Rebmab200, a humanized monoclonal antibody targeting the sodium phosphate transporter NaPi2b displays strong immune mediated cytotoxicity against cancer: a novel reagent for targeted antibody therapy of cancer
NaPi2b, a sodium-dependent phosphate transporter, is highly expressed in ovarian carcinomas and is recognized by the murine monoclonal antibody MX35. The antibody had shown excellent targeting to ovarian cancer in several early phase clinical trials but being murine the antibody's full therapeu...
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| Veröffentlicht in: | PloS one 2013-07, Vol.8 (7), p.e70332-e70332 |
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| creator | Lopes dos Santos, Mariana Yeda, Fernanda Perez Tsuruta, Lilian Rumi Horta, Bruno Brasil Pimenta, Jr, Alécio A Degaki, Theri Leica Soares, Ibere C Tuma, Maria Carolina Okamoto, Oswaldo Keith Alves, Venancio A F Old, Lloyd J Ritter, Gerd Moro, Ana Maria |
| description | NaPi2b, a sodium-dependent phosphate transporter, is highly expressed in ovarian carcinomas and is recognized by the murine monoclonal antibody MX35. The antibody had shown excellent targeting to ovarian cancer in several early phase clinical trials but being murine the antibody's full therapeutic potential could not be explored. To overcome this impediment we developed a humanized antibody version named Rebmab200, expressed in human PER.C6® cells and cloned by limiting dilution. In order to select a clone with high therapeutic potential clones were characterized using a series of physicochemical assays, flow cytometry, real-time surface plasmon resonance, glycosylation analyses, immunohistochemistry, antibody-dependent cell-mediated cytotoxicity, complement-dependent-cytotoxicity assays and quantitative PCR. Comparative analyses of Rebmab200 and MX35 monoclonal antibodies demonstrated that the two antibodies had similar specificity for NaPi2b by flow cytometry with a panel of 30 cell lines and maintained similar kinetic parameters. Robust and high producer cell clones potentially suitable for use in manufacturing were obtained. Rebmab200 antibodies were assessed by immunohistochemistry using a large panel of tissues including human carcinomas of ovarian, lung, kidney and breast origin. An assessment of its binding towards 33 normal human organs was performed as well. Rebmab200 showed selected strong reactivity with the tested tumor types but little or no reactivity with the normal tissues tested confirming its potential for targeted therapeutics strategies. The remarkable cytotoxicity shown by Rebmab200 in OVCAR-3 cells is a significant addition to the traits of stability and productivity displayed by the top clones of Rebmab200. Antibody-dependent cell-mediated toxicity functionality was confirmed in repeated assays using cancer cell lines derived from ovary, kidney and lung as targets. To explore use of this antibody in clinical trials, GMP production of Rebmab200 has been initiated. As the next step of development, Phase I clinical trials are now planned for translation of Rebmab200 into the clinic. |
| doi_str_mv | 10.1371/journal.pone.0070332 |
| format | Article |
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The antibody had shown excellent targeting to ovarian cancer in several early phase clinical trials but being murine the antibody's full therapeutic potential could not be explored. To overcome this impediment we developed a humanized antibody version named Rebmab200, expressed in human PER.C6® cells and cloned by limiting dilution. In order to select a clone with high therapeutic potential clones were characterized using a series of physicochemical assays, flow cytometry, real-time surface plasmon resonance, glycosylation analyses, immunohistochemistry, antibody-dependent cell-mediated cytotoxicity, complement-dependent-cytotoxicity assays and quantitative PCR. Comparative analyses of Rebmab200 and MX35 monoclonal antibodies demonstrated that the two antibodies had similar specificity for NaPi2b by flow cytometry with a panel of 30 cell lines and maintained similar kinetic parameters. Robust and high producer cell clones potentially suitable for use in manufacturing were obtained. Rebmab200 antibodies were assessed by immunohistochemistry using a large panel of tissues including