2. Academic Validation
  3. Pyrrolobenzodiazepine Dimer Antibody-Drug Conjugates: Synthesis and Evaluation of Noncleavable Drug-Linkers

Pyrrolobenzodiazepine Dimer Antibody-Drug Conjugates: Synthesis and Evaluation of Noncleavable Drug-Linkers

  • J Med Chem. 2017 Dec 14;60(23):9490-9507. doi: 10.1021/acs.jmedchem.7b00736.
Stephen J Gregson 1,  Luke A Masterson 1,  Binqing Wei 2,  Thomas H Pillow 2,  Susan D Spencer 2,  Gyoung-Dong Kang 1,  Shang-Fan Yu 2,  Helga Raab 2,  Jeffrey Lau 2,  Guangmin Li 2,  Gail D Lewis Phillips 2,  Janet Gunzner-Toste 2,  Brian S Safina 2,  Rachana Ohri 2,  Martine Darwish 2,  Katherine R Kozak 2,  Josefa Dela Cruz-Chuh 2,  Andrew Polson 2,  John A Flygare 2,  Philip W Howard 1
Affiliations

Affiliations

  • 1 Spirogen , QMB Innovation Centre, 42 New Road, London E1 2AX, United Kingdom.
  • 2 Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
PMID: 29112410 DOI: 10.1021/acs.jmedchem.7b00736
Abstract

Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody-drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7), or piperazine (8) link to the PBD. In vitro IC50 values were 11-48 ng/mL in HER2 3+ SK-BR-3 and KPL-4 (7 inactive) for the anti-HER2 ADCs (HER2 0 MCF7, all inactive) and 0.10-1.73 μg/mL (7 inactive) in CD22 3+ BJAB and WSU-DLCL2 for anti-CD22 ADCs (CD22 0 Jurkat, all inactive at low doses). In vivo antitumor efficacy for the anti-HER2 ADCs in Founder 5 was observed with tumor stasis at 0.5-1 mg/kg, 1 mg/kg, and 3-6 mg/kg for 6, 8, and 7, respectively. Tumor stasis at 2 mg/kg was observed for anti-CD22 6 in WSU-DLCL2. In summary, noncleavable PBD-ADCs exhibit potent activity, particularly in HER2 models.

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