Antibody-Maytansinoid Conjugates Designed to Bypass Multidrug Resistance

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-03, Vol.70 (6), p.2528-2537
• Main Authors: KOVTUN, Yelena V, AUDETTE, Charlene A, LAI, Katharine C, WIDDISON, Wayne C, KELLOGG, Brenda, JOHNSON, Holly, PINKAS, Jan, LUTZ, Robert J, SINGH, Rajeeva, GOLDMACHER, Victor S, CHARI, Ravi V. J, MAYO, Michele F, JONES, Gregory E, DOHERTY, Heather, MALONEY, Erin K, ERICKSON, Hans K, XIUXIA SUN, WILHELM, Sharon, AB, Olga
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Animals; Antigens, Neoplasm - chemistry; Antigens, Neoplasm - immunology; Antineoplastic agents; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - metabolism; Cell Adhesion Molecules - chemistry; Cell Adhesion Molecules - immunology; Cell Line, Tumor; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Epithelial Cell Adhesion Molecule; Female; Humans; Immunotoxins - chemistry; Immunotoxins - pharmacokinetics; Immunotoxins - pharmacology; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Maleimides - chemistry; Maytansine - analogs & derivatives; Maytansine - chemistry; Maytansine - pharmacokinetics; Maytansine - pharmacology; Medical sciences; Mice; Mice, SCID; Pharmacology. Drug treatments; Polyethylene Glycols - chemistry; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-09-3546

Conjugation of cytotoxic compounds to antibodies that bind to cancer-specific antigens makes these drugs selective in killing cancer cells. However, many of the compounds used in such antibody-drug conjugates (ADC) are substrates for the multidrug transporter MDR1. To evade the MDR1-mediated resistance, we conjugated the highly cytotoxic maytansinoid DM1 to antibodies via the maleimidyl-based hydrophilic linker PEG(4)Mal. Following uptake into target cells, conjugates made with the PEG(4)Mal linker were processed to a cytotoxic metabolite that was retained by MDR1-expressing cells better than a metabolite of similar conjugates prepared with the nonpolar linker N-succinimidyl-4-(maleimidomethyl)cyclohexane-1-carboxylate (SMCC). In accord, PEG(4)Mal-linked conjugates were more potent in killing MDR1-expressing cells in culture. In addition, PEG(4)Mal-linked conjugates were markedly more effective in eradicating MDR1-expressing human xenograft tumors than SMCC-linked conjugates while being tolerated similarly, thus showing an improved therapeutic index. This study points the way to the development of ADCs that bypass multidrug resistance.