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AEG Electrolux COMPETENCE 5133 V User Manual Page 38

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PRS-110: MET receptor antagonist
Dr Shane Olwill
PIERIS
AG
PIERIS
AG
www.m4.de/tsc
Preclinical development of PRS-110, a MET specific
Anticalin
as a monovalent antagonist in
oncology
Anticalin
as
a
monovalent
antagonist
in
oncology
Aims
Ch t i ti f d did t
ti
•
Ch
arac
t
er
i
za
ti
on o
f
d
rug can
did
a
t
e proper
ti
es
• Activity / potency
•
Biophysical properties
•
Biophysical
properties
• Half-life extension format
• Characterize PRS-110 mechanism of action
• HGF-de
p
endent MOA
p
• Ligand-independent MOA
Ribbon representation of a homology model of
PRS-110 based on the tear lipocalin scaffold
• Patient selection / stratification
• Pharmacodynamic markers
[email protected] | www.m4.de/tsc
Results
PRS-110 inhibits distal receptor signaling of
MET (pMet; pERK1/2: pAKT)
PRS-110 biophysical characterisation
shows excellent drug-like properties
c‐Met
pMetY1349
AKTERK
Cell
Proliferation
Cell
Survival
PRS-110 Inhibits HGF-mediated phosphorylation of key sites required for
downstream signaling in HUVEC cells.
(A) analytical SEC showing high purity; B nanoDSC (Tm = 69°C); C-E 12 wk
stability study at 25°C qELISA (C) ; D UV280 signal, E RALLS signal)
PRS-110 binds to the SEMA domain of MET
Receptor
PRS-110 traffics MET to late endosomes
The PRS-110 epitope (red) was mapped on to the structure of MET
Confocal images show clustering of MET in response to treatment with
PRS
110 and
colocalisation
of MET with
LAMP
1
[email protected] | www.m4.de/tsc
PRS
-
110
and
colocalisation
of
MET
with
LAMP
-
1
Results
PRS-110 results in tumor regression in a
ligand-independent tumor model
PRS-110 results in tumor regression in a
ligand-dependent tumor model
100% TGI
80% TGI
Tumor
Regression
Caki-1 tumor xenograft model showing dose dependent TGI with
PRS-110 (i.p. QD)
U87-MG tumor xenograft model showing dose dependent TGI and
tumor regression observed with PRS-110 (i.p. QD)
PRS-110 leads to a reduction in total MET in
tumor biopsies (PD Marker)
150
Specific uptake of
89
Z
r
-PRS-110 in H441
xenograft observed by microPET imaging
50
100
Total cMET (%)
***
Total Met evaluation of excised xenograft tumors following 7 days
Ve
h
ic
l
e
PR
S
-1
1
0
0
c-Met dependent tumor uptake observed with radiolabeled version of
PRS
110 (89Zr
PRS
110
)
[email protected] | www.m4.de/tsc
therapy with PRS-110 (7.5mg/kg i.p. QD)
PRS
-
110
(89Zr
-
PRS
-
110
)
35
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