MT110: A novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors
We have developed a novel single-chain Ep-CAM-/CD3-bispecific single-chain antibody construct designated MT110. MT110 redirected unstimulated human peripheral T cells to induce the specific lysis of every Ep-CAM-expressing tumor cell line tested. MT110 induced a costimulation independent polyclonal...
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| Veröffentlicht in: | Molecular Immunology 2006-03, Vol.43 (8), p.1129-1143 |
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| creator | Brischwein, Klaus Schlereth, Bernd Guller, Benjamin Steiger, Carola Wolf, Andreas Lutterbuese, Ralf Offner, Sonja Locher, Mathias Urbig, Thomas Raum, Tobias Kleindienst, Petra Wimberger, Pauline Kimmig, Rainer Fichtner, Iduna Kufer, Peter Hofmeister, Robert da Silva, Antonio J. Baeuerle, Patrick A. |
| description | We have developed a novel single-chain Ep-CAM-/CD3-bispecific single-chain antibody construct designated MT110. MT110 redirected unstimulated human peripheral T cells to induce the specific lysis of every Ep-CAM-expressing tumor cell line tested. MT110 induced a costimulation independent polyclonal activation of CD4- and CD8-positive T cells as seen by de novo expression of CD69 and CD25, and secretion of interferon gamma, tumor necrosis factor alpha, and interleukins 2, 4 and 10. CD8-positive T cells made the major contribution to redirected tumor cell lysis by MT110. With a delay, CD4-positive cells could also contribute presumably as consequence of a dramatic upregulation of granzyme B expression. MT110 was highly efficacious in a NOD/SCID mouse model with subcutaneously growing SW480 human colon cancer cells. Five daily doses of 1
μg MT110 on days 0–4 completely prevented tumor outgrowth in all mice treated. The bispecific antibody construct also led to a durable eradication of established tumors in all mice treated with 1
μg doses of MT110 on days 8–12 after tumor inoculation. Finally, MT110 could eradicate patient-derived metastatic ovarian cancer tissue growing under the skin of NOD/SCID mice. MT110 appears as an attractive bispecific antibody candidate for treatment of human Ep-CAM-overexpressing carcinomas. |
| doi_str_mv | 10.1016/j.molimm.2005.07.034 |
| format | Article |
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μg MT110 on days 0–4 completely prevented tumor outgrowth in all mice treated. The bispecific antibody construct also led to a durable eradication of established tumors in all mice treated with 1
μg doses of MT110 on days 8–12 after tumor inoculation. Finally, MT110 could eradicate patient-derived metastatic ovarian cancer tissue growing under the skin of NOD/SCID mice. MT110 appears as an attractive bispecific antibody candidate for treatment of human Ep-CAM-overexpressing carcinomas.</description><identifier>ISSN: 0161-5890</identifier><identifier>EISSN: 1872-9142</identifier><identifier>EISSN: 1365-2567</identifier><identifier>DOI: 10.1016/j.molimm.2005.07.034</identifier><identifier>PMID: 16139892</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Antibodies, Bispecific - immunology ; Antibodies, Bispecific - therapeutic use ; Antibodies, Monoclonal - immunology ; Antibodies, Monoclonal - therapeutic use ; Antibody Specificity ; Antigens, CD19 - metabolism ; BiTE ; CD3 ; CD3 Complex - metabolism ; CD4-Positive T-Lymphocytes - metabolism ; CD8-Positive T-Lymphocytes - metabolism ; Cell Line, Tumor ; Cytotoxicity, Immunologic ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Ep-CAM ; Humans ; Kinetics ; Lymphocyte Activation - immunology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Neoplasms - drug therapy ; Neoplasms - pathology ; Recombinant Proteins - isolation & purification ; Single-Chain Antibodies ; Single-chain antibody ; Tumor ; Xenograft model</subject><ispartof>Molecular Immunology, 2006-03, Vol.43 (8), p.1129-1143</ispartof><rights>2005 Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c391t-56178ceb1004a6844be8069973d108594f85b8171c85e04016d2666091244a563</citedby><cites>FETCH-LOGICAL-c391t-56178ceb1004a6844be8069973d108594f85b8171c85e04016d2666091244a563</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0161589005002956$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16139892$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Brischwein, Klaus</creatorcontrib><creatorcontrib>Schlereth, Bernd</creatorcontrib><creatorcontrib>Guller, Benjamin</creatorcontrib><creatorcontrib>Steiger, Carola</creatorcontrib><creatorcontrib>Wolf, Andreas</creatorcontrib><creatorcontrib>Lutterbuese, Ralf</creatorcontrib><creatorcontrib>Offner, Sonja</creatorcontrib><creatorcontrib>Locher, Mathias</creatorcontrib><creatorcontrib>Urbig, Thomas</creatorcontrib><creatorcontrib>Raum, Tobias</creatorcontrib><creatorcontrib>Kleindienst, Petra</creatorcontrib><creatorcontrib>Wimberger, Pauline</creatorcontrib><creatorcontrib>Kimmig, Rainer</creatorcontrib><creatorcontrib>Fichtner, Iduna</creatorcontrib><creatorcontrib>Kufer, Peter</creatorcontrib><creatorcontrib>Hofmeister, Robert</creatorcontrib><creatorcontrib>da Silva, Antonio J.</creatorcontrib><creatorcontrib>Baeuerle, Patrick A.</creatorcontrib><title>MT110: A novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors</title><title>Molecular Immunology</title><addtitle>Mol Immunol</addtitle><description>We have developed a novel single-chain Ep-CAM-/CD3-bispecific single-chain antibody construct designated MT110. MT110 redirected unstimulated human peripheral T cells to induce the specific lysis of every Ep-CAM-expressing tumor cell line tested. MT110 induced a costimulation independent polyclonal activation of CD4- and CD8-positive T cells as seen by de novo expression of CD69 and CD25, and secretion of interferon gamma, tumor necrosis factor alpha, and interleukins 2, 4 and 10. CD8-positive T cells made the major contribution to redirected tumor cell lysis by MT110. With a delay, CD4-positive cells could also contribute presumably as consequence of a dramatic upregulation of granzyme B expression. MT110 was highly efficacious in a NOD/SCID mouse model with subcutaneously growing SW480 human colon cancer cells. Five daily doses of 1
μg MT110 on days 0–4 completely prevented tumor outgrowth in all mice treated. The bispecific antibody construct also led to a durable eradication of established tumors in all mice treated with 1
μg doses of MT110 on days 8–12 after tumor inoculation. Finally, MT110 could eradicate patient-derived metastatic ovarian cancer tissue growing under the skin of NOD/SCID mice. MT110 appears as an attractive bispecific antibody candidate for treatment of human Ep-CAM-overexpressing carcinomas.</description><subject>Animals</subject><subject>Antibodies, Bispecific - immunology</subject><subject>Antibodies, Bispecific - therapeutic use</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibodies, Monoclonal - therapeutic use</subject><subject>Antibody Specificity</subject><subject>Antigens, CD19 - metabolism</subject><subject>BiTE</subject><subject>CD3</subject><subject>CD3 Complex - metabolism</subject><subject>CD4-Positive T-Lymphocytes - metabolism</subject><subject>CD8-Positive T-Lymphocytes - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cytotoxicity, Immunologic</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Ep-CAM</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Lymphocyte Activation - immunology</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - pathology</subject><subject>Recombinant Proteins - isolation & purification</subject><subject>Single-Chain Antibodies</subject><subject>Single-chain antibody</subject><subject>Tumor</subject><subject>Xenograft model</subject><issn>0161-5890</issn><issn>1872-9142</issn><issn>1365-2567</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU2LFDEQhoMo7rj6D0Ry8tZtpTufHoRl8QtWvKznkE5Xb2fojzFJ7zL_3gwz4E1PocLzVlXyEPKWQc2AyQ_7el6nMM91AyBqUDW0_BnZMa2ayjDePCe7grFKaANX5FVKewCQIMVLclXuW6NNsyPLj3vG4CO9ocv6iBPtQjqgD0PwNIXlYcLKjy4s1C05dGt_pH5dUo6bz_Qp5JGO4WGkOBTe-SMtIEbXlyKXMMWUXTeFNGJP8zavMb0mLwY3JXxzOa_Jry-f72-_VXc_v36_vbmrfGtYroRkSnvsGAB3UnPeoQZpjGp7BloYPmjRaaaY1wKBl3f2jZQSDGs4d0K21-T9ue8hrr-3soedQ_I4TW7BdUtWgVTKtPq_YANN2yhxAvkZ9HFNKeJgDzHMLh4tA3sSYvf2LMSehFhQtggpsXeX_ls3Y_83dDFQgE9nAMt3PAaMNvmAi8c-RPTZ9mv494Q_GIKdAQ</recordid><startdate>20060301</startdate><enddate>20060301</enddate><creator>Brischwein, Klaus</creator><creator>Schlereth, Bernd</creator><creator>Guller, Benjamin</creator><creator>Steiger, Carola</creator><creator>Wolf, Andreas</creator><creator>Lutterbuese, Ralf</creator><creator>Offner, Sonja</creator><creator>Locher, Mathias</creator><creator>Urbig, Thomas</creator><creator>Raum, Tobias</creator><creator>Kleindienst, Petra</creator><creator>Wimberger, Pauline</creator><creator>Kimmig, Rainer</creator><creator>Fichtner, Iduna</creator><creator>Kufer, Peter</creator><creator>Hofmeister, Robert</creator><creator>da Silva, Antonio J.</creator><creator>Baeuerle, Patrick A.</creator><general>Elsevier Ltd</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>7QO</scope><scope>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20060301</creationdate><title>MT110: A novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors</title><author>Brischwein, Klaus ; Schlereth, Bernd ; Guller, Benjamin ; Steiger, Carola ; Wolf, Andreas ; Lutterbuese, Ralf ; Offner, Sonja ; Locher, Mathias ; Urbig, Thomas ; Raum, Tobias ; Kleindienst, Petra ; Wimberger, Pauline ; Kimmig, Rainer ; Fichtner, Iduna ; Kufer, Peter ; Hofmeister, Robert ; da Silva, Antonio J. ; Baeuerle, Patrick A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c391t-56178ceb1004a6844be8069973d108594f85b8171c85e04016d2666091244a563</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Animals</topic><topic>Antibodies, Bispecific - immunology</topic><topic>Antibodies, Bispecific - therapeutic use</topic><topic>Antibodies, Monoclonal - immunology</topic><topic>Antibodies, Monoclonal - therapeutic use</topic><topic>Antibody Specificity</topic><topic>Antigens, CD19 - metabolism</topic><topic>BiTE</topic><topic>CD3</topic><topic>CD3 Complex - metabolism</topic><topic>CD4-Positive T-Lymphocytes - metabolism</topic><topic>CD8-Positive T-Lymphocytes - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cytotoxicity, Immunologic</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>Ep-CAM</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Lymphocyte Activation - immunology</topic><topic>Mice</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - pathology</topic><topic>Recombinant Proteins - isolation & purification</topic><topic>Single-Chain Antibodies</topic><topic>Single-chain antibody</topic><topic>Tumor</topic><topic>Xenograft model</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Brischwein, Klaus</creatorcontrib><creatorcontrib>Schlereth, Bernd</creatorcontrib><creatorcontrib>Guller, Benjamin</creatorcontrib><creatorcontrib>Steiger, Carola</creatorcontrib><creatorcontrib>Wolf, Andreas</creatorcontrib><creatorcontrib>Lutterbuese, Ralf</creatorcontrib><creatorcontrib>Offner, Sonja</creatorcontrib><creatorcontrib>Locher, Mathias</creatorcontrib><creatorcontrib>Urbig, Thomas</creatorcontrib><creatorcontrib>Raum, Tobias</creatorcontrib><creatorcontrib>Kleindienst, Petra</creatorcontrib><creatorcontrib>Wimberger, Pauline</creatorcontrib><creatorcontrib>Kimmig, Rainer</creatorcontrib><creatorcontrib>Fichtner, Iduna</creatorcontrib><creatorcontrib>Kufer, Peter</creatorcontrib><creatorcontrib>Hofmeister, Robert</creatorcontrib><creatorcontrib>da Silva, Antonio J.