Ofatumumab demonstrates activity against rituximab-sensitive and -resistant cell lines, lymphoma xenografts and primary tumour cells from patients with B-cell lymphoma
Summary Ofatumumab is a new monoclonal antibody (mAb) targeting a novel membrane‐proximal epitope on CD20. To better define ofatumumab’s activity, we conducted pre‐clinical studies in rituximab‐sensitive cell lines (RSCL), rituximab‐resistant cell lines (RRCL), ofatumumab‐exposed cell lines (OECLs),...
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| Veröffentlicht in: | British journal of haematology 2012-02, Vol.156 (4), p.490-498 |
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| creator | Barth, Matthew J. Hernandez-Ilizaliturri, Francisco J. Mavis, Cory Tsai, Ping-Chiao Gibbs, John F. Deeb, George Czuczman, Myron S. |
| description | Summary
Ofatumumab is a new monoclonal antibody (mAb) targeting a novel membrane‐proximal epitope on CD20. To better define ofatumumab’s activity, we conducted pre‐clinical studies in rituximab‐sensitive cell lines (RSCL), rituximab‐resistant cell lines (RRCL), ofatumumab‐exposed cell lines (OECLs), primary lymphoma cells, and a lymphoma xenograft model. RRCL and OECL were generated by repeated exposure of sensitive cells to escalating doses of rituximab or ofatumumab ± human serum. Antibody‐dependent cellular cytotoxicity (ADCC) and complement‐mediated cytotoxicity (CMC) assays were performed to assess cellular sensitivity to rituximab or ofatumumab. Ofatumumab elicited a higher rate of CMC in RSCL, RRCL and primary tumour cells. The chronic exposure of lymphoma cells to ofatumumab resulted in rituximab resistance but less ofatumumab resistance. In an in vivo severe combined immunodeficiency mouse model of human lymphoma, ofatumumab prolonged median survival compared to rituximab. While rituximab CMC diminished with CD20 down‐regulation in RRCL passages, ofatumumab activity in vitro diminished to a lesser degree. Our data suggest that ofatumumab is more potent than rituximab in rituximab‐sensitive or rituximab‐resistant models and has the potential to decrease the development of biological resistance in patients with repeated exposure to anti‐CD20 mAbs. |
| doi_str_mv | 10.1111/j.1365-2141.2011.08966.x |
| format | Article |
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Ofatumumab is a new monoclonal antibody (mAb) targeting a novel membrane‐proximal epitope on CD20. To better define ofatumumab’s activity, we conducted pre‐clinical studies in rituximab‐sensitive cell lines (RSCL), rituximab‐resistant cell lines (RRCL), ofatumumab‐exposed cell lines (OECLs), primary lymphoma cells, and a lymphoma xenograft model. RRCL and OECL were generated by repeated exposure of sensitive cells to escalating doses of rituximab or ofatumumab ± human serum. Antibody‐dependent cellular cytotoxicity (ADCC) and complement‐mediated cytotoxicity (CMC) assays were performed to assess cellular sensitivity to rituximab or ofatumumab. Ofatumumab elicited a higher rate of CMC in RSCL, RRCL and primary tumour cells. The chronic exposure of lymphoma cells to ofatumumab resulted in rituximab resistance but less ofatumumab resistance. In an in vivo severe combined immunodeficiency mouse model of human lymphoma, ofatumumab prolonged median survival compared to rituximab. While rituximab CMC diminished with CD20 down‐regulation in RRCL passages, ofatumumab activity in vitro diminished to a lesser degree. Our data suggest that ofatumumab is more potent than rituximab in rituximab‐sensitive or rituximab‐resistant models and has the potential to decrease the development of biological resistance in patients with repeated exposure to anti‐CD20 mAbs.</description><identifier>ISSN: 0007-1048</identifier><identifier>EISSN: 1365-2141</identifier><identifier>DOI: 10.1111/j.1365-2141.2011.08966.x</identifier><identifier>PMID: 22150234</identifier><identifier>CODEN: BJHEAL</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Animal models ; Animals ; Antibodies, Monoclonal - administration & dosage ; Antibodies, Monoclonal - pharmacology ; Antibodies, Monoclonal, Murine-Derived - administration & dosage ; Antibodies, Monoclonal, Murine-Derived - pharmacology ; Antibody-dependent cell-mediated cytotoxicity ; Antigens, CD20 - genetics ; Antigens, CD20 - metabolism ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - pharmacology ; Biological and medical sciences ; CD20 ; CD20 antigen ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Chronic exposure ; Complement ; Complement System Proteins - metabolism ; Cytotoxicity ; Cytotoxicity, Immunologic - drug effects ; Data processing ; Disease Models, Animal ; double prime B-cell lymphoma ; Drug Resistance, Neoplasm - genetics ; Epitopes ; Gene Expression Regulation, Neoplastic - drug effects ; Hematologic and hematopoietic diseases ; Humans ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Lymphoma, B-Cell - drug therapy ; Lymphoma, B-Cell - genetics ; Lymphoma, B-Cell - metabolism ; Medical sciences ; Mice ; Mice, SCID ; Monoclonal antibodies ; non-Hodgkin lymphoma ; ofatumumab ; Rituximab ; Severe combined immunodeficiency ; Tumor cell lines ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>British journal of haematology, 2012-02, Vol.156 (4), p.490-498</ispartof><rights>2011 Blackwell Publishing Ltd</rights><rights>2015 INIST-CNRS</rights><rights>2011 Blackwell Publishing Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4696-51d007ffc499c60620efab6bef0b18e86727666a4f9e93a75687d7c6c7debbc33</citedby><cites>FETCH-LOGICAL-c4696-51d007ffc499c60620efab6bef0b18e86727666a4f9e93a75687d7c6c7debbc33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1365-2141.2011.08966.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1365-2141.2011.08966.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,1427,27901,27902,45550,45551,46384,46808</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25461793$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22150234$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Barth, Matthew J.</creatorcontrib><creatorcontrib>Hernandez-Ilizaliturri, Francisco J.</creatorcontrib><creatorcontrib>Mavis, Cory</creatorcontrib><creatorcontrib>Tsai, Ping-Chiao</creatorcontrib><creatorcontrib>Gibbs, John F.</creatorcontrib><creatorcontrib>Deeb, George</creatorcontrib><creatorcontrib>Czuczman, Myron S.</creatorcontrib><title>Ofatumumab demonstrates activity against rituximab-sensitive and -resistant cell lines, lymphoma xenografts and primary tumour cells from patients with B-cell lymphoma</title><title>British journal of haematology</title><addtitle>Br J Haematol</addtitle><description>Summary
Ofatumumab is a new monoclonal antibody (mAb) targeting a novel membrane‐proximal epitope on CD20. To better define ofatumumab’s activity, we conducted pre‐clinical studies in rituximab‐sensitive cell lines (RSCL), rituximab‐resistant cell lines (RRCL), ofatumumab‐exposed cell lines (OECLs), primary lymphoma cells, and a lymphoma xenograft model. RRCL and OECL were generated by repeated exposure of sensitive cells to escalating doses of rituximab or ofatumumab ± human serum. Antibody‐dependent cellular cytotoxicity (ADCC) and complement‐mediated cytotoxicity (CMC) assays were performed to assess cellular sensitivity to rituximab or ofatumumab. Ofatumumab elicited a higher rate of CMC in RSCL, RRCL and primary tumour cells. The chronic exposure of lymphoma cells to ofatumumab resulted in rituximab resistance but less ofatumumab resistance. In an in vivo severe combined immunodeficiency mouse model of human lymphoma, ofatumumab prolonged median survival compared to rituximab. While rituximab CMC diminished with CD20 down‐regulation in RRCL passages, ofatumumab activity in vitro diminished to a lesser degree. Our data suggest that ofatumumab is more potent than rituximab in rituximab‐sensitive or rituximab‐resistant models and has the potential to decrease the development of biological resistance in patients with repeated exposure to anti‐CD20 mAbs.