dc.contributor.author | Knewtson, Kelsey E. | |
dc.contributor.author | Perera, Chamani | |
dc.contributor.author | Hymel, David | |
dc.contributor.author | Gao, Zhe | |
dc.contributor.author | Lee, Molly M. | |
dc.contributor.author | Peterson, Blake R. | |
dc.date.accessioned | 2020-12-21T20:20:41Z | |
dc.date.available | 2020-12-21T20:20:41Z | |
dc.date.issued | 2019-07-31 | |
dc.identifier.citation | Kelsey E. Knewtson, Chamani Perera, David Hymel, Zhe Gao, Molly M. Lee, and Blake R. Peterson
ACS Omega 2019 4 (7), 12955-12968
DOI: 10.1021/acsomega.9b01585 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/30985 | |
dc.description.abstract | Antibody–drug conjugates are an important class of cancer therapeutics. These agents generally bind a specific cell surface receptor, undergo receptor-mediated endocytosis, and enter the endosomal–lysosomal system, where the environment in these organelles facilitates the release of a membrane-permeable cytotoxin. By using a membrane-impermeable cytotoxin, we describe here a method that allows the cytotoxicity of an antibody conjugate to be triggered by co-administration with an endosome-disruptive peptide that exhibits low toxicity. This approach was validated by conjugation of an anionic derivative of the tubulin-binding cytotoxin colchinol methyl ether to lysine residues of the HER2-targeting antibody trastuzumab (Herceptin) via a disulfide. When this antibody binds HER2 on SKBR3 breast cancer cells and undergoes endocytosis, the membrane-impermeable cytotoxin is released, but it becomes trapped in endosomes, resulting in relatively low cytotoxicity (IC50 > 1 μM). However, co-administration with an essentially nontoxic (IC50 > 10 μM) cholesterol-linked endosome-disruptive peptide promotes the release of this small molecule into the cytoplasm, conferring subnanomolar cytotoxic potency (IC50 = 0.11 ± 0.07 nM). Studies of a structurally related fluorophore conjugate revealed that the endosome-disruptive peptide does not substantially enhance cleavage of the disulfide (t1/2 = 8 ± 2 h) within endosomes, suggesting that the mechanism of endosomal escape involves the efflux of some small molecules without facilitating substantial influx of reduced glutathione. | en_US |
dc.publisher | American Chemical Society | en_US |
dc.rights | Copyright © 2019 American Chemical Society | en_US |
dc.title | Antibody–Drug Conjugate that Exhibits Synergistic Cytotoxicity with an Endosome–Disruptive Peptide | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Knewtson, Kelsey E. | |
kusw.kuauthor | Perera, Chamani | |
kusw.kuauthor | Hymel, David | |
kusw.kuauthor | Gao, Zhe | |
kusw.kuauthor | Lee, Molly M. | |
kusw.kuauthor | Peterson, Blake R. | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.1021/acsomega.9b01585 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0001-8251-3579 | en_US |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | openAccess | en_US |