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ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies

Francesca Zammarchi, Simon Corbett, Lauren Adams, Peter C. Tyrer, Konstantinos Kiakos, Narinder Janghra, Teresa Marafioti, Charles E. Britten, Carin E.G. Havenith, Simon Chivers, Francois D'Hooge, David G. Williams, Arnaud Tiberghien, Philip W. Howard, John A Hartley and Patrick H. van Berkel

Key points

  • ADCT-402 is a novel CD19-targeted ADC delivering SG3199, a highly cytotoxic DNA minor groove interstrand cross-linking PBD dimer warhead

  • ADCT-402 has potent and selective anti-tumor activity against CD19-expressing haematological malignancies warranting clinical development

Abstract

Human CD19 antigen is a 95-kDa type I membrane glycoprotein in the immunoglobulin superfamily whose expression is limited to the various stages of B-cell development and differentiation and is maintained in the majority of B-cell malignancies, including leukemias and non-Hodgkin lymphomas of B-cell origin. Coupled with its differential and favourable expression profile, CD19 has rapid internalization kinetics and it is not shed into the circulation, making it an ideal target for the development of antibody-drug conjugates (ADCs) to treat B-cell malignancies. ADCT-402 (loncastuximab tesirine) is a novel CD19-targeted ADC delivering SG3199, a highly cytotoxic DNA minor groove interstrand cross-linking pyrrolobenzodiazepine (PBD) dimer warhead. It showed potent and highly targeted in vitro cytotoxicity in CD19-expressing human cell lines. ADCT-402 was specifically bound, internalized and trafficked to lysosomes in CD19-expressing cells and following release of warhead, resulted in formation of DNA cross-links which persisted for 36 h. Bystander killing of CD19-negative cells by ADCT-402 was also observed. In vivo, single doses of ADCT-402 resulted in highly potent, dose-dependent anti-tumor activity in several subcutaneous and disseminated human tumor models with marked superiority to comparator ADCs delivering tubulin inhibitors. Dose-dependent DNA cross-links and γ-H2AX DNA damage response were measured in tumors by 24 h after single dose administration, while matched PBMCs showed no evidence of DNA damage. Pharmacokinetic analysis in rat and cynomolgus monkey showed excellent stability and tolerability of ADCT-402 in vivo. Together, these impressive data were used to support the clinical testing of this novel ADC in patients with CD19-expressing B-cell malignancies.

  • Submitted October 27, 2017.
  • Accepted December 21, 2017.