Antibody–Drug Conjugates (ADCs) Derived from Interchain Cysteine Cross-Linking Demonstrate Improved Homogeneity and Other Pharmacological Properties over Conventional Heterogeneous ADCs
| Autor: | Randall L. Halcomb, Amanda Valdiosera, David Y. Jackson, Lawrence Chinn, Jonathan S. Melnick, Migone Thi Sau, Mark R. Flory, Derrick Houser, Edward H. van der Horst, Maureen Fitch-Bruhns, Simeon Bowers, Edward Ha, Jorge Monteon, Jan Willem Theunissen, Gary Probst, Tiffany Wong, Paul W. Sauer, Zoia Levashova, Kristy Venstrom, Abel Bermudez, Sindy Liao-Chan, Christopher R. Behrens |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Antibody-drug conjugate Immunoconjugates Lung Neoplasms Receptor ErbB-2 Stereochemistry Blotting Western Fluorescent Antibody Technique Pharmaceutical Science Antineoplastic Agents Apoptosis Fusion Regulatory Protein-1 Mice SCID Conjugated system Article Rats Sprague-Dawley Mice chemistry.chemical_compound Mice Inbred NOD In vivo Drug Discovery Tumor Cells Cultured Animals Humans Cysteine Bifunctional Maleimide Cell Proliferation Chemistry dBm Antibodies Monoclonal Trastuzumab Flow Cytometry Xenograft Model Antitumor Assays Combinatorial chemistry Rats body regions Cross-Linking Reagents Molecular Medicine Female Linker Conjugate |
| Zdroj: | Mol Pharm |
| ISSN: | 1543-8392 1543-8384 |
| Popis: | Conventional antibody–drug conjugates (ADCs) are heterogeneous mixtures of chemically distinct molecules that vary in both drugs/antibody (DAR) and conjugation sites. Suboptimal properties of heterogeneous ADCs have led to new site-specific conjugation methods for improving ADC homogeneity. Most site-specific methods require extensive antibody engineering to identify optimal conjugation sites and introduce unique functional groups for conjugation with appropriately modified linkers. Alternative nonrecombinant methods have emerged in which bifunctional linkers are utilized to cross-link antibody interchain cysteines and afford ADCs containing four drugs/antibody. Although these methods have been shown to improve ADC homogeneity and stability in vitro, their effect on the pharmacological properties of ADCs in vivo is unknown. In order to determine the relative impact of interchain cysteine cross-linking on the therapeutic window and other properties of ADCs in vivo, we synthesized a derivative of the known ADC payload, MC-MMAF, that contains a bifunctional dibromomaleimide (DBM) linker instead of a conventional maleimide (MC) linker. The DBM-MMAF derivative was conjugated to trastuzumab and a novel anti-CD98 antibody to afford ADCs containing predominantly four drugs/antibody. The pharmacological properties of the resulting cross-linked ADCs were compared with analogous heterogeneous ADCs derived from conventional linkers. The results demonstrate that DBM linkers can be applied directly to native antibodies, without antibody engineering, to yield highly homogeneous ADCs via cysteine cross-linking. The resulting ADCs demonstrate improved pharmacokinetics, superior efficacy, and reduced toxicity in vivo compared to analogous conventional heterogeneous ADCs. |
| Databáze: | OpenAIRE |
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