Superior in vivo efficacy of afucosylated trastuzumab in the treatment of HER2-amplified breast cancer.
The enhancement of immune effector functions has been proposed as a potential strategy for increasing the efficacy of therapeutic antibodies. Here, we show that removing fucose from trastuzumab (Herceptin) increased its binding to FcgammaRIIIa, enhanced antibody-dependent cell-mediated cytotoxicity, and more than doubled the median progression-free survival when compared with conventional trastuzumab in treating preclinical models of HER2-amplified breast cancer. Our results show that afucosylated trastuzumab has superior efficacy in treating in vivo models of HER2-amplified breast cancer and support the development of effector function-enhanced antibodies for solid tumor therapy.
Junttila
Teemu T
TT
Genentech, Inc., South San Francisco, CA 94080, USA.
Parsons
Kathryn
K
Olsson
Christine
C
Lu
Yanmei
Y
Xin
Yan
Y
Theriault
Julie
J
Crocker
Lisa
L
Pabonan
Oliver
O
Baginski
Tomasz
T
Meng
Gloria
G
Totpal
Klara
K
Kelley
Robert F
RF
Sliwkowski
Mark X
MX
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D005643:Fucose / Q000737:chemistry; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D017452:Receptors, IgG / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D005643:Fucose; D018719:Erb-b2 Receptor Tyrosine Kinases; D017452:Receptors, IgG; D000068878:Trastuzumab; C496124:FCGR3A protein, human