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Systemic Anti–Hepatocyte Growth
Factor Monoclonal Antibody Therapy Induces the Regression of
Intracranial Glioma Xenografts
K. Jin Kim1,
Lihong Wang1, Yi-Chi Su1,
G. Yancey Gillespie2,
Amandeep Salhotra3,
Bachchu Lal3 and
John Laterra3
Authors' Affiliations: 1Galaxy
Biotech, LLC, Mountain View, California; 2Division of
Neurosurgery, University of Alabama at Birmingham, Birmingham,
Alabama; and 3Department of Neurology, The Kennedy Krieger
Research Institute and The Johns Hopkins University School of
Medicine, Baltimore, Maryland. Requests for reprints: K. Jin Kim,
Galaxy Biotech, LLC, 2462 Wyandotte Street, Mountain View, CA 94033.
Phone: 650-964-4966, ext. 214; Fax: 650-694-7717; E-mail: kjinkim@msn.com
.
Purpose. Hepatocyte
growth factor (HGF) and its receptor Met are involved in
the initiation, progression, and metastasis of numerous
systemic and central nervous system tumors.
Thus, an anti-HGF monoclonal antibody (mAb) capable of
blocking the HGF-Met interaction could have broad
applicability in cancer therapy.
Experimental Design. An
anti-HGF mAb L2G7 that blocks binding of HGF to Met was
generated by hybridoma technology, and its ability to
inhibit the various biological activities of HGF was
measured by in vitro assays.
The ability of L2G7 to inhibit the growth of tumors was
determined by establishing s.c. and intracranial xenografts
of human U87 and U118 glioma cell lines in nude mice, and
treatment with 100 µg of L2G7 or control given i.p. twice
per week.
Results. MAb L2G7
strongly inhibited all biological activities of HGF
measured in vitro, including cell proliferation, cell scattering,
and endothelial tubule formation.
Treatment with L2G7 completely inhibited the growth of
established s.c. xenografts in nude mice.
Moreover, systemic administration of L2G7 from day 5
induced the regression of intracranial U87 xenografts and
dramatically prolonged the survival of tumor-bearing mice from
a median of 39 to >90 days.
L2G7 treatment of large intracranial tumors (average tumor
size, 26.7 mm3) from day 18 induced substantial
tumor regression (control group, 134.3 mm3; L2G7
treated group, 11.7 mm3) by day 29 and again prolonged
animal survival.
Conclusions. These
findings show that blocking the HGF-Met interaction with
systemically given anti-HGF mAb can have profound antitumor effects
even within the central nervous system, a site previously believed
to be resistant to systemic antibody-based therapeutics.
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