Single domain based bispecific antibody, Muc1-Bi-1, and its humanized form, Muc1-Bi-2, induce potent cancer cell killing in muc1 positive tumor cells
Muc1 is one of the most studied tumor antigens. However, antibodies or antibody-toxin conjugates against Muc1 have not shown significant efficacy for tumors with Muc1 overexpression. In this study, we employed bispecific antibody approach to target Muc1 positive tumor cells. A novel bispecific antib...
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| Veröffentlicht in: | PloS one 2018-01, Vol.13 (1), p.e0191024-e0191024 |
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| creator | Li, Yumei Zhou, Changhua Li, Jing Liu, Jiayu Lin, Limin Li, Li Cao, Donglin Li, Qing Wang, Zhong |
| description | Muc1 is one of the most studied tumor antigens. However, antibodies or antibody-toxin conjugates against Muc1 have not shown significant efficacy for tumors with Muc1 overexpression. In this study, we employed bispecific antibody approach to target Muc1 positive tumor cells. A novel bispecific antibody, Muc1-Bi-1, was constructed by linking single domain antibodies, anti-Muc1-VHH and anti-CD16-VHH. Muc1-Bi-2, the humanized form of Muc1-Bi-1, was also constructed by grafting. Both Muc1-Bi bispecific antibodies can be efficiently expressed and purified from bacteria. In vitro, the Muc1-Bi bispecific antibodies can recruit Natural Killer (NK) cells to drive potent and specific cell killing of Muc1-overexpressing tumor cells. In xenograft model, the Muc1-Bi bispecific antibodies can suppress tumor growth in the presence of human peripheral blood mononuclear cells (PBMC). These data suggested that the single domain based Muc1-Bi may provide a valid strategy for targeting tumors with Muc1 overexpression. |
| doi_str_mv | 10.1371/journal.pone.0191024 |
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However, antibodies or antibody-toxin conjugates against Muc1 have not shown significant efficacy for tumors with Muc1 overexpression. In this study, we employed bispecific antibody approach to target Muc1 positive tumor cells. A novel bispecific antibody, Muc1-Bi-1, was constructed by linking single domain antibodies, anti-Muc1-VHH and anti-CD16-VHH. Muc1-Bi-2, the humanized form of Muc1-Bi-1, was also constructed by grafting. Both Muc1-Bi bispecific antibodies can be efficiently expressed and purified from bacteria. In vitro, the Muc1-Bi bispecific antibodies can recruit Natural Killer (NK) cells to drive potent and specific cell killing of Muc1-overexpressing tumor cells. In xenograft model, the Muc1-Bi bispecific antibodies can suppress tumor growth in the presence of human peripheral blood mononuclear cells (PBMC). These data suggested that the single domain based Muc1-Bi may provide a valid strategy for targeting tumors with Muc1 overexpression.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0191024</identifier><identifier>PMID: 29357376</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amino acids ; Animals ; Antibodies ; Antibodies, Bispecific - genetics ; Antibodies, Bispecific - immunology ; Antigen (tumor-associated) ; Antigens ; Bacteria ; Biochemistry ; Biology ; Biology and life sciences ; Bispecific antibodies ; Cancer ; Cancer therapies ; CD16 antigen ; Cell Line, Tumor ; Cell Proliferation ; CHO Cells ; Chromatography ; Cricetulus ; Cytotoxicity ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Humans ; Immunoglobulins ; Immunotherapy ; Leukocytes (mononuclear) ; Lymphocytes ; Medicine and health sciences ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mucin-1 - immunology ; Nanobodies ; Natural killer cells ; Neoplasms - pathology ; Ovarian cancer ; Peripheral blood mononuclear cells ; Pharmaceutical sciences ; Proteins ; Research and Analysis Methods ; Toxins ; Tumor cells ; Tumorigenesis ; Tumors ; Xenografts</subject><ispartof>PloS one, 2018-01, Vol.13 (1), p.e0191024-e0191024</ispartof><rights>2018 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://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>2018 Li