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Figure S1 from ADCT-602, a Novel PBD Dimer–containing Antibody–Drug Conjugate for Treating CD22-positive Hematologic Malignancies

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posted on 2024-04-02, 07:22 authored by Francesca Zammarchi, Karin E. Havenith, Nikoleta Sachini, Narinder Janghra, Simon Chivers, Esohe Idusogie, Eugenio Gaudio, Chiara Tarantelli, Francois Bertelli, Kathleen Santos, Peter Tyrer, Simon Corbett, Filippo Spriano, Gaetanina Golino, Luciano Cascione, Francesco Bertoni, John A. Hartley, Patrick H. van Berkel

Supplementary Fig. S1. Structure and characterization of ADCT-602. (A) Full-length amino acid sequence of light and heavy chains of hLL2-C220, with the mutations C219S in the light chain and C225V and C228V in the heavy chain indicated in bold. (B) Structure of ADCT-602 with the PBD dimer payload tesirine (SG3249) conjugated at C219 of hLL2-CC20 (C220 according to the EU numbering system) in the heavy chain. (C) ADCT-602 characterized by size exclusion chromatography and by (D) reduced reversed-phase chromatography. L indicates elution of the light chain, whereas H0 and H1 indicate elution of the unconjugated H-chain or H-chain conjugated to SG3249, respectively. (E) RP-HPLC analysis of the reduced tryptic digest of 2 batches of ADCT-602 (red and black traces). Ala alanine; PABC poly(A)-binding protein C-terminal; PBD pyrrolobenzodiazepine; Val valine.

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ADC Therapeutics SA

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ARTICLE 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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