</creatorcontrib><creatorcontrib>Baeuerle, Patrick A.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular Immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Brischwein, Klaus</au><au>Schlereth, Bernd</au><au>Guller, Benjamin</au><au>Steiger, Carola</au><au>Wolf, Andreas</au><au>Lutterbuese, Ralf</au><au>Offner, Sonja</au><au>Locher, Mathias</au><au>Urbig, Thomas</au><au>Raum, Tobias</au><au>Kleindienst, Petra</au><au>Wimberger, Pauline</au><au>Kimmig, Rainer</au><au>Fichtner, Iduna</au><au>Kufer, Peter</au><au>Hofmeister, Robert</au><au>da Silva, Antonio J.</au><au>Baeuerle, Patrick A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MT110: A novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors</atitle><jtitle>Molecular Immunology</jtitle><addtitle>Mol Immunol</addtitle><date>2006-03-01</date><risdate>2006</risdate><volume>43</volume><issue>8</issue><spage>1129</spage><epage>1143</epage><pages>1129-1143</pages><issn>0161-5890</issn><eissn>1872-9142</eissn><eissn>1365-2567</eissn><abstract>We have developed a novel single-chain Ep-CAM-/CD3-bispecific single-chain antibody construct designated MT110. MT110 redirected unstimulated human peripheral T cells to induce the specific lysis of every Ep-CAM-expressing tumor cell line tested. MT110 induced a costimulation independent polyclonal activation of CD4- and CD8-positive T cells as seen by de novo expression of CD69 and CD25, and secretion of interferon gamma, tumor necrosis factor alpha, and interleukins 2, 4 and 10. CD8-positive T cells made the major contribution to redirected tumor cell lysis by MT110. With a delay, CD4-positive cells could also contribute presumably as consequence of a dramatic upregulation of granzyme B expression. MT110 was highly efficacious in a NOD/SCID mouse model with subcutaneously growing SW480 human colon cancer cells. Five daily doses of 1
μg MT110 on days 0–4 completely prevented tumor outgrowth in all mice treated. The bispecific antibody construct also led to a durable eradication of established tumors in all mice treated with 1
μg doses of MT110 on days 8–12 after tumor inoculation. Finally, MT110 could eradicate patient-derived metastatic ovarian cancer tissue growing under the skin of NOD/SCID mice. MT110 appears as an attractive bispecific antibody candidate for treatment of human Ep-CAM-overexpressing carcinomas.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>16139892</pmid><doi>10.1016/j.molimm.2005.07.034</doi><tpages>15</tpages></addata></record> |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Wiley Free Content; IngentaConnect Free/Open Access Journals; PubMed Central |
| subjects | Animals Antibodies, Bispecific - immunology Antibodies, Bispecific - therapeutic use Antibodies, Monoclonal - immunology Antibodies, Monoclonal - therapeutic use Antibody Specificity Antigens, CD19 - metabolism BiTE CD3 CD3 Complex - metabolism CD4-Positive T-Lymphocytes - metabolism CD8-Positive T-Lymphocytes - metabolism Cell Line, Tumor Cytotoxicity, Immunologic Disease Models, Animal Dose-Response Relationship, Drug Ep-CAM Humans Kinetics Lymphocyte Activation - immunology Mice Mice, Inbred NOD Mice, SCID Neoplasms - drug therapy Neoplasms - pathology Recombinant Proteins - isolation & purification Single-Chain Antibodies Single-chain antibody Tumor Xenograft model |
| title | MT110: A novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors |
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