title: Natural Product Splicing Inhibitors: A New Class of Antibody-Drug Conjugate (ADC) Payloads.
abstract: There is a considerable ongoing work to identify new cytotoxic payloads that are appropriate for antibody-based delivery, acting via mechanisms beyond DNA damage and microtubule disruption, highlighting their importance to the field of cancer therapeutics. New modes of action will allow a more diverse set of tumor types to be targeted and will allow for possible mechanisms to evade the drug resistance that will invariably develop to existing payloads. Spliceosome inhibitors are known to be potent antiproliferative agents capable of targeting both actively dividing and quiescent cells. A series of thailanstatin-antibody conjugates were prepared in order to evaluate their potential utility in the treatment of cancer. After exploring a variety of linkers, we found that the most potent antibody-drug conjugates (ADCs) were derived from direct conjugation of the carboxylic acid-containing payload to surface lysines of the antibody (a "linker-less" conjugate). Activity of these lysine conjugates was correlated to drug-loading, a feature not typically observed for other payload classes. The thailanstatin-conjugates were potent in high target expressing cells, including multidrug-resistant lines, and inactive in nontarget expressing cells. Moreover, these ADCs were shown to promote altered splicing products in N87 cells in vitro, consistent with their putative mechanism of action. In addition, the exposure of the ADCs was sufficient to result in excellent potency in a gastric cancer xenograft model at doses as low as 1.5 mg/kg that was superior to the clinically approved ADC T-DM1. The results presented herein therefore open the door to further exploring splicing inhibition as a potential new mode-of-action for novel ADCs.
authors.forename: Sujiet
authors.initials: S
authors.lastname: Puthenveetil
authors.affiliation: Oncology-Rinat Research & Development, Pfizer , 401 North Middletown Road, Pearl River, New York 10965, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Loganzo
authors.forename: Haiyin
authors.initials: H
authors.lastname: He
authors.forename: Ken
authors.initials: K
authors.lastname: Dirico
authors.forename: Michael
authors.initials: M
authors.lastname: Green
authors.forename: Jesse
authors.initials: J
authors.lastname: Teske
authors.affiliation: Oncology-Rinat Research & Development, Pfizer , 401 North Middletown Road, Pearl River, New York 10965, United States.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Musto
authors.forename: Tracey
authors.initials: T
authors.lastname: Clark
authors.forename: Brian
authors.initials: B
authors.lastname: Rago
authors.forename: Frank
authors.initials: F
authors.lastname: Koehn
authors.affiliation: Drug Safety Research and Development, Pfizer , 401 North Middletown Road, Pearl River, New York 10977, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Veneziale
authors.affiliation: Drug Safety Research and Development, Pfizer , 401 North Middletown Road, Pearl River, New York 10977, United States.
authors.forename: Hadi
authors.initials: H
authors.lastname: Falahaptisheh
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Han
authors.forename: Frank
authors.initials: F
authors.lastname: Barletta
authors.affiliation: Oncology-Rinat Research & Development, Pfizer , 401 North Middletown Road, Pearl River, New York 10965, United States.
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.forename: Chakrapani
authors.initials: C
authors.lastname: Subramanyam
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: L Nathan
authors.initials: LN
authors.lastname: Tumey
authors.affiliation: Oncology-Rinat Research & Development, Pfizer , 401 North Middletown Road, Pearl River, New York 10965, United States.
authors.forename: Puja
authors.initials: P
authors.lastname: Sapra
authors.affiliation: Oncology-Rinat Research & Development, Pfizer , 401 North Middletown Road, Pearl River, New York 10965, United States.
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Gerber
authors.affiliation: Oncology-Rinat Research & Development, Pfizer , 401 North Middletown Road, Pearl River, New York 10965, United States.
authors.forename: Dangshe
authors.initials: D
authors.lastname: Ma
authors.forename: Edmund I
authors.initials: EI
authors.lastname: Graziani
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001688:Biological Products / Q000737:chemistry*; D002264:Carboxylic Acids / Q000737:chemistry; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003545:Cysteine / Q000737:chemistry; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008239:Lysine / Q000737:chemistry; D008301:Maleimides / Q000737:chemistry; D051379:Mice; D011714:Pyrans / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001688:Biological Products; D002264:Carboxylic Acids; D018796:Immunoconjugates; D008301:Maleimides; D011714:Pyrans; C582010:thailanstatin A; C043592:maleimide; D008239:Lysine; D003545:Cysteine