title: Modulation of drug-linker design to enhance in vivo potency of homogeneous antibody-drug conjugates.
abstract: Antibody-drug conjugates (ADCs) are a promising class of anticancer agents which have undergone substantial development over the past decade and are now achieving clinical success. The development of novel site-specific conjugation technologies enables the systematic study of architectural features within the antibody conjugated drug linker that may affect overall therapeutic indices. Here we describe the results of a systematic study investigating the impact of drug-linker design on the in vivo properties of a series of homogeneous ADCs with a conserved site of conjugation, a monodisperse drug loading, a lysosomal release functionality and monomethyl auristatin E as a cytotoxic payload. The ADCs, which differed only in the relative position of certain drug-linker elements within the reagent, were first evaluated in vitro using anti-proliferation assays and in vivo using mouse pharmacokinetics (PK). Regardless of the position of a discrete polymer unit, the ADCs showed comparable in vitro potencies, but the in vivo PK properties varied widely. The best performing drug-linker design was further used to prepare ADCs with different drug loadings of 4, 6 and 8 drugs per antibody and compared to Adcetris® in a Karpas-299 mouse xenograft model. The most efficacious ADC showed complete tumor regression and 10/10 tumor free survivors at a single 0.5mg/kg dose. This study revealed drug-linker design as a critical parameter in ADC development, with the potential to enhance ADC in vivo potency for producing more efficacious ADCs.
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom. Electronic address: martin.pabst@abzena.com.
authors.forename: Martin
authors.initials: M
authors.lastname: Pabst
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: McDowell
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Manin
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kyle
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Camper
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Elena
authors.initials: E
authors.lastname: De Juan
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Vimal
authors.initials: V
authors.lastname: Parekh
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Felicity
authors.initials: F
authors.lastname: Rudge
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Hiteshri
authors.initials: H
authors.lastname: Makwana
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Terrence
authors.initials: T
authors.lastname: Kantner
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Hemal
authors.initials: H
authors.lastname: Parekh
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Michelet
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: XiaoBo
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Gina
authors.initials: G
authors.lastname: Popa
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Tucker
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Farzad
authors.initials: F
authors.lastname: Khayrzad
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Derek
authors.initials: D
authors.lastname: Pollard
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kozakowska
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Resende
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Jenkins
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Fabio
authors.initials: F
authors.lastname: Simoes
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Dave
authors.initials: D
authors.lastname: Morris
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Williams
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Badescu
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Baker
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bird
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom. Electronic address: mark.frigerio@abzena.com.
authors.forename: Mark
authors.initials: M
authors.lastname: Frigerio
authors.affiliation: Abzena plc., Babraham Research Campus, CB22 3AT Cambridge, United Kingdom.
authors.forename: Antony
authors.initials: A
authors.lastname: Godwin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000737:chemistry / Q000627:therapeutic use; D017730:Ki-1 Antigen / Q000276:immunology; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018796:Immunoconjugates; D007074:Immunoglobulin G; D017730:Ki-1 Antigen; D009842:Oligopeptides; D011092:Polyethylene Glycols; C495575:monomethyl auristatin E
keywords: Antibody-drug conjugates; Drug design; In vivo efficacy; Lysosomal release; Mouse xenograft; Pharmacokinetics