title: Design and Synthesis of Tesirine, a Clinical Antibody-Drug Conjugate Pyrrolobenzodiazepine Dimer Payload.
abstract: Pyrrolobenzodiazepine dimers are an emerging class of warhead in the field of antibody-drug conjugates (ADCs). Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. One of the reactive imines was capped with a cathepsin B-cleavable valine-alanine linker. A robust synthetic route was developed to allow the production of tesirine on clinical scale, employing a flexible, convergent strategy. Tesirine was evaluatedin vitroboth in stochastic and engineered ADC constructs and was confirmed as a potent and versatile payload. The conjugation of tesirine to anti-DLL3 rovalpituzumab has resulted in rovalpituzumab-tesirine (Rova-T), currently under evaluation for the treatment of small cell lung cancer.
authors.affiliation: QMB Innovation Centre, Spirogen , 42 New Road, E1 2AX London, U.K.
authors.forename: Arnaud C
authors.initials: AC
authors.lastname: Tiberghien
authors.affiliation: QMB Innovation Centre, Spirogen , 42 New Road, E1 2AX London, U.K.
authors.forename: Jean-Noel
authors.initials: JN
authors.lastname: Levy
authors.affiliation: QMB Innovation Centre, Spirogen , 42 New Road, E1 2AX London, U.K.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Masterson
authors.affiliation: QMB Innovation Centre, Spirogen , 42 New Road, E1 2AX London, U.K.
authors.forename: Neki V
authors.initials: NV
authors.lastname: Patel
authors.affiliation: QMB Innovation Centre, Spirogen , 42 New Road, E1 2AX London, U.K.
authors.forename: Lauren R
authors.initials: LR
authors.lastname: Adams
authors.affiliation: QMB Innovation Centre, Spirogen , 42 New Road, E1 2AX London, U.K.
authors.forename: Simon
authors.initials: S
authors.lastname: Corbett
authors.affiliation: QMB Innovation Centre, Spirogen , 42 New Road, E1 2AX London, U.K.
authors.forename: David G
authors.initials: DG
authors.lastname: Williams
authors.affiliation: QMB Innovation Centre, Spirogen , 42 New Road, E1 2AX London, U.K.
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.affiliation: QMB Innovation Centre, Spirogen , 42 New Road, E1 2AX London, U.K.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Howard
keywords: Rova-T; SG3249; Tesirine; antibody−drug conjugates; talirine