</description><subject>Animal models</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - administration & dosage</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Antibodies, Monoclonal, Murine-Derived - administration & dosage</subject><subject>Antibodies, Monoclonal, Murine-Derived - pharmacology</subject><subject>Antibody-dependent cell-mediated cytotoxicity</subject><subject>Antigens, CD20 - genetics</subject><subject>Antigens, CD20 - metabolism</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>CD20</subject><subject>CD20 antigen</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Chronic exposure</subject><subject>Complement</subject><subject>Complement System Proteins - metabolism</subject><subject>Cytotoxicity</subject><subject>Cytotoxicity, Immunologic - drug effects</subject><subject>Data processing</subject><subject>Disease Models, Animal</subject><subject>double prime B-cell lymphoma</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Epitopes</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Lymphoma, B-Cell - drug therapy</subject><subject>Lymphoma, B-Cell - genetics</subject><subject>Lymphoma, B-Cell - metabolism</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, SCID</subject><subject>Monoclonal antibodies</subject><subject>non-Hodgkin lymphoma</subject><subject>ofatumumab</subject><subject>Rituximab</subject><subject>Severe combined immunodeficiency</subject><subject>Tumor cell lines</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><issn>0007-1048</issn><issn>1365-2141</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1u1DAUhS0EotPCKyBvkFiQYOfHThYs6IjOAIVuQJXYWI5z3XrIz2A7NPNEvCbOJAxbvLHl-51z79VBCFMS03De7GKasjxKaEbjhFAak6JkLB4fodWp8BitCCE8oiQrztC5cztCaEpy-hSdJQnNSZJmK_T7Rks_tEMrK1xD23fOW-nBYam8-WX8Acs7acIvtsYPowlc5KBzJlQBy67GkQVnnJedxwqaBjemA_caN4d2f9-3Eo_Q9XdWau-O-N4GD3vAoWk_2KPEYW37Fu-lN9AF7MH4e3wZzW6LzTP0RMvGwfPlvkDfrt5_XW-j65vNh_W760hlrGRRTuuws9YqK0vFCEsIaFmxCjSpaAEF4wlnjMlMl1Cmkues4DVXTPEaqkql6QV6Nfvubf9zAOdFa9w0ieygH5ygJCFFzvKkCGgxo8r2zlnQYtktQGKKSezElIaY0hBTTOIYkxiD9MXSZahaqE_Cv7kE4OUCSKdko63slHH_uDxjlJfTuG9n7sE0cPjvAcTlx-30Cvpo1ocEYTzppf0hGE95Lm6_bMTt-vu2_LxZi0_pH_DFwgA</recordid><startdate>201202</startdate><enddate>201202</enddate><creator>Barth, Matthew J.</creator><creator>Hernandez-Ilizaliturri, Francisco J.</creator><creator>Mavis, Cory</creator><creator>Tsai, Ping-Chiao</creator><creator>Gibbs, John F.</creator><creator>Deeb, George</creator><creator>Czuczman, Myron S.</creator><general>Blackwell Publishing Ltd</general><general>Blackwell</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>H94</scope></search><sort><creationdate>201202</creationdate><title>Ofatumumab demonstrates activity against rituximab-sensitive and -resistant cell lines, lymphoma xenografts and primary tumour cells from patients with B-cell lymphoma</title><author>Barth, Matthew J. ; Hernandez-Ilizaliturri, Francisco J. ; Mavis, Cory ; Tsai, Ping-Chiao ; Gibbs, John F. ; Deeb, George ; Czuczman, Myron S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4696-51d007ffc499c60620efab6bef0b18e86727666a4f9e93a75687d7c6c7debbc33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Antibodies, Monoclonal - administration & dosage</topic><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Antibodies, Monoclonal, Murine-Derived - administration & dosage</topic><topic>Antibodies, Monoclonal, Murine-Derived - pharmacology</topic><topic>Antibody-dependent cell-mediated cytotoxicity</topic><topic>Antigens, CD20 - genetics</topic><topic>Antigens, CD20 - metabolism</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>CD20</topic><topic>CD20 antigen</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Chronic exposure</topic><topic>Complement</topic><topic>Complement System Proteins - metabolism</topic><topic>Cytotoxicity</topic><topic>Cytotoxicity, Immunologic - drug effects</topic><topic>Data processing</topic><topic>Disease Models, Animal</topic><topic>double prime B-cell lymphoma</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Epitopes</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Lymphoma, B-Cell - drug therapy</topic><topic>Lymphoma, B-Cell - genetics</topic><topic>Lymphoma, B-Cell - metabolism</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, SCID</topic><topic>Monoclonal antibodies</topic><topic>non-Hodgkin lymphoma</topic><topic>ofatumumab</topic><topic>Rituximab</topic><topic>Severe combined immunodeficiency</topic><topic>Tumor cell lines</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Barth, Matthew J.