et al 2018 Li et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-5bab952e9fdc4723c2d80f8e1cd7e0e6907d4b321c6e13ab02371c83c5caea0b3</citedby><cites>FETCH-LOGICAL-c526t-5bab952e9fdc4723c2d80f8e1cd7e0e6907d4b321c6e13ab02371c83c5caea0b3</cites><orcidid>0000-0003-0864-3038</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777659/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777659/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29357376$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Yumei</creatorcontrib><creatorcontrib>Zhou, Changhua</creatorcontrib><creatorcontrib>Li, Jing</creatorcontrib><creatorcontrib>Liu, Jiayu</creatorcontrib><creatorcontrib>Lin, Limin</creatorcontrib><creatorcontrib>Li, Li</creatorcontrib><creatorcontrib>Cao, Donglin</creatorcontrib><creatorcontrib>Li, Qing</creatorcontrib><creatorcontrib>Wang, Zhong</creatorcontrib><title>Single domain based bispecific antibody, Muc1-Bi-1, and its humanized form, Muc1-Bi-2, induce potent cancer cell killing in muc1 positive tumor cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Muc1 is one of the most studied tumor antigens. However, antibodies or antibody-toxin conjugates against Muc1 have not shown significant efficacy for tumors with Muc1 overexpression. In this study, we employed bispecific antibody approach to target Muc1 positive tumor cells. A novel bispecific antibody, Muc1-Bi-1, was constructed by linking single domain antibodies, anti-Muc1-VHH and anti-CD16-VHH. Muc1-Bi-2, the humanized form of Muc1-Bi-1, was also constructed by grafting. Both Muc1-Bi bispecific antibodies can be efficiently expressed and purified from bacteria. In vitro, the Muc1-Bi bispecific antibodies can recruit Natural Killer (NK) cells to drive potent and specific cell killing of Muc1-overexpressing tumor cells. In xenograft model, the Muc1-Bi bispecific antibodies can suppress tumor growth in the presence of human peripheral blood mononuclear cells (PBMC). These data suggested that the single domain based Muc1-Bi may provide a valid strategy for targeting tumors with Muc1 overexpression.</description><subject>Amino acids</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antibodies, Bispecific - genetics</subject><subject>Antibodies, Bispecific - immunology</subject><subject>Antigen (tumor-associated)</subject><subject>Antigens</subject><subject>Bacteria</subject><subject>Biochemistry</subject><subject>Biology</subject><subject>Biology and life sciences</subject><subject>Bispecific antibodies</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>CD16 antigen</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>CHO Cells</subject><subject>Chromatography</subject><subject>Cricetulus</subject><subject>Cytotoxicity</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Flow Cytometry</subject><subject>Humans</subject><subject>Immunoglobulins</subject><subject>Immunotherapy</subject><subject>Leukocytes (mononuclear)</subject><subject>Lymphocytes</subject><subject>Medicine and health sciences</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Mucin-1 - immunology</subject><subject>Nanobodies</subject><subject>Natural killer cells</subject><subject>Neoplasms - pathology</subject><subject>Ovarian cancer</subject><subject>Peripheral blood mononuclear cells</subject><subject>Pharmaceutical sciences</subject><subject>Proteins</subject><subject>Research and Analysis Methods</subject><subject>Toxins</subject><subject>Tumor cells</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><subject>Xenografts</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptkttu1DAQhiMEoqXwBggsccPFZvEhjuMbJKg4VCriAri2fJhsvST2YieVynvwvnjZtLSIK4_G3_wz82uq6inBa8IEebWNcwp6WO9igDUmkmDa3KuOiWS0bilm92_FR9WjnLcYc9a17cPqiErGBRPtcfXriw-bAZCLo_YBGZ3BIePzDqzvvUU6TN5Ed7VCn2ZL6re-JquSdMhPGV3Mow7-Z6noYxr_InSFfHCzBbSLE4QJWR0sJGRhGNB3PwylZyHQWPiCZD_5S0DTPMYDkx9XD3o9ZHiyvCfVt_fvvp5-rM8_fzg7fXNeW07bqeZGG8kpyN7ZRlBmqetw3wGxTgCGVmLhGsMosS0Qpg2mxTjbMcutBo0NO6meH3R3Q8xqcTQrIjspuSSMFeLsQLiot2qX_KjTlYraqz-JmDZKp8nbAZRlDhqmO06Za0ooTckQYoTosOYOF63XS7fZjOBscSbp4Y7o3Z_gL9QmXiouhGi5LAIvF4EUf8yQJzX6vDdMB4jzfm6JG0ka2hb0xT_o_7drDpRNMecE_c0wBKv9lV1Xqf2VqeXKStmz24vcFF2fFfsN_xnRTQ</recordid><startdate>20180101</startdate><enddate>20180101</enddate><creator>Li, Yumei</creator><creator>Zhou, Changhua</creator><creator>Li, Jing</creator><creator>Liu, Jiayu</creator><creator>Lin, Limin</creator><creator>Li, Li</creator><creator>Cao, Donglin</creator><creator>Li, Qing</creator><creator>Wang, Zhong</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>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0003-0864-3038</orcidid></search><sort><creationdate>20180101</creationdate><title>Single domain based bispecific antibody, Muc1-Bi-1, and its humanized form, Muc1-Bi-2, induce potent cancer cell killing in muc1 positive tumor cells</title><author>Li, Yumei ; Zhou, Changhua ; Li, Jing ; Liu, Jiayu ; Lin, Limin ; Li, Li ; Cao, Donglin ; Li, Qing ; Wang, Zhong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-5bab952e9fdc4723c2d80f8e1cd7e0e6907d4b321c6e13ab02371c83c5caea0b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Amino acids</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antibodies, Bispecific - 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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>Li, Yumei</au><au>Zhou, Changhua</au><au>Li, Jing</au><au>Liu, Jiayu</au><au>Lin, Limin</au><au>Li, Li</au><au>Cao, Donglin</au><au>Li, Qing</au><au>Wang, Zhong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Single domain based bispecific antibody, Muc1-Bi-1, and its humanized form, Muc1-Bi-2, induce potent cancer cell killing in muc1 positive tumor cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2018-01-01</date><risdate>2018</risdate><volume>13</volume><issue>1</issue><spage>e0191024</spage><epage>e0191024</epage><pages>e0191024-e0191024</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Muc1 is one of the most studied tumor antigens. However, antibodies or antibody-toxin conjugates against Muc1 have not shown significant efficacy for tumors with Muc1 overexpression. In this study, we employed bispecific antibody approach to target Muc1 positive tumor cells. A novel bispecific antibody, Muc1-Bi-1, was constructed by linking single domain antibodies, anti-Muc1-VHH and anti-CD16-VHH. Muc1-Bi-2, the humanized form of Muc1-Bi-1, was also constructed by grafting. Both Muc1-Bi bispecific antibodies can be efficiently expressed and purified from bacteria. In vitro, the Muc1-Bi bispecific antibodies can recruit Natural Killer (NK) cells to drive potent and specific cell killing of Muc1-overexpressing tumor cells. In xenograft model, the Muc1-Bi bispecific antibodies can suppress tumor growth in the presence of human peripheral blood mononuclear cells (PBMC). These data suggested that the single domain based Muc1-Bi may provide a valid strategy for targeting tumors with Muc1 overexpression.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>29357376</pmid><doi>10.1371/journal.pone.0191024</doi><orcidid>https://orcid.org/0000-0003-0864-3038</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Amino acids Animals Antibodies Antibodies, Bispecific - genetics Antibodies, Bispecific - immunology Antigen (tumor-associated) Antigens Bacteria Biochemistry Biology Biology and life sciences Bispecific antibodies Cancer Cancer therapies CD16 antigen Cell Line, Tumor Cell Proliferation CHO Cells Chromatography Cricetulus Cytotoxicity Enzyme-Linked Immunosorbent Assay Flow Cytometry Humans Immunoglobulins Immunotherapy Leukocytes (mononuclear) Lymphocytes Medicine and health sciences Mice Mice, Inbred NOD Mice, SCID Mucin-1 - immunology Nanobodies Natural killer cells Neoplasms - pathology Ovarian cancer Peripheral blood mononuclear cells Pharmaceutical sciences Proteins Research and Analysis Methods Toxins Tumor cells Tumorigenesis Tumors Xenografts |
| title | Single domain based bispecific antibody, Muc1-Bi-1, and its humanized form, Muc1-Bi-2, induce potent cancer cell killing in muc1 positive tumor cells |
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