Folate-immunoglobulin G as an anticancer therapeutic antibody.
Folate receptor-alpha (FR) is a promising cellular marker for tumor-specific drug delivery. Conjugation of folic acid to therapeutic and imaging agents has been shown to enhance their delivery to FR (+) cancer cells in vitro and in tumor-bearing mice via an FR-mediated cellular uptake mechanism. In this study, immunoglobulin G (IgG) was conjugated to folate and evaluated as a therapeutic antibody against folate receptor (FR)-positive tumors. Murine IgG (mIgG) was conjugated to folate via an amide bond to yield folate-conjugated mIgG (f-mIgG) that contained an average of approximately 2.6 folates per molecule. Selective uptake of f-IgG by FR (+) tumor cells was determined by fluorescence microscopy and by flow cytometry. Lysis of L1210JF cells by NK cells from murine donors was increased 1.4-9.0-fold at the effector:target (E:T) ratio of 25:1, relative to control mIgG. In mice bearing L1210JF tumors, f-mIgG was found to significantly inhibit tumor growth and to have prolonged the median survival time (MeST). Significantly, the antitumor efficacy of f-mIgG was greatly increased when combined with liposomal G3139, an 18-mer phosphorothioate oligonucleotide. In fact, the combination resulted in a 100% cure rate among the tumor-bearing mice. Injection of f-mIgG significantly increased serum INF-gamma and IL-6 level in mice compared with mIgG and dramatically increased serum INF-gamma and IL-6 level when combined with liposomal G3139. These results suggested that f-IgG, a novel immunotherapy agent, has potent activity as a therapeutic antibody to the FR-positive cancer, and the therapeutic activity is enhanced by immunomodulatory agents.
Li
Hong
H
Division of Pharmaceutics, NSF Nanoscale Science and Engineering Center, The Ohio State University, Columbus, Ohio 43210, USA.
Lu
Yanhui
Y
Piao
Longzhu
L
Wu
Jun
J
Yang
Xiaojuan
X
Kondadasula
Sri Vidya
SV
Carson
William E
WE
Lee
Robert J
RJ
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000737:chemistry* / Q000627:therapeutic use*; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry* / Q000627:therapeutic use*; D007938:Leukemia / Q000188:drug therapy*; D008081:Liposomes; D051379:Mice; D008811:Mice, Inbred DBA; D011956:Receptors, Cell Surface / Q000378:metabolism*
D002352:Carrier Proteins; D016207:Cytokines; D058973:Folate Receptors, GPI-Anchored; D007074:Immunoglobulin G; D008081:Liposomes; D011956:Receptors, Cell Surface; D005492:Folic Acid