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

• Published in: Journal of medicinal chemistry Vol. 60; no. 23; pp. 9490 - 9507
• Main Authors: Gregson, Stephen J., Masterson, Luke A., Wei, Binqing, Pillow, Thomas H., Spencer, Susan D., Kang, Gyoung-Dong, Yu, Shang-Fan, Raab, Helga, Lau, Jeffrey, Li, Guangmin, Lewis Phillips, Gail D., Gunzner-Toste, Janet, Safina, Brian S., Ohri, Rachana, Darwish, Martine, Kozak, Katherine R., dela Cruz-Chuh, Josefa, Polson, Andrew, Flygare, John A., Howard, Philip W.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.12.2017; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Benzodiazepines - chemistry; Benzodiazepines - pharmacology; Benzodiazepines - therapeutic use; Breast Neoplasms - drug therapy; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Medicinal; Dimerization; Female; Humans; Immunoconjugates - chemistry; Immunoconjugates - pharmacology; Immunoconjugates - therapeutic use; Life Sciences & Biomedicine; Mice; Models, Molecular; Neoplasms - drug therapy; Pharmacology & Pharmacy; Pyrroles - chemistry; Pyrroles - pharmacology; Pyrroles - therapeutic use; Receptor, ErbB-2 - antagonists & inhibitors; Science & Technology; Sialic Acid Binding Ig-like Lectin 2 - antagonists & inhibitors; ADC; DETERMINES; DESIGN; EFFICACY; RECURRENT; ROVALPITUZUMAB TESIRINE; CYTOTOXIC DRUG; IDENTIFICATION; CANCER; SITE-SPECIFIC CONJUGATION
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00736

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.