Antibody–Drug Conjugate that Exhibits Synergistic
Cytotoxicity with an Endosome–Disruptive Peptide
Posted on 2019-07-31 - 13:22
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.
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Knewtson, Kelsey
E.; Perera, Chamani; Hymel, David; Gao, Zhe; Lee, Molly M.; Peterson, Blake R. (2019). Antibody–Drug Conjugate that Exhibits Synergistic
Cytotoxicity with an Endosome–Disruptive Peptide. ACS Publications. Collection. https://doi.org/10.1021/acsomega.9b01585
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AUTHORS (6)
KK
Kelsey
E. Knewtson
CP
Chamani Perera
DH
David Hymel
ZG
Zhe Gao
ML
Molly M. Lee
BP
Blake R. Peterson
KEYWORDS
10 μ MdisulfideAntibodycholesterol-linked endosome-disruptive peptideendosome-disruptive peptidereleaseendocytosicell surface receptor1 μ Mmembrane-impermeable cytotoxinco-administrationendosomalExhibits Synergistic CytotoxicitySKBR 3 breast cancer cellstubulin-binding cytotoxin colchinol methyl ethersubnanomolar cytotoxic potencyIC 50conjugateHER 2-targeting antibody trastuzumabmoleculecytotoxicity