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Supplementary Table S1. Summary of cell lines used.
Cell line
Purpose
Reference
H441
H441 responds to HGF in assays of cell migration; here, H441 is used as a
functional MET agonist assay.
Kong-Beltran et al. Cancer Cell 2004; 6:
75
H596
H596 proliferation increases upon HGF stimulation; here, H596 is used as a
model of HGF-dependent MET activation.
Kong-Beltran et al. Cancer Res 2006;
66: 283
U87MG
The in vivo growth of U87MG is driven by an HGF/MET autocrine loop and the
model has been used to investigate many anti-HGF and anti-MET therapeutics.
Burgess et al. Cancer Res 2006; 66:
1721
DU145
DU145 cells scatter in response to HGF treatment; here, DU145 is used as a
functional MET agonist assay.
Humphrey et al. Am J Pathol 1995; 147:
386
HepG2
HepG2 responds to HGF in several functional assays including invasion and
tubulogenesis ; here, HepG2 is used as a functional MET agonist assay.
Neaud et al. Hepatology 1997; 26: 1458
Michaud et al. mAbs 2012; 4: 710
PHH (primary
human
hepatocytes)
Hepatocytes have been shown to proliferation in response to HGF; here, human
hepatocytes are used as a functional MET agonist assay.
Nakamura et al. FEBS Letters 1987;
224:311
Gohda et al. JCI 1988; 81: 414
MKN45
MKN45 is MET amplified and MET is constitutively active and is used as a
model of HGF-independent MET activation.
Smolen et al. PNAS 2006; 103: 2316
H1437
H1437 has an R988C juxtamembrane domain MET mutation and was used to
determine if mutant MET can be internalized.
Ma et al. Cancer Res 2005; 65:1479
NIH3T3-M1149T
The M1149T MET tyrosine kinase domain mutation was introduced into NIH3T3
to determine if mutant MET can be internalized.
Schmidt et al. Oncogene 1999; 18:2343
LoVo
LoVo expresses unprocessed 190kD pro-MET and was used to determine if this
MET alteration can be internalized.
Mondino et al. Mol Cell Biol 1991; 11:
6084
EBC-1
EBC-1 is MET amplified and MET is constitutively active and is used as a model
of HGF-independent MET activation.
Lutterbach et al. Cancer Res 2007;
67:2081
SNU-5
SNU-5 is MET amplified and MET is constitutively active and is used as a model
of HGF-independent MET activation.
Smolen et al. PNAS 2006; 103: 2316
Caki-1
Caki-1 proliferates in response to HGF and HGF protects Caki-1 cells from
apoptosis; here Caki-1 is used as a functional MET agonist assay.
Horie et al. J Urology 1999; 161: 990
Huang et al. Tumor Biol 2014;
doi10.1007/s13277-014-1774-7
Supplementary Table S2. Summary of Repeat-Dose Toxicity Study with LY2875358
Species
Strain
No./Sex/Group
Age
Monkey,
Cynomolgus
3 (0.3, 7 mg/kg)
6 (0, 180 mg/kg)
1.5-2.5 years
Doses,
Route,
Duration
Parameters
Evaluated
0a, 0.3, 7, and 180 mg/kg TKb, survival, BW, FC,
clin signs, phys, ophthal,
Q7D
ECG, safety pharmc,
ADA, PDd, clin pathe,
Intravenous
pathf, urine biomarkersg,
h
5 wk + 16 wk recovery IHC
phase
Noteworthy
Findings
≥0.3 mg/kg:  thyroid weight,
follicular thyroid dilatation, ↑ECD
7 mg/kg (M): Enlarged thyroid
180 mg/kg (F): Blood in urine Weeks 2 and 5
Recovery Phase:
Limited to detection of ADAs in 3 of
12 animalsi
NOAEL = 180 mg/kg
Abbreviations:  = increase; ADA = antidrug antibody; BW = body weight; clin = clinical; CNS = central nervous
system; ECD = extracellular domain; ECG = electrocardiography; ELISA = enzyme-linked immunosorbent
assay; FC = food consumption; F = female; IgG = immunoglobulin G; IHC = immunohistochemistry;
M = male; MET = mesenchymal-epithelial transition factor; NOAEL = no-observed-adverse-effect level; No. =
Number; ophthal = ophthalmic examinations; path = pathology; PD = pharmacodynamics; phys = physical
examinations; safety pharm = safety pharmacology; TK = toxicokinetics; wk = week; Q7D = Once every 7 days
a Vehicle control group. Vehicle = 10 mM sodium citrate buffer (pH 6.0), 150 mM sodium chloride, 0.02%
polysorbate 80 in sterile water for injection.
b Total IgG LY2875358 assay; extracellular domain of MET analysis.
c Respiratory exams, neurologic exams with detailed CNS/behavioral observations, body temperature.
d Total MET analysis in kidney, skin, and liver by ELISA and Western analysis.
e Hematology, clinical chemistry, and urinalysis.
f Organ weights, gross pathology, and histopathology.
g Neutrophil gelatinase-associated lipocalin (NGAL), microalbumin, clusterin.
h Ki67 staining in liver, kidney, and spleen.
i Presence of drug antibody may have interfered with assay’s ability to detect ADAs at the end of the recovery
phase as well as at the end of the treatment phase.