</creatorcontrib><creatorcontrib>Hernandez-Ilizaliturri, Francisco J.</creatorcontrib><creatorcontrib>Mavis, Cory</creatorcontrib><creatorcontrib>Tsai, Ping-Chiao</creatorcontrib><creatorcontrib>Gibbs, John F.</creatorcontrib><creatorcontrib>Deeb, George</creatorcontrib><creatorcontrib>Czuczman, Myron S.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>British journal of haematology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Barth, Matthew J.</au><au>Hernandez-Ilizaliturri, Francisco J.</au><au>Mavis, Cory</au><au>Tsai, Ping-Chiao</au><au>Gibbs, John F.</au><au>Deeb, George</au><au>Czuczman, Myron S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ofatumumab demonstrates activity against rituximab-sensitive and -resistant cell lines, lymphoma xenografts and primary tumour cells from patients with B-cell lymphoma</atitle><jtitle>British journal of haematology</jtitle><addtitle>Br J Haematol</addtitle><date>2012-02</date><risdate>2012</risdate><volume>156</volume><issue>4</issue><spage>490</spage><epage>498</epage><pages>490-498</pages><issn>0007-1048</issn><eissn>1365-2141</eissn><coden>BJHEAL</coden><abstract>Summary
Ofatumumab is a new monoclonal antibody (mAb) targeting a novel membrane‐proximal epitope on CD20. To better define ofatumumab’s activity, we conducted pre‐clinical studies in rituximab‐sensitive cell lines (RSCL), rituximab‐resistant cell lines (RRCL), ofatumumab‐exposed cell lines (OECLs), primary lymphoma cells, and a lymphoma xenograft model. RRCL and OECL were generated by repeated exposure of sensitive cells to escalating doses of rituximab or ofatumumab ± human serum. Antibody‐dependent cellular cytotoxicity (ADCC) and complement‐mediated cytotoxicity (CMC) assays were performed to assess cellular sensitivity to rituximab or ofatumumab. Ofatumumab elicited a higher rate of CMC in RSCL, RRCL and primary tumour cells. The chronic exposure of lymphoma cells to ofatumumab resulted in rituximab resistance but less ofatumumab resistance. In an in vivo severe combined immunodeficiency mouse model of human lymphoma, ofatumumab prolonged median survival compared to rituximab. While rituximab CMC diminished with CD20 down‐regulation in RRCL passages, ofatumumab activity in vitro diminished to a lesser degree. Our data suggest that ofatumumab is more potent than rituximab in rituximab‐sensitive or rituximab‐resistant models and has the potential to decrease the development of biological resistance in patients with repeated exposure to anti‐CD20 mAbs.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>22150234</pmid><doi>10.1111/j.1365-2141.2011.08966.x</doi><tpages>9</tpages></addata></record> |
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| subjects | Animal models Animals Antibodies, Monoclonal - administration & dosage Antibodies, Monoclonal - pharmacology Antibodies, Monoclonal, Murine-Derived - administration & dosage Antibodies, Monoclonal, Murine-Derived - pharmacology Antibody-dependent cell-mediated cytotoxicity Antigens, CD20 - genetics Antigens, CD20 - metabolism Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacology Biological and medical sciences CD20 CD20 antigen Cell Line, Tumor Cell Proliferation - drug effects Cell Survival - drug effects Chronic exposure Complement Complement System Proteins - metabolism Cytotoxicity Cytotoxicity, Immunologic - drug effects Data processing Disease Models, Animal double prime B-cell lymphoma Drug Resistance, Neoplasm - genetics Epitopes Gene Expression Regulation, Neoplastic - drug effects Hematologic and hematopoietic diseases Humans Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Lymphoma, B-Cell - drug therapy Lymphoma, B-Cell - genetics Lymphoma, B-Cell - metabolism Medical sciences Mice Mice, SCID Monoclonal antibodies non-Hodgkin lymphoma ofatumumab Rituximab Severe combined immunodeficiency Tumor cell lines Xenograft Model Antitumor Assays Xenografts |
| title | Ofatumumab demonstrates activity against rituximab-sensitive and -resistant cell lines, lymphoma xenografts and primary tumour cells from patients with B-cell lymphoma |
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