Comparison of Pyrrolobenzodiazepine Dimer Bis-imine versus Mono-imine: DNA Interstrand Cross-linking, Cytotoxicity, Antibody-Drug Conjugate Efficacy and Toxicity.

Abstract

Antibody-drug conjugates (ADC) delivering pyrrolobenzodiazepine (PBD) DNA cross-linkers are currently being evaluated in clinical trials, with encouraging results in Hodgkin and non-Hodgkin lymphomas. The first example of an ADC delivering a PBD DNA cross-linker (loncastuximab tesirine) has been recently approved by the FDA for the treatment of relapsed and refractory diffuse large B-cell lymphoma. There has also been considerable interest in mono-alkylating PBD analogs. We conducted a head-to-head comparison of a conventional PBD bis-imine and a novel PBD mono-imine. Key Mitsunobu chemistry allowed clean and convenient access to the mono-imine class. Extensive DNA-binding studies revealed that the mono-imine mediated a type of DNA interaction that is described as "pseudo cross-linking," as well as alkylation. The PBD mono-imine ADC demonstrated robust antitumor activity in mice bearing human tumor xenografts at doses 3-fold higher than those that were efficacious for the PBD bis-imine ADC. A single-dose toxicology study in rats demonstrated that the MTD of the PBD mono-alkylator ADC was approximately 3-fold higher than that of the ADC bearing a bis-imine payload, suggesting a comparable therapeutic index for this molecule. However, although both ADCs caused myelosuppression, renal toxicity was observed only for the bis-imine, indicating possible differences in toxicologic profiles that could influence tolerability and therapeutic index. These data show that mono-amine PBDs have physicochemical and pharmacotoxicologic properties distinct from their cross-linking analogs and support their potential utility as a novel class of ADC payload.

• Authors: Arnaud C Tiberghien, Balakumar Vijayakrishnan, Arman Esfandiari, Mahammad Ahmed, Raul Pardo, John Bingham, Lauren Adams, Kathleen Santos, Gyoung-Dong Kang, Kathryn M Pugh, Shameen Afif-Rider, Kapil Vashisht, Kemal Haque, Ravinder Tammali, Edward Rosfjord, Adriana Savoca, John A Hartley, Philip W Howard
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 22 Issue 2 Pg. 254-263 (02 01 2023) ISSN: 1538-8514 [Electronic] United States
• PMID: 36722141 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• pyrrolo(2,1-c)(1,4)benzodiazepine
• DNA
• Imines
• Immunoconjugates

Topics

• Humans
• Animals
• Mice
• Rats
• Lymphoma, Non-Hodgkin
• Alkylation
• DNA
• Imines
• Immunoconjugates (pharmacology)