dc.contributor.author |
Su, Dian |
en |
dc.contributor.author |
Chen, Jinhua |
en |
dc.contributor.author |
Cosino, Ely |
en |
dc.contributor.author |
Dela Cruz-Chuh, Josefa |
en |
dc.contributor.author |
Davis, Helen |
en |
dc.contributor.author |
Del Rosario, Geoffrey |
en |
dc.contributor.author |
Figueroa, Isabel |
en |
dc.contributor.author |
Goon, Leanne |
en |
dc.contributor.author |
He, Jintang |
en |
dc.contributor.author |
Kamath, Amrita V |
en |
dc.contributor.author |
Kaur, Surinder |
en |
dc.contributor.author |
Kozak, Katherine R |
en |
dc.contributor.author |
Lau, Jeffrey |
en |
dc.contributor.author |
Lee, Donna |
en |
dc.contributor.author |
Lee, M Violet |
en |
dc.contributor.author |
Leipold, Douglas |
en |
dc.contributor.author |
Liu, Luna |
en |
dc.contributor.author |
Liu, Peter |
en |
dc.contributor.author |
Lu, Guo-Liang |
en |
dc.contributor.author |
Nelson, Chris |
en |
dc.contributor.author |
Ng, Carl |
en |
dc.contributor.author |
Pillow, Thomas H |
en |
dc.contributor.author |
Polakis, Paul |
en |
dc.contributor.author |
Polson, Andrew G |
en |
dc.contributor.author |
Rowntree, Rebecca K |
en |
dc.contributor.author |
Saad, Ola |
en |
dc.contributor.author |
Safina, Brian |
en |
dc.contributor.author |
Stagg, Nicola J |
en |
dc.contributor.author |
Tercel, Moana |
en |
dc.contributor.author |
Vandlen, Richard |
en |
dc.contributor.author |
Vollmar, Breanna S |
en |
dc.contributor.author |
Wai, John |
en |
dc.contributor.author |
Wang, Tao |
en |
dc.contributor.author |
Wei, BinQing |
en |
dc.contributor.author |
Xu, Keyang |
en |
dc.contributor.author |
Xue, Juanjuan |
en |
dc.contributor.author |
Xu, Zijin |
en |
dc.contributor.author |
Yan, Gang |
en |
dc.contributor.author |
Yao, Hui |
en |
dc.contributor.author |
Yu, Shang-Fan |
en |
dc.contributor.author |
Zhang, Donglu |
en |
dc.contributor.author |
Zhong, Fiona |
en |
dc.contributor.author |
Dragovich, Peter S |
en |
dc.date.accessioned |
2019-11-04T19:38:38Z |
en |
dc.date.issued |
2019-05 |
en |
dc.identifier.issn |
1043-1802 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/48822 |
en |
dc.description.abstract |
This work discloses the first examples of antibody-drug conjugates (ADCs) that are constructed from linker-drugs bearing dimeric seco-CBI payloads (duocarmycin analogs). Several homogeneous, CD22-targeting THIOMAB antibody-drug conjugates (TDCs) containing the dimeric seco-CBI entities are shown to be highly efficacious in the WSU-DLCL2 and BJAB mouse xenograft models. Surprisingly, the seco-CBI-containing conjugates are also observed to undergo significant biotransformation in vivo in mice, rats, and monkeys and thereby form 1:1 adducts with the Alpha-1-Microglobulin (A1M) plasma protein from these species. Variation of both the payload mAb attachment site and length of the linker-drug is shown to alter the rates of adduct formation. Subsequent experiments demonstrated that adduct formation attenuates the in vitro antiproliferation activity of the affected seco-CBI-dimer TDCs, but does not significantly impact the in vivo efficacy of the conjugates. In vitro assays employing phosphatase-treated whole blood suggest that A1M adduct formation is likely to occur if the seco-CBI-dimer TDCs are administered to humans. Importantly, protein adduct formation leads to the underestimation of total antibody (Tab) concentrations using an ELISA assay but does not affect Tab values determined via an orthogonal LC-MS/MS method. Several recommendations regarding bioanalysis of future in vivo studies involving related seco-CBI-containing ADCs are provided based on these collective findings. |
en |
dc.format.medium |
Print-Electronic |
en |
dc.language |
eng |
en |
dc.relation.ispartofseries |
Bioconjugate chemistry |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
Cell Line, Tumor |
en |
dc.subject |
Animals |
en |
dc.subject |
Haplorhini |
en |
dc.subject |
Humans |
en |
dc.subject |
Mice |
en |
dc.subject |
Rats |
en |
dc.subject |
Alpha-Globulins |
en |
dc.subject |
Antineoplastic Agents |
en |
dc.subject |
Immunoconjugates |
en |
dc.subject |
Xenograft Model Antitumor Assays |
en |
dc.subject |
Cell Proliferation |
en |
dc.subject |
Dimerization |
en |
dc.title |
Antibody-Drug Conjugates Derived from Cytotoxic seco-CBI-Dimer Payloads Are Highly Efficacious in Xenograft Models and Form Protein Adducts In Vivo. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1021/acs.bioconjchem.9b00133 |
en |
pubs.issue |
5 |
en |
pubs.begin-page |
1356 |
en |
pubs.volume |
30 |
en |
dc.rights.holder |
Copyright: The author |
en |
pubs.end-page |
1370 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Journal Article |
en |
pubs.elements-id |
769962 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Auckland Cancer Research |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1520-4812 |
en |
pubs.record-created-at-source-date |
2019-04-11 |
en |
pubs.dimensions-id |
30966735 |
en |