Development and Properties of β-Glucuronide Linkers for Monoclonal Antibody−Drug Conjugates
| Autor: | Kim M. Kissler, Nicole M. Okeley, Starr X. Bernhardt, Toni Kline, Joel S. Lenox, Ruth Moser, Ivan Stone, Jamie B. Andreyka, Scott C. Jeffrey, Minh T. Nguyen, Xinqun Zhang, Peter D. Senter |
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| Rok vydání: | 2006 |
| Předmět: |
Cell Survival
Stereochemistry medicine.drug_class Biomedical Engineering Pharmaceutical Science Bioengineering Mice SCID Pharmacology Monoclonal antibody Mice Structure-Activity Relationship Glucuronides Cell Line Tumor Neoplasms medicine Animals Cytotoxic T cell Doxorubicin Cytotoxicity Molecular Structure biology Chemistry Organic Chemistry Antibodies Monoclonal Cross-Linking Reagents biology.protein Female Antibody Glucuronide Linker Biotechnology medicine.drug Conjugate |
| Zdroj: | Bioconjugate Chemistry. 17:831-840 |
| ISSN: | 1520-4812 1043-1802 |
| Popis: | A beta-glucuronide-based linker for attaching cytotoxic agents to monoclonal antibodies (mAbs) was designed and evaluated. We employed the cytotoxic auristatin derivatives MMAE (1a) and MMAF (1b) and doxorubicin propyloxazoline (DPO, 2) to give the beta-glucuronide drug-linkers 9a, 9b, and 17, respectively. Cysteine-quenched derivatives of 9b and 17 were determined to be substrates for E. coli beta-glucuronidase, resulting in facile drug release. The beta-glucuronide MMAF drug-linker 9b was highly stable in rat plasma with an extrapolated half-life of 81 days. Each drug-linker when conjugated to mAbs c1F6 (anti-CD70) and cAC10 (anti-CD30) gave monomeric antibody-drug conjugates (ADCs) with as many as eight drugs per mAb and had high levels of immunologically specific cytotoxic activity on cancer cell lines. cAC10-9a displayed pronounced antitumor activity in a subcutaneous Karpas 299 lymphoma tumor model. A single dose treatment led to cures in all animals at the 0.5 mg/kg dose level and above, and the conjugate was well tolerated at 100 mg/kg. In mice with subcutaneous renal cell carcinoma xenografts, the MMAF conjugate c1F6-9b was tolerated at 25 mg/kg and efficacious at 0.75 mg/kg. These results demonstrate that the beta-glucuronide linker system is an effective strategy for targeting cytotoxic agents providing ADCs with high degrees of efficacy at well-tolerated doses. |
| Databáze: | OpenAIRE |
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