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Systematic Variation of Pyrrolobenzodiazepine (PBD)-Dimer Payload Physicochemical Properties Impacts Efficacy and Tolerability of the Corresponding Antibody-Drug Conjugates

Authors :
Peter S. Dragovich
Jun Guo
Josefa dela Cruz-Chuh
Guangmin Li
Binqing Wei
Zijin Xu
Leanna Staben
Geoff Del Rosario
Shang-Fan Yu
Thomas H. Pillow
Katherine R. Kozak
Mary Ann Go
Jinhua Chen
Rebecca K. Rowntree
John S. Wai
Carl Ng
Keyang Xu
Donglu Zhang
S. Cyrus Khojasteh
Gail Lewis Phillips
Source :
Journal of medicinal chemistry. 63(17)
Publication Year :
2020

Abstract

Cytotoxic pyrrolobenzodiazepine (PBD)-dimer molecules are frequently utilized as payloads for antibody-drug conjugates (ADCs), and many examples are currently in clinical development. In order to further explore this ADC payload class, the physicochemical properties of various PBD-dimer molecules were modified by the systematic introduction of acidic and basic moieties into their chemical structures. The impact of these changes on DNA binding, cell membrane permeability, and in vitro antiproliferation potency was, respectively, determined using a DNA alkylation assay, PAMPA assessments, and cell-based cytotoxicity measurements conducted with a variety of cancer lines. The modified PBD-dimer compounds were subsequently incorporated into CD22-targeting ADCs, and these entities were profiled in a variety of in vitro and in vivo experiments. The introduction of a strongly basic moiety into the PBD-dimer scaffold afforded a conjugate with dramatically worsened mouse tolerability properties relative to ADCs derived from related payloads, which lacked the basic group.

Details

ISSN :
15204804
Volume :
63
Issue :
17
Database :
OpenAIRE
Journal :
Journal of medicinal chemistry
Accession number :
edsair.doi.dedup.....1f05642a14801d439bd63d27f4c631bb