human carcinomas of ovarian, lung, kidney and breast origin. An assessment of its binding towards 33 normal human organs was performed as well. Rebmab200 showed selected strong reactivity with the tested tumor types but little or no reactivity with the normal tissues tested confirming its potential for targeted therapeutics strategies. The remarkable cytotoxicity shown by Rebmab200 in OVCAR-3 cells is a significant addition to the traits of stability and productivity displayed by the top clones of Rebmab200. Antibody-dependent cell-mediated toxicity functionality was confirmed in repeated assays using cancer cell lines derived from ovary, kidney and lung as targets. To explore use of this antibody in clinical trials, GMP production of Rebmab200 has been initiated. As the next step of development, Phase I clinical trials are now planned for translation of Rebmab200 into the clinic.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0070332</identifier><identifier>PMID: 23936189</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>20th century ; Animals ; Antibodies, Monoclonal - immunology ; Antibodies, Monoclonal - pharmacology ; Antibodies, Monoclonal, Humanized - genetics ; Antibodies, Monoclonal, Humanized - immunology ; Antibodies, Monoclonal, Humanized - pharmacology ; Antibody Specificity - immunology ; Antibody-Dependent Cell Cytotoxicity - drug effects ; Antibody-Dependent Cell Cytotoxicity - immunology ; Antibody-dependent cell-mediated cytotoxicity ; Antigens ; Assaying ; Biology ; Biotechnology ; Cancer ; Cancer therapies ; Cell Line, Tumor ; Cell Survival - drug effects ; Cell Survival - immunology ; Chemistry ; Clinical trials ; Complement System Proteins - immunology ; Cytometry ; Cytotoxicity ; Dihydrofolate reductase ; Dilution ; Female ; Flow Cytometry ; Gene amplification ; Glycosylation ; Human performance ; Humans ; Immunoglobulins ; Immunohistochemistry ; Immunotherapy ; Kidneys ; Kinetics ; Localization ; Lung carcinoma ; Medical research ; Medicine ; Mice ; Monoclonal antibodies ; Neoplasms - drug therapy ; Neoplasms - immunology ; Neoplasms - pathology ; Organs ; Ovarian cancer ; Ovarian carcinoma ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - immunology ; Ovarian Neoplasms - pathology ; Parameter robustness ; Phosphate transporter ; Phosphates ; Protein Binding - immunology ; Proteins ; Sodium ; Sodium phosphate ; Sodium-Phosphate Cotransporter Proteins, Type IIb - antagonists & inhibitors ; Sodium-Phosphate Cotransporter Proteins, Type IIb - immunology ; Surface Plasmon Resonance ; Tissues ; Toxicity ; Tumor cell lines ; Tumors</subject><ispartof>PloS one, 2013-07, Vol.8 (7), p.e70332-e70332</ispartof><rights>2013 dos Santos et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 dos Santos et al 2013 dos Santos et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-60568e687188733d8c7f9c58c1ef6a56df0d92b5d9770156929986d72e32e8743</citedby><cites>FETCH-LOGICAL-c592t-60568e687188733d8c7f9c58c1ef6a56df0d92b5d9770156929986d72e32e8743</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729455/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729455/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23936189$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Isalan, Mark</contributor><creatorcontrib>Lopes dos Santos, Mariana</creatorcontrib><creatorcontrib>Yeda, Fernanda Perez</creatorcontrib><creatorcontrib>Tsuruta, Lilian Rumi</creatorcontrib><creatorcontrib>Horta, Bruno Brasil</creatorcontrib><creatorcontrib>Pimenta, Jr, Alécio A</creatorcontrib><creatorcontrib>Degaki, Theri Leica</creatorcontrib><creatorcontrib>Soares, Ibere C</creatorcontrib><creatorcontrib>Tuma, Maria Carolina</creatorcontrib><creatorcontrib>Okamoto, Oswaldo Keith</creatorcontrib><creatorcontrib>Alves, Venancio A F</creatorcontrib><creatorcontrib>Old, Lloyd J</creatorcontrib><creatorcontrib>Ritter, Gerd</creatorcontrib><creatorcontrib>Moro, Ana Maria</creatorcontrib><title>Rebmab200, a humanized monoclonal antibody targeting the sodium phosphate transporter NaPi2b displays strong immune mediated cytotoxicity against cancer: a novel reagent for targeted antibody therapy of cancer</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>NaPi2b, a sodium-dependent phosphate transporter, is highly expressed in ovarian carcinomas and is