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Pyrrolobenzodiazepine dimers, which are DNA cross\u2010linkers, are a class of payloads used in antibody\u2013drug conjugates (ADCs). SG3710 was designed to rebridge two adjacent cysteines, such as those that form the canonical interchain disulfide bond between the light and heavy chain in Fab fragments. The rebridging generated homogenous Fab conjugates, with a drug\u2010to\u2010Fab ratio of one, as demonstrated by the preparation of rebridged Fabs derived from the anti\u2010HER2 trastuzumab antibody and from a negative control antibody both prepared using recombinant expression and papain digestion. The resulting anti\u2010HER2 trastuzumab Fab\u2010rebridged conjugate retained antigen binding, was stable in rat serum, and demonstrated potent and antigen\u2010dependent cancer cell\u2010killing ability. Disulfide rebridging with SG3710 is a generic approach to prepare Fab\u2013pyrrolobenzodiazepine dimer conjugates, which does not require the Fabs to be engineered for conjugation. Thus, SG3710 offers a flexible and straightforward platform for the controlled assembly of pyrrolobenzodiazepine dimer conjugates from any Fab for oncology applications.<\/jats:p>","DOI":"10.1002\/cmdc.201900077","type":"journal-article","created":{"date-parts":[[2019,4,13]],"date-time":"2019-04-13T10:39:00Z","timestamp":1555151940000},"page":"1185-1195","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Characterization of Disulfide Bond Rebridged Fab\u2013Drug Conjugates Prepared Using a Dual Maleimide Pyrrolobenzodiazepine Cytotoxic Payload"],"prefix":"10.1002","volume":"14","author":[{"given":"Ben T.","family":"Ruddle","sequence":"first","affiliation":[{"name":"AstraZeneca Antibody Discovery and Protein Engineering  One MedImmune Way Gaithersburg MD 20878 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Fleming","sequence":"additional","affiliation":[{"name":"AstraZeneca Antibody Discovery and Protein Engineering  One MedImmune Way Gaithersburg MD 20878 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herren","family":"Wu","sequence":"additional","affiliation":[{"name":"AstraZeneca Antibody Discovery and Protein Engineering  One MedImmune Way Gaithersburg MD 20878 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changshou","family":"Gao","sequence":"additional","affiliation":[{"name":"AstraZeneca Antibody Discovery and Protein Engineering  One MedImmune Way Gaithersburg MD 20878 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9379-1646","authenticated-orcid":false,"given":"Nazzareno","family":"Dimasi","sequence":"additional","affiliation":[{"name":"AstraZeneca Antibody Discovery and Protein Engineering  One MedImmune Way Gaithersburg MD 20878 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,5,3]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2016.268"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2289"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1586\/14737140.2016.1131614"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm500766w"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1517\/14712598.8.4.527"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-061516-121357"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3253"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201510610"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201510610"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/mp500781a"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddtec.2018.10.005"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddtec.2018.09.006"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-2093"},{"key":"e_1_2_7_13_1","unstructured":"European Medicines Agency Adcetris CHMP Assessment Report 2012 EMA\/702390\/2012:https:\/\/www.ema.europa.eu\/en\/documents\/assessment-report\/adcetris-epar-public-assessment-report\u2002en.pdf(accessed May 2 2019)."},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-08-0295"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00520"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2016.06.025"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.6b00995"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/antib7020016"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.2415"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/bc500148x"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.5b00116"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.5b00432"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7645"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1039\/C5CC03557K"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1039\/C5SC02666K"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1039\/C6SC03655D"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.bioconjchem.5b00682"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2019.1578611"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.6b00062"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.8b02876"},{"key":"e_1_2_7_31_1","first-page":"732","volume":"16","author":"Kahl B. 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