title: Regioselective and stoichiometrically controlled conjugation of photodynamic sensitizers to a HER2 targeting antibody fragment.
abstract: The rapidly increasing interest in the synthesis of antibody-drug conjugates as powerful targeted anticancer agents demonstrates the growing appreciation of the power of antibodies and antibody fragments as highly selective targeting moieties. This targeting ability is of particular interest in the area of photodynamic therapy, as the applicability of current clinical photosensitizers is limited by their relatively poor accumulation in target tissue in comparison to healthy tissue. Although synthesis of porphyrin-antibody conjugates has been previously demonstrated, existing work in this area has been hindered by the limitations of conventional antibody conjugation methods. This work describes the attachment of azide-functionalized, water-soluble porphyrins to a tratuzumab Fab fragment via a novel conjugation methodology. This method allows for the synthesis of a homogeneous product without the loss of structural stability associated with conventional methods of disulfide modification. Biological evaluation of the synthesized conjugates demonstrates excellent selectivity for a HER2 positive cell line over the control, with no dark toxicity observed in either case.
authors.affiliation: Department of Chemistry, University of Hull , Cottingham Road, Hull, HU6 7RX, United Kingdom.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bryden
authors.forename: Antoine
authors.initials: A
authors.lastname: Maruani
authors.forename: Huguette
authors.initials: H
authors.lastname: Savoie
authors.forename: Vijay
authors.initials: V
authors.lastname: Chudasama
authors.forename: Mark E B
authors.initials: ME
authors.lastname: Smith
authors.forename: Stephen
authors.initials: S
authors.lastname: Caddick
authors.forename: Ross W
authors.initials: RW
authors.lastname: Boyle
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry* / Q000494:pharmacology; D004220:Disulfides / Q000737:chemistry; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011166:Porphyrins / Q000737:chemistry*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D004220:Disulfides; D007140:Immunoglobulin Fab Fragments; D017319:Photosensitizing Agents; D011166:Porphyrins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab