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

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.

Generation of DAR1 Antibody-Drug Conjugates for Ultrapotent Payloads Using Tailored GlycoConnect Technology

“…Unfortunately, ADCs based on a PBD dimer payload, and for that matter also based on calicheamicin, are administered to patients substantially below 1 mg/kg, which likely will also be the case for other ultrapotent payloads like PNU-159,682, amanitin, eribulin, and potentially others, which compromises tumor target saturation, efficient biodistribution, and solid tumor penetration. To increase tolerability of the PBD dimer ADCs, efforts have been directed to reduce the potency of the PBD dimer by making changes to the C-ring or by utilizing mono-alkylating variants . In this paper, we have shown how the GlycoConnect technology can be applied in a generic fashion for the generation of ADCs with single drug loading (DAR1 ADCs) based on tailored bis-BCN-functionalized linker-drug constructs.…”

“…To increase tolerability of the PBD dimer ADCs, efforts have been directed to reduce the potency of the PBD dimer by making changes to the C-ring 18 or by utilizing mono-alkylating variants. 19 In this paper, we have shown how the GlycoConnect technology can be applied in a generic fashion for the generation of ADCs with single drug loading (DAR1 ADCs) based on tailored bis-BCN-functionalized linker-drug constructs. A variety of highly potent payloads were amenable to efficient crosslinking based on metal-free click chemistry of the bis-BCN-modified linker-drug with enzymatically remodeled trastuzumab harboring two azidosugars (one on each heavy chain).…”

Development of DHES0815A; a novel HER2-directed antibody-drug conjugate comprised of a reduced potency mono-alkylating agent linked to a domain I binding HER2 antibody

“…The parent PBD dimer SG2057 and PBD mono-alkylator derivatives were assessed for in vitro alkylation of double-stranded DNA oligonucleotides as previously described (42).…”

Cathepsin B as a target in cancer therapy and imaging

“…In April 2021, Zynlonta was developed with the Val-Ala-PAB linker to treat patients with relapsed or refractory large B-cell lymphoma. 98 Tivdak, the first and only approved ADC for treating patients with recurrent or metastatic cervical cancer with disease progression, also utilized the CTB cleavable peptide Mc-Val-Cit-PAB as the spacer.…”