A Case Study Comparing Heterogeneous Lysine- and Site-Specific Cysteine-Conjugated Maytansinoid Antibody-Drug Conjugates (ADCs) Illustrates the Benefits of Lysine Conjugation
| Autor: | Daniel Tavares, Nicholas C. Yoder, Shan Jin, Wayne C. Widdison, Lintao Wang, Hans K. Erickson, Kathleen R. Whiteman, Molly A. McShea, Chen Bai, Erin K. Maloney, Olga Ab, Thomas A. Keating, John M. Lambert, Sharon D. Wilhelm, Alan Wilhelm |
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| Rok vydání: | 2019 |
| Předmět: |
Antibody-drug conjugate
Immunoconjugates medicine.drug_class Cell Survival Lysine Pharmaceutical Science Uterine Cervical Neoplasms 02 engineering and technology Mice SCID Conjugated system Monoclonal antibody Maytansinoid 030226 pharmacology & pharmacy 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Drug Discovery medicine Animals Humans Maytansine Cysteine Chemistry Antibodies Monoclonal 021001 nanoscience & nanotechnology Small molecule Xenograft Model Antitumor Assays Tumor Burden body regions Treatment Outcome Biochemistry Injections Intravenous Molecular Medicine Female 0210 nano-technology Linker Conjugate HeLa Cells |
| Zdroj: | Molecular pharmaceutics. 16(9) |
| ISSN: | 1543-8392 |
| Popis: | Antibody-drug conjugates are an emerging class of cancer therapeutics constructed from monoclonal antibodies conjugated with small molecule effectors. First-generation molecules of this class often employed heterogeneous conjugation chemistry, but many site-specifically conjugated ADCs have been described recently. Here, we undertake a systematic comparison of ADCs made with the same antibody and the same macrocyclic maytansinoid effector but conjugated either heterogeneously at lysine residues or site-specifically at cysteine residues. Characterization of these ADCs in vitro reveals generally similar properties, including a similar catabolite profile, a key element in making a meaningful comparison of conjugation chemistries. In a mouse model of cervical cancer, the lysine-conjugated ADC affords greater efficacy on a molar payload basis. Rather than making general conclusions about ADCs conjugated by a particular chemistry, we interpret these results as highlighting the complexity of ADCs and the interplay between payload class, linker chemistry, target antigen, and other variables that determine efficacy in a given setting. |
| Databáze: | OpenAIRE |
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