ADCT-602, a Novel PBD Dimer-containing Antibody-Drug Conjugate for Treating CD22-positive Hematologic Malignancies

  • Mol Cancer Ther. 2024 Apr 2;23(4):520-531. doi: 10.1158/1535-7163.MCT-23-0506.
Francesca Zammarchi  1 ,  Karin E Havenith  1 ,  Nikoleta Sachini  1 ,  Narinder Janghra  1 ,  Simon Chivers  1 ,  Esohe Idusogie  2 ,  Eugenio Gaudio  3 ,  Chiara Tarantelli  3 ,  Francois Bertelli  4 ,  Kathleen Santos  4 ,  Peter Tyrer  4 ,  Simon Corbett  5 ,  Filippo Spriano  3 ,  Gaetanina Golino  3 ,  Luciano Cascione  3 ,  Francesco Bertoni  3  6 ,  John A Hartley  5 ,  Patrick H van Berkel  1
Affiliations
  • 1. ADC Therapeutics (UK) Ltd, London, United Kingdom.
  • 2. ADC Therapeutics America, Inc, Murray Hill, United States.
  • 3. Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland.
  • 4. AstraZeneca (MedImmune/Spirogen), London, United Kingdom.
  • 5. University College London, London, United Kingdom.
  • 6. Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
PMID: 38324336 DOI: 10.1158/1535-7163.MCT-23-0506
Abstract

Relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and lymphomas have poor patient outcomes; novel therapies are needed. CD22 is an attractive target for antibody-drug conjugates (ADCs), being highly expressed in R/R B-ALL with rapid internalization kinetics. ADCT-602 is a novel CD22-targeting ADC, consisting of humanized mAb hLL2-C220, site specifically conjugated to the pyrrolobenzodiazepine dimer-based payload tesirine. In preclinical studies, ADCT-602 demonstrated potent, specific cytotoxicity in CD22-positive lymphomas and leukemias. ADCT-602 was specifically bound, internalized, and trafficked to lysosomes in CD22-positive tumor cells; after cytotoxin release, DNA interstrand crosslink formation persisted for 48 hours. In the presence of CD22-positive tumor cells, ADCT-602 caused bystander killing of CD22-negative tumor cells. A single ADCT-602 dose led to potent, dose-dependent, in vivo antitumor activity in subcutaneous and disseminated human lymphoma/leukemia models. Pharmacokinetic analyses (rat and cynomolgus monkey) showed excellent stability and tolerability of ADCT-602. Cynomolgus monkey B cells were efficiently depleted from circulation after one dose. Gene signature association analysis revealed IRAK1 as a potential marker for ADCT-602 resistance. Combining ADCT-602 + pacritinib was beneficial in ADCT-602-resistant cells. Chidamide increased CD22 expression on B-cell tumor surfaces, increasing ADCT-602 activity. These data support clinical testing of ADCT-602 in R/R B-ALL (NCT03698552) and CD22-positive hematologic cancers.

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