title: Exploring the effects of linker composition on site-specifically modified antibody-drug conjugates.
abstract: In the context of antibody-drug conjugates (ADCs), noncleavable linkers provide a means to deliver cytotoxic small molecules to cell targets while reducing systemic toxicity caused by nontargeted release of the free drug. Additionally, noncleavable linkers afford an opportunity to change the chemical properties of the small molecule to improve potency or diminish affinity for multidrug transporters, thereby improving efficacy. We employed the aldehyde tag coupled with the hydrazino-iso-Pictet-Spengler (HIPS) ligation to generate a panel of site-specifically conjugated ADCs that varied only in the noncleavable linker portion. The ADC panel comprised antibodies carrying a maytansine payload ligated through one of five different linkers. Both the linker-maytansine constructs alone and the resulting ADC panel were characterized in a variety of in vitro and in vivo assays measuring biophysical and functional properties. We observed that slight differences in linker design affected these parameters in disparate ways, and noted that efficacy could be improved by selecting for particular attributes. These studies serve as a starting point for the exploration of more potent noncleavable linker systems.
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Albers
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Albert W
authors.initials: AW
authors.lastname: Garofalo
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Penelope M
authors.initials: PM
authors.lastname: Drake
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Romas
authors.initials: R
authors.lastname: Kudirka
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: de Hart
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Barfield
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Baker
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Banas
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA. Electronic address: drabuka@redwoodbioscience.com.
authors.forename: David
authors.initials: D
authors.lastname: Rabuka
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008968:Molecular Conformation
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D018796:Immunoconjugates
keywords: Aldehyde tag; Antibody–drug conjugate; Noncleavable linker