A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody-Drug Conjugates (ADCs)
Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine...
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| Veröffentlicht in: | Molecular cancer therapeutics 2018-03, Vol.17 (3), p.650-660 |
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| creator | Miller, Michael L Shizuka, Manami Wilhelm, Alan Salomon, Paulin Reid, Emily E Lanieri, Leanne Sikka, Surina Maloney, Erin K Harvey, Lauren Qiu, Qifeng Archer, Katie E Bai, Chen Vitharana, Dilrukshi Harris, Luke Singh, Rajeeva Ponte, Jose F Yoder, Nicholas C Kovtun, Yelena Lai, Katharine C Ab, Olga Pinkas, Jan Keating, Thomas A Chari, Ravi V J |
| description | Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here, we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar
potency, but improved bystander killing and
efficacy, compared with those of the cross-linker. Thus, the improved
tolerability and antitumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment.
. |
| doi_str_mv | 10.1158/1535-7163.MCT-17-0940 |
| format | Article |
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potency, but improved bystander killing and
efficacy, compared with those of the cross-linker. Thus, the improved
tolerability and antitumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment.
.</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.MCT-17-0940</identifier><identifier>PMID: 29440292</identifier><language>eng</language><publisher>United States: American Association for Cancer Research Inc</publisher><subject>Alkylation ; Animal models ; Animals ; Anticancer properties ; Antineoplastic Agents, Alkylating - chemistry ; Antineoplastic Agents, Alkylating - metabolism ; Antineoplastic Agents, Alkylating - pharmacology ; Antitumor activity ; Biocompatibility ; Cancer ; Cancer therapies ; Cell Line, Tumor ; Cell Survival - drug effects ; Conjugates ; Cross-Linking Reagents - chemistry ; Crosslinking ; Cytotoxic agents ; Cytotoxicity ; Deoxyribonucleic acid ; DNA ; DNA - genetics ; DNA - metabolism ; Drug delivery systems ; Drug Design ; Humans ; Immunoconjugates - chemistry ; Immunoconjugates - metabolism ; Immunoconjugates - pharmacology ; Intercalating Agents - chemistry ; Intercalating Agents - metabolism ; Intercalating Agents - pharmacology ; Mice ; Neoplasms - drug therapy ; Neoplasms - pathology ; Therapeutic Index, Drug ; Toxicity ; Tumor Burden - drug effects ; Xenograft Model Antitumor Assays</subject><ispartof>Molecular cancer therapeutics, 2018-03, Vol.17 (3), p.650-660</ispartof><rights>2018 American Association for Cancer Research.</rights><rights>Copyright American Association for Cancer Research Inc Mar 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c384t-15dafd8aa847d72f4b8bb4204986fb99a6292f50216d685e2845a25dfc7cca823</citedby><cites>FETCH-LOGICAL-c384t-15dafd8aa847d72f4b8bb4204986fb99a6292f50216d685e2845a25dfc7cca823</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29440292$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Miller, Michael L</creatorcontrib><creatorcontrib>Shizuka, Manami</creatorcontrib><creatorcontrib>Wilhelm, Alan</creatorcontrib><creatorcontrib>Salomon, Paulin</creatorcontrib><creatorcontrib>Reid, Emily E</creatorcontrib><creatorcontrib>Lanieri, Leanne</creatorcontrib><creatorcontrib>Sikka, Surina</creatorcontrib><creatorcontrib>Maloney, Erin K</creatorcontrib><creatorcontrib>Harvey, Lauren</creatorcontrib><creatorcontrib>Qiu, Qifeng</creatorcontrib><creatorcontrib>Archer, Katie E</creatorcontrib><creatorcontrib>Bai, Chen</creatorcontrib><creatorcontrib>Vitharana, Dilrukshi</creatorcontrib><creatorcontrib>Harris, Luke</creatorcontrib><creatorcontrib>Singh, Rajeeva</creatorcontrib><creatorcontrib>Ponte, Jose F</creatorcontrib><creatorcontrib>Yoder, Nicholas C</creatorcontrib><creatorcontrib>Kovtun, Yelena</creatorcontrib><creatorcontrib>Lai, Katharine C</creatorcontrib><creatorcontrib>Ab, Olga</creatorcontrib><creatorcontrib>Pinkas, Jan</creatorcontrib><creatorcontrib>Keating, Thomas A</creatorcontrib><creatorcontrib>Chari, Ravi V J</creatorcontrib><title>A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody-Drug Conjugates (ADCs)</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here, we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar
potency, but improved bystander killing and
efficacy, compared with those of the cross-linker. Thus, the improved
tolerability and antitumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment.
