Abstract
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.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Adenocarcinoma / drug therapy
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Adenocarcinoma / metabolism
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Animals
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Antigens, Neoplasm / chemistry
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Antigens, Neoplasm / immunology
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Carcinoma, Renal Cell / drug therapy
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Carcinoma, Renal Cell / metabolism
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Cell Adhesion Molecules / chemistry
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Cell Adhesion Molecules / immunology
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Cell Line, Tumor
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / metabolism
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Drug Resistance, Multiple
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Drug Resistance, Neoplasm
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Epithelial Cell Adhesion Molecule
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Female
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Humans
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Immunotoxins / chemistry
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Immunotoxins / pharmacokinetics
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Immunotoxins / pharmacology*
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Kidney Neoplasms / drug therapy
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Kidney Neoplasms / metabolism
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Maleimides / chemistry
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Maytansine / analogs & derivatives*
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Maytansine / chemistry
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Maytansine / pharmacokinetics
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Maytansine / pharmacology
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Mice
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Mice, SCID
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Polyethylene Glycols / chemistry
Substances
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15-amino-4,7,10,13-tetraoxapentadecanoic acid
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antigens, Neoplasm
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Cell Adhesion Molecules
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EPCAM protein, human
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Epithelial Cell Adhesion Molecule
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Immunotoxins
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Maleimides
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Maytansine
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Polyethylene Glycols
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N-(4-carboxycyclohexylmethyl)maleimide N-hydroxysuccinimide ester