recognized by the murine monoclonal antibody MX35. The antibody had shown excellent targeting to ovarian cancer in several early phase clinical trials but being murine the antibody's full therapeutic potential could not be explored. To overcome this impediment we developed a humanized antibody version named Rebmab200, expressed in human PER.C6® cells and cloned by limiting dilution. In order to select a clone with high therapeutic potential clones were characterized using a series of physicochemical assays, flow cytometry, real-time surface plasmon resonance, glycosylation analyses, immunohistochemistry, antibody-dependent cell-mediated cytotoxicity, complement-dependent-cytotoxicity assays and quantitative PCR. Comparative analyses of Rebmab200 and MX35 monoclonal antibodies demonstrated that the two antibodies had similar specificity for NaPi2b by flow cytometry with a panel of 30 cell lines and maintained similar kinetic parameters. Robust and high producer cell clones potentially suitable for use in manufacturing were obtained. Rebmab200 antibodies were assessed by immunohistochemistry using a large panel of tissues including human carcinomas of ovarian, lung, kidney and breast origin. An assessment of its binding towards 33 normal human organs was performed as well. Rebmab200 showed selected strong reactivity with the tested tumor types but little or no reactivity with the normal tissues tested confirming its potential for targeted therapeutics strategies. The remarkable cytotoxicity shown by Rebmab200 in OVCAR-3 cells is a significant addition to the traits of stability and productivity displayed by the top clones of Rebmab200. Antibody-dependent cell-mediated toxicity functionality was confirmed in repeated assays using cancer cell lines derived from ovary, kidney and lung as targets. To explore use of this antibody in clinical trials, GMP production of Rebmab200 has been initiated. As the next step of development, Phase I clinical trials are now planned for translation of Rebmab200 into the clinic.</description><subject>20th century</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Antibodies, Monoclonal, Humanized - genetics</subject><subject>Antibodies, Monoclonal, Humanized - immunology</subject><subject>Antibodies, Monoclonal, Humanized - pharmacology</subject><subject>Antibody Specificity - immunology</subject><subject>Antibody-Dependent Cell Cytotoxicity - drug effects</subject><subject>Antibody-Dependent Cell Cytotoxicity - immunology</subject><subject>Antibody-dependent cell-mediated cytotoxicity</subject><subject>Antigens</subject><subject>Assaying</subject><subject>Biology</subject><subject>Biotechnology</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - immunology</subject><subject>Chemistry</subject><subject>Clinical trials</subject><subject>Complement System Proteins - immunology</subject><subject>Cytometry</subject><subject>Cytotoxicity</subject><subject>Dihydrofolate reductase</subject><subject>Dilution</subject><subject>Female</subject><subject>Flow Cytometry</subject><subject>Gene amplification</subject><subject>Glycosylation</subject><subject>Human performance</subject><subject>Humans</subject><subject>Immunoglobulins</subject><subject>Immunohistochemistry</subject><subject>Immunotherapy</subject><subject>Kidneys</subject><subject>Kinetics</subject><subject>Localization</subject><subject>Lung carcinoma</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Mice</subject><subject>Monoclonal antibodies</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - immunology</subject><subject>Neoplasms - pathology</subject><subject>Organs</subject><subject>Ovarian cancer</subject><subject>Ovarian carcinoma</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - immunology</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Parameter robustness</subject><subject>Phosphate transporter</subject><subject>Phosphates</subject><subject>Protein Binding - immunology</subject><subject>Proteins</subject><subject>Sodium</subject><subject>Sodium phosphate</subject><subject>Sodium-Phosphate Cotransporter Proteins, Type IIb - antagonists & inhibitors</subject><subject>Sodium-Phosphate Cotransporter Proteins, Type IIb - immunology</subject><subject>Surface Plasmon Resonance</subject><subject>Tissues</subject><subject>Toxicity</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptUttu1DAQjRCIlsIfILDECw_s4tiJLzwgoYpLpQoQgmfLsSdZV4kdbKci_CV_RJZNS4t4suU558yZ8SmKxyXelpSXLy_CFL3ut2PwsMWYY0rJneK4lJRsGMH07o37UfEgpQuMayoYu18cESopK4U8Ln59gWbQDcH4BdJoNw3au59g0RB8MH1YGiDts2uCnVHWsYPsfIfyDlAK1k0DGnchjTudAeWofRpDzBDRR_3ZkQZZl8ZezwmlHMPCc8MweUADWLcwLDJzDjn8cMblGelOO58yMtobiK8WOz5cQo8i6A58Rm2Iq4WF-dfUDqIeZxTalfiwuNfqPsGj9Twpvr17-_X0w-b80_uz0zfnG1NLkjcM10wAE7wUglNqheGtNLUwJbRM18y22ErS1FZyjsuaSSKlYJYToAQEr-hJ8fSgO_YhqfU3kiqrCkuOF90FcXZA2KAv1BjdoOOsgnbqz0OIndIxO9ODspJRxmRbtYCrWoDmVS0FrRpLQUi27_Z67TY1y_rMspCo-1uityve7VQXLhXlRFZ1vQg8XwVi-D5BympwyUDfaw9h2vsmuGSEyT302T_Q_09XHVAmhpQitNdmSqz2Cb1iqX1C1ZrQhfbk5iDXpKtI0t_qvOjB</recordid><startdate>20130731</startdate><enddate>20130731</enddate><creator>Lopes dos Santos, Mariana</creator><creator>Yeda, Fernanda Perez</creator><creator>Tsuruta, Lilian Rumi</creator><creator>Horta, Bruno Brasil</creator><creator>Pimenta, Jr, Alécio A</creator><creator>Degaki, Theri Leica</creator><creator>Soares, Ibere C</creator><creator>Tuma, Maria Carolina</creator><creator>Okamoto, Oswaldo Keith</creator><creator>Alves, Venancio A F</creator><creator>Old, Lloyd J</creator><creator>Ritter, Gerd</creator><creator>Moro, Ana Maria</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130731</creationdate><title>Rebmab200, a humanized monoclonal antibody targeting the sodium phosphate transporter NaPi2b displays strong immune mediated cytotoxicity against cancer: a novel reagent for targeted antibody therapy of cancer</title><author>Lopes dos Santos, Mariana ; Yeda, Fernanda Perez ; Tsuruta, Lilian Rumi ; Horta, Bruno Brasil ; Pimenta, Jr, Alécio A ; Degaki, Theri Leica ; Soares, Ibere C ; Tuma, Maria Carolina ; Okamoto, Oswaldo Keith ; Alves, Venancio A F ; Old, Lloyd J ; Ritter, Gerd ; Moro, Ana Maria</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c592t-60568e687188733d8c7f9c58c1ef6a56df0d92b5d9770156929986d72e32e8743</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>20th century</topic><topic>Animals</topic><topic>Antibodies, Monoclonal - 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drug therapy</topic><topic>Neoplasms - immunology</topic><topic>Neoplasms - pathology</topic><topic>Organs</topic><topic>Ovarian cancer</topic><topic>Ovarian carcinoma</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - immunology</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Parameter robustness</topic><topic>Phosphate transporter</topic><topic>Phosphates</topic><topic>Protein Binding - immunology</topic><topic>Proteins</topic><topic>Sodium</topic><topic>Sodium phosphate</topic><topic>Sodium-Phosphate Cotransporter Proteins, Type IIb - antagonists & inhibitors</topic><topic>Sodium-Phosphate Cotransporter Proteins, Type IIb - immunology</topic><topic>Surface Plasmon Resonance</topic><topic>Tissues</topic><topic>Toxicity</topic><topic>Tumor cell lines</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lopes dos Santos, Mariana</creatorcontrib><creatorcontrib>Yeda, Fernanda Perez</creatorcontrib><creatorcontrib>Tsuruta, Lilian Rumi</creatorcontrib><creatorcontrib>Horta, Bruno Brasil</creatorcontrib><creatorcontrib>Pimenta, Jr, Alécio A</creatorcontrib><creatorcontrib>Degaki, Theri Leica</creatorcontrib><creatorcontrib>Soares, Ibere C</creatorcontrib><creatorcontrib>Tuma, Maria Carolina</creatorcontrib><creatorcontrib>Okamoto, Oswaldo Keith</creatorcontrib><creatorcontrib>Alves, Venancio A F</creatorcontrib><creatorcontrib>Old, Lloyd J</creatorcontrib><creatorcontrib>Ritter, Gerd</creatorcontrib><creatorcontrib>Moro, Ana Maria</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lopes dos Santos, Mariana</au><au>Yeda, Fernanda Perez</au><au>Tsuruta, Lilian Rumi</au><au>Horta, Bruno Brasil</au><au>Pimenta, Jr, Alécio A</au><au>Degaki, Theri Leica</au><au>Soares, Ibere C</au><au>Tuma, Maria Carolina</au><au>Okamoto, Oswaldo Keith</au><au>Alves, Venancio A F</au><au>Old, Lloyd J</au><au>Ritter, Gerd</au><au>Moro, Ana Maria</au><au>Isalan, Mark</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rebmab200, a humanized monoclonal antibody targeting the sodium phosphate transporter NaPi2b displays strong immune mediated cytotoxicity against cancer: a novel reagent for targeted antibody therapy of