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

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 favorable expression profile, CD19 has rapid internalization kinetics and 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 crosslinking pyrrolobenzodiazepine (PDB) 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 the PBD warhead, resulted in formation of DNA crosslinks that persisted for 36 hours. Bystander killing of CD19 cells by ADCT-402 was also observed. In vivo, single doses of ADCT-402 resulted in highly potent, dose-dependent antitumor activity in several subcutaneous and disseminated human tumor models with marked superiority to comparator ADCs delivering tubulin inhibitors. Dose-dependent DNA crosslinks and γ-H2AX DNA damage response were measured in tumors by 24 hours after single dose administration, whereas matched peripheral blood mononuclear cells 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.

DNA damaging agent-based antibody-drug conjugates for cancer therapy

“…Two anti-CD19 ADCs (SGN-CD19B and ADCT-402) using PBD dimer payload are currently in phase I clinical trials. ADCT-402 shows an encouraging complete RR of 34.3% so far, which is comparable to phase I data from denintuzumab mafodotin and coltuximab ravtansine (payloads = anti-microtubule agents) [65]. …”

Preclinical activity of the antibody‐drug conjugate denintuzumab mafodotin (SGN‐CD19A) against pediatric acute lymphoblastic leukemia xenografts

“…The clinical activity for ADCT-402, a CD19-targeted ADC with a pyrrolobenzodiazepine payload, will help to address this question. 47 In conclusion, this study has shown that denintuzumab mafodotin is active against pediatric ALL PDXs, both as a single agent and in combination with an induction therapy platform. However, the level of activity does not distinguish itself from that of vincristine as a single agent.…”

“…Does the lack of clinical activity comparable to that of other ALL immunotherapy approaches indicate that CD19 is a poorer target for ADCs compared to other lymphoid surface antigens possibly due to less efficient CD19 internalization compared with, for example, CD22? Alternatively, is the limited activity related to the tubulin‐binding cytotoxic payload? The clinical activity for ADCT‐402, a CD19‐targeted ADC with a pyrrolobenzodiazepine payload, will help to address this question …”

Advances in targeted therapy for malignant lymphoma

“…117 Loncastuximab tesirine (ADCT-402) is a novel CD19-targeted ADC that delivers SG3199, a highly cytotoxic pyrrolobenzodiazepine dimer, and showed highly targeted cytotoxicity in vitro and antitumor activity in vivo in preclinical studies. 118 A pivotal phase 2 study (NCT03589469) is currently ongoing on relapsed or refractory DLBCL, as well as phase 1 studies (NCT02669017, NCT03684694, and NCT03685344) on relapsed or refractory B-NHLs.…”