEQ ID NO:5, both the sequence shown in SEQ ID NO:2 and SEQ ID NO:4, and both the sequence shown in SEQ ID NO:2 and SEQ ID NO:5;   e) a monoclonal antibody having an amino acid sequence encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of the sequence shown in SEQ ID NO:1, the sequence shown in SEQ ID NO:3, and both the sequence shown in SEQ ID NO:1 and SEQ ID NO:3;   f) a monoclonal antibody that binds to an epitope capable of binding the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   g) a monoclonal antibody that binds to an epitope comprising residues 82-87 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   h) a monoclonal antibody that binds to an epitope comprising residues 82-89 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   i) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay;   j) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-i), wherein said antibody is recombinantly produced; and   k) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-j), wherein said fragment retains the capability of specifically binding to said human CD40 antigen.