A novel method to improve the detection of cancer and metastases by peptide scanning under the protection of enzyme inhibitors: PepProtect 1

One of the key issues for the success of using peptide-tracers in patients for
diagnosis and therapy is the stability of the compounds. Unfortunately, most
labeled peptides are very unstable in the physiology of the human body, being
degraded by enzymes. Peptides, including radiopeptides, can be chemically
modified to improve stability against enzymatic breakdown, but subsequent
evaluation to reveal candidates of choice remains challenging, as stabilization
often interferes with receptor affinity.
Recently, a radically different approach has been developed; we have
demonstrated a highly effective method to improve the stability of
peptide-tracers in the blood stream. In mouse models this method leads to
unprecedented enhancement of tumor uptake without impairing background
clearance. With a single co-injection of a suitable enzyme inhibitor we
stabilized circulating peptide-tracers, significantly increasing their supply
and binding to receptors on the tumor cells and impressively amplifying
tumor-to-background ratios. This exciting strategy exploits our recent findings
that one single enzyme: neutral endopeptidase (NEP, EC 3.4.24.11, neprylysin)
is a major player in the in vivo degradation of a wide array of peptide-tracers

1.To monitor the safety and tolerability of racecadotril in combination with
111In-DOTA-MG11
2.To study in patients whether the neutral endopeptidase (NEP) inhibitor
racecadotril improves the in vivo stability of the radiopeptide 111In-DOTA-MG11

The study is a phase I single center, open clinical trial

Patients will twice undergo a scan with 111-In-DOTA-MG11, once at baseline
without racecadotril and once with racecadotril, as intended intervention.

-Patients will undergo 2 days of investigations at *baseline-2* visit
(injection, scanning and blood samples); 1 day of investigations at
*baseline-1* visit (oral racecadotril, observation, 1 blood sample); 2 days of
investigations at *intervention* visit (oral racecadotril, injection, scanning,
blood samples). One follow-up visit is planned; in conjunction with a regular
outpatient visit.
-The risk of undesirable effects is minimal; minor, self-limiting side-effects
of short duration are expected ([hypotension, tachycardia, nausea, dizziness]
similar to the side effects from the Pentagastrin® test)
-Radiation burden is expected to be in the range of 11 mSv for a single 200 MBq
111In-DOTA-MG11 administration (analoguous to other known hydrophilic
111In-radiopeptides). For 2 visits, with associated low-dose CT in SPECT/CT
scans, the total radiation burden for a patient in this study will be in the
range of 27 mSv. This is within category IIIb, according to the recent NCRD
publication *Human Exposure to Ionising Radiation for Clinical and Research
Purposes: Radiation Dose & Risk Estimates*. This is justified, as the benefits
of the study are aimed directly at: *directly related to saving lives or
mitigating serious diseases in the future*, which is a category IIIb
justification.
-Potential direct benefits: improved diagnosis/staging of MTC may lead to
improved, personalized treatment strategy for some individual MTC patients,
with possible better prognosis and/or less chance of unnessary/futile surgery
procedures.
-Potential future benefits: the (successful) protection of radioloabelled
DOTA-MG11 may be further developed and applied for PET/CT imaging (using
Ga-68), or for peptide targeted radiation therapy (e.g. using Lu-177).
-Potential future benefits: the principle of protecting naturally instable
radiopeptides may aid in developing other instable radiopeptides, aimed at
other forms of cancer (e.g. breast, prostate) into practice as useful clinical
tools.