Somatostatin receptor agonists and antagonists Melpomeni Fani

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1 Somatostatin receptor agonists and antagonists Melpomeni Fani Clinic of Radiology and Nuclear Medicine University of Basel Hospital, Switzerland

2 Somatostatin and somatostatin receptors Human Somatostatin (SS-14) peptide hormone (SS-14 and SS-28) regulates the release of many hormones and inhibits the secretion of peptides and neuroregulators from a variety of Ala Gly Cys Lys Asn Phe Phe Trp S S Lys neuroendocrine tumors, and in some cases reduces tumor growth Cys Ser Thr Phe Thr 5 G-protein coupled receptor subtypes (sstr1, sstr2, sstr3, sstr4 and sstr5) not useful to be developed into targeting (radio)ligands because of metabolic instability (T1/2 2-3 min)

3 From the natural somatostatin to stabilized analogs Octreotide (Sandostatin ) Human Somatostatin (SS-14) Novartis Ala Gly Cys Lys Asn Phe Phe Trp S S Cys Ser Thr Phe Thr Lys DPhe Cys Phe S S Thr(ol) Cys Thr D Trp Lys

4 First radiolabelled somatostatin analogs 123I-TOC 123I DPhe Cys Tyr S S D Trp Lys Thr(ol) Cys Thr 111In-DTPA-Octreotide (Octreoscan ) 111In DTPA DPhe Cys Phe S S D Trp Lys Thr(ol) Cys Thr FDA approval: June 2, 1994

5 Radiolabelled somatostatin analogs routinely applied into the clinic 111In-DTPA-Octreotide (Octreoscan ) 111In DOTA-TOC DTPA DPhe Cys Phe D Trp S State-of-the-art DOTA DPhe Cys Tyr D Trp S S Lys S Lys Thr(ol) Cys Thr Thr(ol) Cys Thr DOTA-NOC DOTA-TATE DOTA DPhe Cys 1-Nal S S Thr(ol) Cys Thr D Trp Lys DOTA DPhe Cys Tyr S S Thr Cys Thr D Trp Lys

6 Affinity profile (IC50, nm) Compound sstr1 sstr2 sstr3 sstr4 sstr5 111In-DTPA-octreotidea > ± ± 13 > ± 52 68Ga-DOTA-TOCa > ± ± 140 > Ga-DOTA-TATEa > ± 0.04 > Ga-DOTA-NOCb > ± ± ± ± ± ± ± 1.6 All values are IC50±SEM in nm areubi JC et al., Eur J Nucl Med 2000;27: bantunes P et al., Eur J Nucl Med Mol Imaging 2007;34:

7 Somatostatin receptor imaging in NETs Ex. G2 NET of the Ileum FDA approved (registered) investigation time: > 24 h Octreoscan 68Ga-DOTA-TOC scintigraphy 24 h p.i. PET 1 h p.i. not approved investigation time: 90 min radiation exposure: 9 msv radiation exposure: 3 msv sensitivity: ~ 70% sensitivity: ~ 85% Courtesy of G. Nicolas, University of Basel Hospital, Switzerland

8 68Ga-DOTA-TATE vs 111In-DTPA-OC Octreoscan 68Ga-DOTA-TATE scintigraphy 4 h p.i. PET 1 h p.i. Courtesy of D. Wild, University Hospital Freiburg, Germany

9 68Ga-DOTA-TATE vs 68Ga-DOTA-NOC 68Ga-DOTA-TATE PET 1h p.i. sst2 receptor Sensitivity ~ 85% 68Ga-DOTA-NOC PET 1h p.i. sst2,3,5 receptor Sensitivity ~ 95% D. Wild et al., J Nucl Med 2013;54:364 discrepant results: Kabasakal L, et al., Eur J Nucl Med Mol Imaging 2012;39:1271

10 The reason of success: The target Immunohistochemical Detection of sstr2 incidence density JC Reubi, Endocrine Rev 2003;24:

11 Ligands targeting G-Protein Coupled Receptors Agonists G-Protein Coupled Receptors (adjusted)

12 In vitro internalization Control SS-14 In-DOTA-NOC Agonist-induced internalization Confocal microscopy images after 30 incubation in HEK-sstr3 cells

13 Time course of agonist-induced sst2 internalization in vivo Agonist (TATE) in AR42J (sstr2-positive cells) A B C D E F 0 min 10 min 20 min 1h 6h 24 h Agonist (TATE) in Pancreas (sstr2-positive tissue) G H I J K L 0 min 10 min 20 min 1h 24 h 1h Antag Waser B, et al., J Nucl Med 2009;50:936

14 Internalization rate and tumor/pancreas uptake Storch D., et al., J Nucl Med 2005;46:1561

15 Internalization and tumor retention/washout The pansomatostatin ligand 111In-KE88 targets both sstr2 and sstr3 tumors but is only internalizes in sstr3 (the non-internalizing ligand shows fast washout) sstr2 sstr3 No internalization internalization kidneys 15 min 30 min 60 min 120 min 240 min Ginj M., et al., Clin Cancer Res 2008;14:2019

16 Further developments in the field The importance of the vector

17 Antagonists instead of Agonists Agonist Antagonist Stimulate receptor function Do not stimulate activity e.g. receptor internalization or Ca2+-release Block agonist induced activity

18 The pioneers of radiolabelled somatostatin receptor antagonists Jean E. Rivier (peptide analogs) Jean Claude Reubi (affinity, antagonism) Helmut R. Maecke (radiolabelled analogs)

19 In vitro internalization? TOC (agonist) Ga-NODAGA-LM3 (antagonist) Antagonist does not induce internalization Confocal microscopy images after 30 incubation in HEK-sstr2 cells Fani M, et al., J Nucl Med 2011;52:1110

20 In vivo internalization? Agonist (TATE) in AR42J tumors A 0 min 1h 6h 24 h Antagonist (DOTA-BASS) in AR42J tumors Waser B, et al., J Nucl Med 2009;50:936

21 Are radiolabelled receptor antagonists superior to agonists? TATE: D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr %IA/g BASS: p-no2-phe-cyclo(d-cys-tyr-d-trp-lys-thr-cys)d-tyr-nh2 Antagonists have more binding sites than agonists!! In-DOTA-sst3-ODN8 In-DOTA-sst -ODN ,30 0,30 bound/free bound/free tu m or hs st 2- e Antagonists showed much higher tumor uptake!! 111 In-DOTA-NOC In-DOTA-NOC 0,35 0,35 M us cl re as Pa nc ey K id n Li ve r 0,40 0,40 0,25 0,25 75-fold 0,010 0,010 0,20 0,20 0,15 0,15 higher 0,005 0,005 0,10 0,10 Bmax 0,05 0,05 0,000 0, ,00 0, bound bound (pm) (pm) Ginj M, et al., PNAS 2006;103:

22 111In-Octreoscan 0.68 %IA Agonist 111In-DOTA-BASS 1.3 %IA Antagonist 111In-DOTA-JR %IA Antagonist Scintigraphy 24 h p.i.

23 111In-Octreoscan 0.68 %IA Agonist 111In-DOTA-BASS 1.3 %IA Antagonist 111In-DOTA-JR %IA Antagonist Scintigraphy 24 h p.i.

24 The importance of the chelator

25 Selected chelators for radiometals almost all radiometals 68Ga, 64Cu, 111In (18F) (111In, 68Ga, 90Y, 177Lu, 213Bi, 46/47Sc, ) O HO N N O N OH HO O O DOTA NOTA (NODAGA) OH

26 68Ga-DOTA-LM3 & 68Ga-NODAGA-LM3 LM3: p-cl-phe-cyclo(d-cys-tyr-d-aph(cbm)-lys-thr-cys)-d-tyr-nh2 D-Aph(Cbm): D-4-amino-carbamoyl-phenylalanine Code DOTA-LM3 Introduction of a chelate 68Ga-DOTA-LM3 Exchange of the chelator 68Ga-NODAGA-LM3 sstr2 (IC50; nm) 0.39 ± ± ± 0.3 Reference agonist 68Ga-DOTA-TATE 0.2 ± 0.04 Fani M, et al., J Nucl Med 2011;52:1110