.</description><subject>Alkylation</subject><subject>Animal models</subject><subject>Animals</subject><subject>Anticancer properties</subject><subject>Antineoplastic Agents, Alkylating - chemistry</subject><subject>Antineoplastic Agents, Alkylating - metabolism</subject><subject>Antineoplastic Agents, Alkylating - pharmacology</subject><subject>Antitumor activity</subject><subject>Biocompatibility</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Conjugates</subject><subject>Cross-Linking Reagents - chemistry</subject><subject>Crosslinking</subject><subject>Cytotoxic agents</subject><subject>Cytotoxicity</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA - genetics</subject><subject>DNA - metabolism</subject><subject>Drug delivery systems</subject><subject>Drug Design</subject><subject>Humans</subject><subject>Immunoconjugates - chemistry</subject><subject>Immunoconjugates - metabolism</subject><subject>Immunoconjugates - pharmacology</subject><subject>Intercalating Agents - chemistry</subject><subject>Intercalating Agents - metabolism</subject><subject>Intercalating Agents - pharmacology</subject><subject>Mice</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - pathology</subject><subject>Therapeutic Index, Drug</subject><subject>Toxicity</subject><subject>Tumor Burden - drug effects</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUFP3DAQha2qFVDgJ7Sy1AscDLZjJ84xykJZaaE9LGfLiZ3F28Texk7VPfWv47DAoacZjb55mnkPgC8EXxHCxTXhGUcFybOr-3qNSIFwyfAHcJLmAglO2MeX_sAcg88hbDEmoqTkCBzTkjFMS3oC_lVw8VChpYtmVG20bgN_qn3vlYYLE-zGGQ2jhze9HaxT0cB69CGglXW_ZnY57Eb_xwQYnwxcPyWNnZmibeHSafMX-g5WLtrG6z1ajNMG1t5tp03SCfCiWtTh8gx86lQfzPlrPQWPtzfr-g6tfnxf1tUKtZlgERGuVaeFUoIVuqAda0TTMIpZKfKuKUuVp286jinJdS64oYJxRbnu2qJtlaDZKbg46KZ7f08mRDnY0Jq-V874KUiKMaXJHsYS-u0_dOun0aXrEkVIJoosKxLFD1Q7GzKaTu5GO6hxLwmWc0Jydl_O7suUkCSFnBNKe19f1admMPp96y2S7BkhRotu</recordid><startdate>201803</startdate><enddate>201803</enddate><creator>Miller, Michael L</creator><creator>Shizuka, Manami</creator><creator>Wilhelm, Alan</creator><creator>Salomon, Paulin</creator><creator>Reid, Emily E</creator><creator>Lanieri, Leanne</creator><creator>Sikka, Surina</creator><creator>Maloney, Erin K</creator><creator>Harvey, Lauren</creator><creator>Qiu, Qifeng</creator><creator>Archer, Katie E</creator><creator>Bai, Chen</creator><creator>Vitharana, Dilrukshi</creator><creator>Harris, Luke</creator><creator>Singh, Rajeeva</creator><creator>Ponte, Jose F</creator><creator>Yoder, Nicholas C</creator><creator>Kovtun, Yelena</creator><creator>Lai, Katharine C</creator><creator>Ab, Olga</creator><creator>Pinkas, Jan</creator><creator>Keating, Thomas A</creator><creator>Chari, Ravi V J</creator><general>American Association for Cancer Research Inc</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>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201803</creationdate><title>A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody-Drug Conjugates (ADCs)</title><author>Miller, Michael L ; Shizuka, Manami ; Wilhelm, Alan ; Salomon, Paulin ; Reid, Emily E ; Lanieri, Leanne ; Sikka, Surina ; Maloney, Erin K ; Harvey, Lauren ; Qiu, Qifeng ; Archer, Katie E ; Bai, Chen ; Vitharana, Dilrukshi ; Harris, Luke ; Singh, Rajeeva ; Ponte, Jose F ; Yoder, Nicholas C ; Kovtun, Yelena ; Lai, Katharine C ; Ab, Olga ; Pinkas, Jan ; Keating, Thomas A ; Chari, Ravi V J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c384t-15dafd8aa847d72f4b8bb4204986fb99a6292f50216d685e2845a25dfc7cca823</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Alkylation</topic><topic>Animal models</topic><topic>Animals</topic><topic>Anticancer properties</topic><topic>Antineoplastic Agents, Alkylating - chemistry</topic><topic>Antineoplastic Agents, Alkylating - metabolism</topic><topic>Antineoplastic Agents, Alkylating - pharmacology</topic><topic>Antitumor activity</topic><topic>Biocompatibility</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Conjugates</topic><topic>Cross-Linking Reagents - chemistry</topic><topic>Crosslinking</topic><topic>Cytotoxic agents</topic><topic>Cytotoxicity</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA - genetics</topic><topic>DNA - metabolism</topic><topic>Drug delivery systems</topic><topic>Drug Design</topic><topic>Humans</topic><topic>Immunoconjugates - chemistry</topic><topic>Immunoconjugates - metabolism</topic><topic>Immunoconjugates - pharmacology</topic><topic>Intercalating Agents - chemistry</topic><topic>Intercalating Agents - metabolism</topic><topic>Intercalating Agents - pharmacology</topic><topic>Mice</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - pathology</topic><topic>Therapeutic Index, Drug</topic><topic>Toxicity</topic><topic>Tumor Burden - drug effects</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Miller, Michael L</creatorcontrib><creatorcontrib>Shizuka, Manami</creatorcontrib><creatorcontrib>Wilhelm, Alan</creatorcontrib><creatorcontrib>Salomon, Paulin</creatorcontrib><creatorcontrib>Reid, Emily E</creatorcontrib><creatorcontrib>Lanieri, Leanne</creatorcontrib><creatorcontrib>Sikka, Surina</creatorcontrib><creatorcontrib>Maloney, Erin K</creatorcontrib><creatorcontrib>Harvey, Lauren</creatorcontrib><creatorcontrib>Qiu, Qifeng</creatorcontrib><creatorcontrib>Archer, Katie E</creatorcontrib><creatorcontrib>Bai, Chen</creatorcontrib><creatorcontrib>Vitharana, Dilrukshi</creatorcontrib><creatorcontrib>Harris, Luke</creatorcontrib><creatorcontrib>Singh, Rajeeva</creatorcontrib><creatorcontrib>Ponte, Jose F</creatorcontrib><creatorcontrib>Yoder, Nicholas C</creatorcontrib><creatorcontrib>Kovtun, Yelena</creatorcontrib><creatorcontrib>Lai, Katharine C</creatorcontrib><creatorcontrib>Ab, Olga</creatorcontrib><creatorcontrib>Pinkas, Jan</creatorcontrib><creatorcontrib>Keating, Thomas A</creatorcontrib><creatorcontrib>Chari, Ravi V J</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>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Miller, Michael L</au><au>Shizuka, Manami</au><au>Wilhelm, Alan</au><au>Salomon, Paulin</au><au>Reid, Emily E</au><au>Lanieri, Leanne</au><au>Sikka, Surina</au><au>Maloney, Erin K</au><au>Harvey, Lauren</au><au>Qiu, Qifeng</au><au>Archer, Katie E</au><au>Bai, Chen</au><au>Vitharana, Dilrukshi</au><au>Harris, Luke</au><au>Singh, Rajeeva</au><au>Ponte, Jose F</au><au>Yoder, Nicholas C</au><au>Kovtun, Yelena</au><au>Lai, Katharine C</au><au>Ab, Olga</au><au>Pinkas, Jan</au><au>Keating, Thomas A</au><au>Chari, Ravi V J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody-Drug Conjugates (ADCs)</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2018-03</date><risdate>2018</risdate><volume>17</volume><issue>3</issue><spage>650</spage><epage>660</epage><pages>650-660</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here, we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar
potency, but improved bystander killing and
efficacy, compared with those of the cross-linker. Thus, the improved
tolerability and antitumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment.
.</abstract><cop>United States</cop><pub>American Association for Cancer Research Inc</pub><pmid>29440292</pmid><doi>10.1158/1535-7163.MCT-17-0940</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Molecular cancer therapeutics, 2018-03, Vol.17 (3), p.650-660 |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Alkylation Animal models Animals Anticancer properties Antineoplastic Agents, Alkylating - chemistry Antineoplastic Agents, Alkylating - metabolism Antineoplastic Agents, Alkylating - pharmacology Antitumor activity Biocompatibility Cancer Cancer therapies Cell Line, Tumor Cell Survival - drug effects Conjugates Cross-Linking Reagents - chemistry Crosslinking Cytotoxic agents Cytotoxicity Deoxyribonucleic acid DNA DNA - genetics DNA - metabolism Drug delivery systems Drug Design Humans Immunoconjugates - chemistry Immunoconjugates - metabolism Immunoconjugates - pharmacology Intercalating Agents - chemistry Intercalating Agents - metabolism Intercalating Agents - pharmacology Mice Neoplasms - drug therapy Neoplasms - pathology Therapeutic Index, Drug Toxicity Tumor Burden - drug effects Xenograft Model Antitumor Assays |
| title | A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody-Drug Conjugates (ADCs) |
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