cancer</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-07-31</date><risdate>2013</risdate><volume>8</volume><issue>7</issue><spage>e70332</spage><epage>e70332</epage><pages>e70332-e70332</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>NaPi2b, a sodium-dependent phosphate transporter, is highly expressed in ovarian carcinomas and is recognized by the murine monoclonal antibody MX35. The antibody had shown excellent targeting to ovarian cancer in several early phase clinical trials but being murine the antibody's full therapeutic potential could not be explored. To overcome this impediment we developed a humanized antibody version named Rebmab200, expressed in human PER.C6® cells and cloned by limiting dilution. In order to select a clone with high therapeutic potential clones were characterized using a series of physicochemical assays, flow cytometry, real-time surface plasmon resonance, glycosylation analyses, immunohistochemistry, antibody-dependent cell-mediated cytotoxicity, complement-dependent-cytotoxicity assays and quantitative PCR. Comparative analyses of Rebmab200 and MX35 monoclonal antibodies demonstrated that the two antibodies had similar specificity for NaPi2b by flow cytometry with a panel of 30 cell lines and maintained similar kinetic parameters. Robust and high producer cell clones potentially suitable for use in manufacturing were obtained. Rebmab200 antibodies were assessed by immunohistochemistry using a large panel of tissues including human carcinomas of ovarian, lung, kidney and breast origin. An assessment of its binding towards 33 normal human organs was performed as well. Rebmab200 showed selected strong reactivity with the tested tumor types but little or no reactivity with the normal tissues tested confirming its potential for targeted therapeutics strategies. The remarkable cytotoxicity shown by Rebmab200 in OVCAR-3 cells is a significant addition to the traits of stability and productivity displayed by the top clones of Rebmab200. Antibody-dependent cell-mediated toxicity functionality was confirmed in repeated assays using cancer cell lines derived from ovary, kidney and lung as targets. To explore use of this antibody in clinical trials, GMP production of Rebmab200 has been initiated. As the next step of development, Phase I clinical trials are now planned for translation of Rebmab200 into the clinic.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23936189</pmid><doi>10.1371/journal.pone.0070332</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-07, Vol.8 (7), p.e70332-e70332 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1440970871 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 20th century Animals Antibodies, Monoclonal - immunology Antibodies, Monoclonal - pharmacology Antibodies, Monoclonal, Humanized - genetics Antibodies, Monoclonal, Humanized - immunology Antibodies, Monoclonal, Humanized - pharmacology Antibody Specificity - immunology Antibody-Dependent Cell Cytotoxicity - drug effects Antibody-Dependent Cell Cytotoxicity - immunology Antibody-dependent cell-mediated cytotoxicity Antigens Assaying Biology Biotechnology Cancer Cancer therapies Cell Line, Tumor Cell Survival - drug effects Cell Survival - immunology Chemistry Clinical trials Complement System Proteins - immunology Cytometry Cytotoxicity Dihydrofolate reductase Dilution Female Flow Cytometry Gene amplification Glycosylation Human performance Humans Immunoglobulins Immunohistochemistry Immunotherapy Kidneys Kinetics Localization Lung carcinoma Medical research Medicine Mice Monoclonal antibodies Neoplasms - drug therapy Neoplasms - immunology Neoplasms - pathology Organs Ovarian cancer Ovarian carcinoma Ovarian Neoplasms - drug therapy Ovarian Neoplasms - immunology Ovarian Neoplasms - pathology Parameter robustness Phosphate transporter Phosphates Protein Binding - immunology Proteins Sodium Sodium phosphate Sodium-Phosphate Cotransporter Proteins, Type IIb - antagonists & inhibitors Sodium-Phosphate Cotransporter Proteins, Type IIb - immunology Surface Plasmon Resonance Tissues Toxicity Tumor cell lines Tumors |
| title | Rebmab200, a humanized monoclonal antibody targeting the sodium phosphate transporter NaPi2b displays strong immune mediated cytotoxicity against cancer: a novel reagent for targeted antibody therapy of cancer |
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