Tirol Kliniken GmbH

Landeskrankenhaus – Universitätskliniken Innsbruck

Medizinische Universität Innsbruck

Universitätsklinik für NuklearmedizinDirektor: Univ.-Prof. Dr. Irene J. Virgolini

Elisabeth von Guggenberg1, Maximilian Klingler1, Renata Mikołajczak R2, Alicja Hubalewska-Dydejczyk3, Irene Virgolini1

1Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria2Radioisotope Centre POLATOM, National Centre for Nuclear Research, Otwock, Poland3Department of Endocrinology, Jagiellonian University, Medical College, Krakow, Poland

May 8, 2019

Minigastrin analogues for enhancedcholecystokinin-2 receptor targeting and

their theranostic use

Nuclear Medicine Department, Medical University Innsbruck

Minigastrin Analogueschemically modified peptides based on the sequence of human minigastrin (MG)C-terminal cholecystokinin-2 receptor (CCK2R) specific binding side

Cholecystokinin-2 receptor (CCK2R)G-protein coupled receptor(brain, gastrointestinal tract)

NHNH

O

NHNH

O

O

NHNH

O

O

NHNH

O

O

NH2

OH

O

O

OH NH

O OH

S

NHNHNH

OO

NH

O

NH2

O OHO OH

O OOHOH

O O

Minigastrin Analogues

human minigastrin

Gastrin

Nuclear Medicine Department, Medical University Innsbruck

Cholecystokinin-2 Receptor Expression in Cancer

• Medullary thyroid carcinoma (MTC) 92-100%

• Small cell lung cancer (SCLC) 57%

• Gastro-entero-pancreatic tumours (GEP-NET) 22%

(in particular insulinomas >90%)

• Stromal ovarian cancer 100%

(epithelial ovarian, breast/endometrial, prostate 7-14%)

• Astrocytoma 65%

• Gastrointestinal stromal tumours (GIST) 60-100%

• Leiomyosarcomas/Leiomyoma 33-67%

Reubi JC et al. 1997, Cancer Res 57: 1377-1386Reubi JC 2007, Curr Top Med Chem 7: 1239-1242

Sanchez C et al. 2012, Mol Cell Endocrinol 349: 170-179Reubi JC & Waser B 2003, Eur J Nucl Med Mol Imaging 30: 781-793

Nuclear Medicine Department, Medical University Innsbruck

C-cell derived thyroid cancer; accounts only for 5% of all thyroid cancers75% sporadic / 25% hereditary (mutations in the RET protooncogene)

Early diagnosis and radical surgeryearly spread to locoregional lymph nodes makes surgical cure difficult

? Radioactive iodine: ineffective (no sodium iodide symporter)? Chemotherapy: no first-line treatment (remission rate <20%)? External beam radiation: no standard treatment (avoid local recurrence)? Tyrosinkinase Inhibitors: Vandetanib (Caprelsa®), Cabozantinib (Cometriq®)

only used in aggressive and symptomatic forms of MTC (severe side effects)

Peptide Receptor Radionuclide Therapy (PRRT)Somatostatin Analogues (receptor expression low / inhomogenous)Gastrin Analogues (receptor incidence in MTC >90%)

Medullary Thyroid Carcinoma (MTC)

https://www.ncbi.nlm.nih.gov/books/NBK65719.9/table/CDR0000062913__561/?report=objectonly

111In-DTPA-MG0; Gotthardt M et al. EJNMMI 2006 111In-DTPA-MG11; Fröberg AC et al. EJNMMI 2009

Nuclear Medicine Department, Medical University Innsbruck

enzymatic cleavage sites

Previous state of the art:DOTA-MG11

DOTA-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2

In vivo stability of in miceno intact radiopeptide detactable in blood

Tumour targeting in micewith A431-CCK2R xenograftsLow tumour-to-kidney ratioof 0.6

Stabilised Minigastrin Analogues

with Enhanced Tumour Targeting

DOTA-DGlu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1-Nal-NH2

New technology:Site-specific C-terminal modificationDOTA-MGS5

min

mV

111In-DOTA-MG1110 MBq, 4 h p.i.

177Lu-DOTA-MG11

min

mV > 80 %

intact radiopeptide

High in vivo stability of 177Lu-DOTA-MGS5

1 h p.i. 4 h p.i.Improved tumour targeting of 111In-DOTA-MGS5

microSPECT/CT111In-DOTA-MGS510 MBq

A431-CCK2R xenograftsHigh tumour-to-kidneyratio of 6

1 h p.i. 4 h p.i.

