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
  • 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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