title: ADCT-301, a Pyrrolobenzodiazepine (PBD) Dimer-Containing Antibody-Drug Conjugate (ADC) Targeting CD25-Expressing Hematological Malignancies.
abstract: Despite the many advances in the treatment of hematologic malignancies over the past decade, outcomes in refractory lymphomas remain poor. One potential strategy in this patient population is the specific targeting of IL2R-α (CD25), which is overexpressed on many lymphoma and leukemic cells, using antibody-drug conjugates (ADC). ADCT-301 is an ADC composed of human IgG1 HuMax-TAC against CD25, stochastically conjugated through a dipeptide cleavable linker to a pyrrolobenzodiazepine (PBD) dimer warhead with a drug-antibody ratio (DAR) of 2.3. ADCT-301 binds human CD25 with picomolar affinity. ADCT-301 has highly potent and selective cytotoxicity against a panel of CD25-expressing human lymphoma cell lines. Once internalized, the released warhead binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. A strong correlation between loss of viability and DNA cross-link formation is demonstrated. DNA damage persists, resulting in phosphorylation of histone H2AX, cell-cycle arrest in G2-M, and apoptosis. Bystander killing of CD25-negative cells by ADCT-301 is also observed. In vivo, a single dose of ADCT-301 results in dose-dependent and targeted antitumor activity against both subcutaneous and disseminated CD25-positive lymphoma models. In xenografts of Karpas 299, which expressed both CD25 and CD30, marked superiority over brentuximab vedotin (Adcetris) is observed. Dose-dependent increases in DNA cross-linking, γ-H2AX, and PBD payload staining were observed in tumors in vivo indicating a role as relevant pharmacodynamic assays. Together, these data support the clinical testing of this novel ADC in patients with CD25-expressing tumors. Mol Cancer Ther; 15(11); 2709-21. ©2016 AACR.
authors.affiliation: Cancer Research UK Drug DNA Interactions Research Group, UCL Cancer Institute, London, United Kingdom.|Spirogen Ltd, QMB Innovation Centre, London, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Flynn
authors.affiliation: ADC Therapeutics (UK) Limited, QMB Innovation Centre, London, United Kingdom.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zammarchi
authors.affiliation: Spirogen Ltd, QMB Innovation Centre, London, United Kingdom.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Tyrer
authors.affiliation: Department of Pathology, University College London, London, United Kingdom.
authors.forename: Ayse U
authors.initials: AU
authors.lastname: Akarca
authors.affiliation: Department of Pathology, University College London, London, United Kingdom.
authors.forename: Narinder
authors.initials: N
authors.lastname: Janghra
authors.affiliation: ADC Therapeutics (UK) Limited, QMB Innovation Centre, London, United Kingdom.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Britten
authors.affiliation: ADC Therapeutics (UK) Limited, QMB Innovation Centre, London, United Kingdom.
authors.forename: Carin E G
authors.initials: CE
authors.lastname: Havenith
authors.affiliation: Spirogen Ltd, QMB Innovation Centre, London, United Kingdom.
authors.forename: Jean-Noel
authors.initials: JN
authors.lastname: Levy
authors.affiliation: Spirogen Ltd, QMB Innovation Centre, London, United Kingdom.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Tiberghien
authors.affiliation: Spirogen Ltd, QMB Innovation Centre, London, United Kingdom.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Masterson
authors.affiliation: Spirogen Ltd, QMB Innovation Centre, London, United Kingdom.
authors.forename: Conor
authors.initials: C
authors.lastname: Barry
authors.affiliation: Spirogen Ltd, QMB Innovation Centre, London, United Kingdom.
authors.forename: Francois
authors.initials: F
authors.lastname: D'Hooge
authors.affiliation: Department of Pathology, University College London, London, United Kingdom.
authors.forename: Teresa
authors.initials: T
authors.lastname: Marafioti
authors.affiliation: Genmab, Utrecht, the Netherlands.|Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Paul W H I
authors.initials: PW
authors.lastname: Parren
authors.affiliation: Spirogen Ltd, QMB Innovation Centre, London, United Kingdom.
authors.forename: David G
authors.initials: DG
authors.lastname: Williams
authors.affiliation: Spirogen Ltd, QMB Innovation Centre, London, United Kingdom.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Howard
authors.affiliation: ADC Therapeutics (UK) Limited, QMB Innovation Centre, London, United Kingdom.
authors.forename: Patrick H
authors.initials: PH
authors.lastname: van Berkel
authors.affiliation: Cancer Research UK Drug DNA Interactions Research Group, UCL Cancer Institute, London, United Kingdom. john.hartley@ucl.ac.uk.|Spirogen Ltd, QMB Innovation Centre, London, United Kingdom.
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001569:Benzodiazepines / Q000737:chemistry; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006657:Histones / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D011758:Pyrroles / Q000737:chemistry; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; D018796:Immunoconjugates; D053645:Interleukin-2 Receptor alpha Subunit; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines