177Lu-FAP-2286 Demonstrates Potent Anti-tumour Activity in a
FAP-expressing Xenograft Model• HEK293 cells were stably
transfected with human FAP to
generate a cell line with high FAP expression• High FAP
expression was confirmed by IHC;
a representative image of a tumor stained for FAP is shown•
Tumour cells were implanted by subcutaneous injection in
the right flank, and when the tumours reached a MTV of 160±44
mm3; mice were randomized into 4 different groups (n=10/group) and
given a single IV dose of vehicle, cold compound (natLu-FAP-2286),
or 30 MBq or 60 MBq177Lu-FAP-2286 (n=10 animals/group)
• Statistically significant tumour regression was observed at
both dose levels of 177Lu-FAP-2286 evaluated (P3,000
Stability Human plasma (24 h) Remaining compound (%, mean)
106
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without written permission of the authors.Corresponding author:
Andrew Simmons; [email protected].
Pancreas Colorectal Head & Neck Breast
Poster number: 571PPreclinical Evaluation of FAP-2286, a
Peptide-targeted Radionuclide Therapy to Fibroblast Activation
Protein Dirk Zboralski,1 Frank Osterkamp,1 Andrew D. Simmons,2 Anne
Bredenbeck,1 Anne Schumann,1 Matthias Paschke,1 Nicola
Beindorff,3
Ajay-Mohan Mohan,3,4 Minh Nguyen,2 Jim Xiao,2 Thomas C.
Harding,2 Aileen Hoehne,1 Ulrich Reineke,1 Christiane Smerling113B
Pharmaceuticals GmbH, Berlin, Germany; 2Clovis Oncology, Inc.,
Boulder, USA; 3Berlin Experimental Radionuclide Imaging Center,
Charité - Universitätsmedizin Berlin, Germany; 4Charité -
Universitätsmedizin Berlin, Germany
FAP-2286 Potently and Selectively Binds Human FAP• FAP-2286
demonstrated single-digit nanomolar affinity to FAP in both
recombinant
protein and cell-based assays• FAP-2286 inhibited FAP protease
activity with an IC50 value of 3.2 nM, whereas limited
inhibition was observed against the closely related family
members DPP4 and PREP• FAP-2286 was stable for at least 24 hours at
37oC in human plasma
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0
50
100
150
200
250
H-s
core
s
Tumour Growth
Images shown are at 300 µm magnification.
H-Score = 3×(% FAP high area) + 2×(% FAP medium area) + % FAP
low area; median is shown as bar across each column.
FAP binding peptidetargets FAP–expressing cancer-associated
fibroblasts and tumour cells
Radionuclide emits ionizing radiation for imaging and
therapeutic applications
Linker
FAP-2286• FAP-2286 consists of a peptide that potently and
selectively binds to FAP
attached to a linker and tetraazacyclododecane tetraacetic acid
cage that can be used to conjugate radioactive metal ions
• Imaging: Gallium-68 (68Ga) is conjugated to FAP-2286 for
positron emission tomography imaging
• Therapeutic: Lutetium-177 (177Lu) is conjugated to FAP-2286
for therapeutic use. The anticipated mechanism of anti-tumour
activity is through targeting of the β-particle emitter 177Lu to
FAP-positive tumourcells and CAFs, as well as surrounding
FAP-negative tumour cells by crossfire and bystander effects,
resulting in DNA damage and cell death
177Lu-FAP-2286 Demonstrates Anti-tumour Activity in Sarcoma
Patient-derived Xenograft Model• The sarcoma Sarc4809
patient-derived xenograft model
was reported to have high FAP mRNA expression• High FAP
expression was confirmed by IHC;
a representative image of a tumor stained for FAP is shown•
Tumour cells were implanted subcutaneously in the right
flank, and when tumours reached a MTV of 187±124 mm3a single IV
dose of vehicle, cold compound (natLu-FAP-2286), or 30 MBq or 60
MBq177Lu-FAP-2286 was administered (n=10 animals/group)
• Statistically significant tumour growth inhibition was
observed at both dose levels of 177Lu-FAP-2286 evaluated (P