Nuclear Medicine Department, Medical University Innsbruck

A431-CCK2R cells:

A431 human epidermoid carcinoma cell line transfected with human CCK2R

A431-mock:

mock transfected cells

Biodistribution in the Mouse-Tumour-Model

bloodlung

Intestine

liver

kidneys

pancreas

stomach

A431-CCK2R

A431-mock

0

5

10

15

20

25

30

inje

cte

d a

ctivity

[%IA

/g] 23.2±4.7 %IA/g

23.5±1.2 %IA/g

24.5±3.1 %IA/g

Tumour uptake

1 h p.i.68Ga-DOTA-MGS5:

4 h p.i.111In-DOTA-MGS5:177Lu-DOTA-MGS5:

A431-CK2R/mock xenografted female athymic BALB/c nude mice (n= 4)

2x106 cells/mouse (≤0.05 MBq 111In, ≤0.5 MBq 177Lu, ≤1 MBq 68Ga, ≤0.03 nmol)

Nuclear Medicine Department, Medical University Innsbruck

Development Status

Status quo:

• In vitro/in vivo proof-of-principle

• Preclinical characterisation of

tumour targeting properties

• Development of a kit formulation

for 68Ga-labelling

Next steps:

• First PET/CT imaging in

patients with advanced MTC

Nuclear Medicine Department, Medical University Innsbruck

Commercial potential

Highly competitive nuclear medicine/radiopharmaceutical market

(estimated to reach $5-10 billion by 2024/25)

Comparable development (somatostatin analogues)

Advanced Accelerator Applications (AAA)

Two radiopharmaceuticals for the diagnosis and the treatment of neuroendocrine tumours:

- lutetium (177Lu) oxodotreotide (Lutathera®)

- gallium (68Ga) edotreotide (NETSPOT®, SomaKit TOC®)

AAA had sales of 109 million Euro in 2016.

Novartis bought AAA for $3.9 billion in October 2017

Nuclear Medicine Department, Medical University Innsbruck

Commercial potential

New development (minigastrin analogues)

Estimated current number of patients with CCK2R related cancerUS/EU/Japan ~250,000

medullary thyroid cancer ~96,500

small cell lung cancer: ~81,000

gastrointestinal stromal tumours: ~4,750

stromal ovarian cancer: ~24,350

astrocytoma: ~48,150

Estimated costs

1,000 Euro for PET imaging

15,000 Euro for a single therapy

Considering1500 eligible patients with advanced cancer

Sales of 100 million Euro can be expected per year

Nuclear Medicine Department, Medical University Innsbruck

Competition

177Lu-PP-F11N DOTA-(DGlu)5-DGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2Debio 1124 - Debiopharm Group/Paul Scherrer Institute; NCT02088645 – Phase I

111In-CP04 DOTA-(DGlu)5-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2CP04 - Academic initiative, Transcan, GRAN-T-MTC; NCT03246659 – Phase I

0

2

4

6

Tu

mo

ur

to s

tom

ach

ra

tio

s

0

2

4

6

Tu

mo

ur

to k

idn

ey r

atio

s

bloodlung

Intestine

liver

kidneys

pancreas

stomach

A431-CCK2R

A431-mock

0

5

10

15

20

25

30

inje

cte

d d

ose [%

ID/g

]

*Sauter AW et al., EJNMMI 2016, 43: S238-S239

177Lu-DOTA-MGS5

177Lu-CP04

177Lu-PP-F11N

177Lu-DOTA-MGS5 showshighly improved tumouruptake in comparison withcompetitive developments

Nuclear Medicine Department, Medical University Innsbruck

IP Status

• Novel minigastrin analogues are protected as radiolabelled molecules for use in therapy and diagnosis

• A PCT patent application for use in cancer is pending

Solid perspective of patent protection

Nuclear Medicine Department, Medical University Innsbruck

Resources Needed

• GMP production 100,000 €(peptide precursor for radiolabelling)

• Pharmacology/Toxicology 50,000 €(extended single dose toxicity study)

• Diagnostic clinical study 200,000 €(10 patients, 20,000 Euro/patient)

• Therapeutic clinical study …(~50,000 Euro/patient)

Nuclear Medicine Department, Medical University Innsbruck

Risks and Bottlenecks

• Regulatory aspects ofclinical testing

• Different radionuclidesfor diagnosis and therapy

• Failure of proof of principlein humans

very low risk situation

First clinical PET imaging

in a patient with

advanced MTC has

recently been successfully

performed!

Nuclear Medicine Department, Medical University Innsbruck

Poster #A1 Ascenion Booth

Contact: Dr. Elisabeth von GuggenbergNuclear Medicine DepartmentTirol Kliniken – Medical University InnsbruckA-6020 InnsbruckTel.: +43 512 504 80960Email: elisabeth.vonguggenberg@tirol-kliniken.at

Business Contact: Dr. Hubert MüllerAscenion GmbHHerzogstr. 6480803 MünchenTel.: +49 89 318814-32Email: mueller@ascenion.de