title: Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index.
abstract: Target-mediated toxicity constitutes a major limitation for the development of therapeutic antibodies. To redirect the activity of antibodies recognizing widely distributed targets to the site of disease, we have applied a prodrug strategy to create an epidermal growth factor receptor (EGFR)-directed Probody therapeutic-an antibody that remains masked against antigen binding until activated locally by proteases commonly active in the tumor microenvironment. In vitro, the masked Probody showed diminished antigen binding and cell-based activities, but when activated by appropriate proteases, it regained full activity compared to the parental anti-EGFR antibody cetuximab. In vivo, the Probody was largely inert in the systemic circulation of mice, but was activated within tumor tissue and showed antitumor efficacy that was similar to that of cetuximab. The Probody demonstrated markedly improved safety and increased half-life in nonhuman primates, enabling it to be dosed safely at much higher levels than cetuximab. In addition, we found that both Probody-responsive xenograft tumors and primary tumor samples from patients were capable of activating the Probody ex vivo. Probodies may therefore improve the safety profile of therapeutic antibodies without compromising efficacy of the parental antibody and may enable the wider use of empowered antibody formats such as antibody-drug conjugates and bispecifics.
authors.affiliation: CytomX Therapeutics Inc., 343 Oyster Point Boulevard, Suite 100, South San Francisco, CA 94080, USA.
authors.forename: Luc R
authors.initials: LR
authors.lastname: Desnoyers
authors.forename: Olga
authors.initials: O
authors.lastname: Vasiljeva
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Richardson
authors.forename: Annie
authors.initials: A
authors.lastname: Yang
authors.forename: Elizabeth E M
authors.initials: EE
authors.lastname: Menendez
authors.forename: Tony W
authors.initials: TW
authors.lastname: Liang
authors.forename: Chihunt
authors.initials: C
authors.lastname: Wong
authors.forename: Paul H
authors.initials: PH
authors.lastname: Bessette
authors.forename: Kathy
authors.initials: K
authors.lastname: Kamath
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moore
authors.forename: Jason G
authors.initials: JG
authors.lastname: Sagert
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Hostetter
authors.forename: Fei
authors.initials: F
authors.lastname: Han
authors.forename: Jason
authors.initials: J
authors.lastname: Gee
authors.forename: Jeanne
authors.initials: J
authors.lastname: Flandez
authors.forename: Kate
authors.initials: K
authors.lastname: Markham
authors.forename: Margaret
authors.initials: M
authors.lastname: Nguyen
authors.forename: Michael
authors.initials: M
authors.lastname: Krimm
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Wong
authors.forename: Shouchun
authors.initials: S
authors.lastname: Liu
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Daugherty
authors.forename: James W
authors.initials: JW
authors.lastname: West
authors.forename: Henry B
authors.initials: HB
authors.lastname: Lowman
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008252:Macaca fascicularis; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011355:Prodrugs / Q000627:therapeutic use* / Q000633:toxicity; D012867:Skin / Q000187:drug effects / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D011355:Prodrugs; D066246:ErbB Receptors; D000068818:Cetuximab