Antibody-maytansinoid conjugates designed to bypass multidrug resistance.
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.
Kovtun
Yelena V
YV
ImmunoGen, Inc, Waltham, Massachusetts 02451, USA. yelena.kovtun@immunogen.com
Audette
Charlene A
CA
Mayo
Michele F
MF
Jones
Gregory E
GE
Doherty
Heather
H
Maloney
Erin K
EK
Erickson
Hans K
HK
Sun
Xiuxia
X
Wilhelm
Sharon
S
Ab
Olga
O
Lai
Katharine C
KC
Widdison
Wayne C
WC
Kellogg
Brenda
B
Johnson
Holly
H
Pinkas
Jan
J
Lutz
Robert J
RJ
Singh
Rajeeva
R
Goldmacher
Victor S
VS
Chari
Ravi V J
RV
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000276:immunology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008301:Maleimides / Q000737:chemistry; D008453:Maytansine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D011092:Polyethylene Glycols / Q000737:chemistry
C516050:15-amino-4,7,10,13-tetraoxapentadecanoic acid; C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D000922:Immunotoxins; D008301:Maleimides; D008453:Maytansine; D011092:Polyethylene Glycols; C025285:N-(4-carboxycyclohexylmethyl)maleimide N-hydroxysuccinimide ester