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Antibody–Drug Conjugate that Exhibits Synergistic Cytotoxicity with an Endosome–Disruptive Peptide
Knewtson, Kelsey E. Perera, Chamani Hymel, David Gao, Zhe Lee, Molly M. Peterson, Blake R.
Knewtson, Kelsey E.
Perera, Chamani
Hymel, David
Gao, Zhe
Lee, Molly M.
Peterson, Blake R.
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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.
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2019-07-31
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American Chemical Society
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Knewtson_2019.pdf
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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