27 Significantly higher tumor uptake can be achieved with the antagonists, compared to agonists and for the same antagonist it depends on the chelator Ga-DOTA-TATE 68 Ga-DOTA-LM3 68 Ga-NODAGA-LM3 40 ** ± ± ± Sp r le en Lu ng K id n St ey om a In ch te st in e A dr e Pa nal nc re as M us cl e B on e Tu m or ve Li rt ea H lo od 0 B %IA/g * Organs *P < 0.05 and **P < 0.01 statistically significant

28 Image contrast of sstr2-specific antagonists vs agonist 68Ga-DOTA-TATE 68Ga-DOTA-LM3 68Ga-NODAGA-LM3 Coronal % IA/g 0 15 MIP Fani M, et al., J Nucl Med 2011;52:1110

29 The importance of the radionuclide

30 The (radio)metal determines receptor affinity! JR11: Cpa-cyclo[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH2 Cpa = 4-Cl-phenylalanine; Aph(Hor) = 4-amino-L-hydroorotyl-phenylalanine; D-Aph(Cbm) = D-4-amino-carbamoyl-phenylalanine DOTA-JR11 (Radio)metal IC50 (nmol/l) ± 0.12 Ga(III) 29 ± 2.7 Cu(II) 16 ± 1.2 In(III) 3.8 ± 0.7 Lu(III) 0.7 ± 0.15 Y(III) 0.47 ± 0.05 Loss of affinity in the 68GaPET probe Excellent affinity for the therapeutic probe Fani M, et al., J Nucl Med 2012;53:1481

31 68Ga-DOTA-JR11 & 68Ga-NODAGA-JR11 vs 68Ga-DOTA-TATE Compound IC50 (nmol/l) 68Ga-DOTA-JR ± Ga-NODAGA-JR ± Ga-DOTA-TATE 0.2 ± Ga-DOTA-TATE 18% 68Ga-DOTA-JR11 24% 150-fold 68Ga-NODAGA-JR11 31% Fani M, et al., J Nucl Med 2012;53:1481

32 Clinical translation

33 Comparison of 68Ga-DOTA-TOC and 68Ga-NODAGA-JR11 PET/CT (ClinicalTrials.gov NCT ) 68Ga-DOTA-TOC 5 metastases 68Ga-NODAGA-JR11 (68Ga-OPS202) 10 metastases PET 1h p.i.

34 68Ga-NODAGA-JR11 (68Ga-OPS202) vs 68Ga-DOTA-TOC shows increased tumour detection rate due to an improved Tumour-toBackground Uptake Ratio (Phase I/II, 12 pts) (ClinicalTrials.gov NCT ) Tumour-to-Background Ratio (median Tumour (SUVmax) / median Background (SUVmax)) Ga-68-DOTATOC 6,0 Ga-68-OPS202-15µg (A) 68Ga-DOTA-TOC 68Ga-OPS202 4,0 2,0 0,0 T:Liver T:Pancreas T:Intestine T:Spleen 15 µg

35 Comparison of 177Lu-DOTA-JR11 and 177Lu-DOTA-TATE dosimetry 177Lu-DOTA-TATE (Agonist) Isodose curves based on 3D voxel dosimetry analysis 177Lu-DOTA-JR11 (Antagonist) Isodose curves based on 3D voxel dosimetry analysis Gy/GBq Gy/GBq mean dose: 1.4 Gy/GBq mean dose: 5.7 Gy/GBq Tumor-to-kidney Tumor-to-kidney dose ratio: 1.1 dose ratio: 2.5 Wild D, et al., J Nucl Med 2014; 24;55:1248

36 Status of radiolabelled somatostatin receptor antagonists DOTA-JR11: OPS201 Clinical Trials NODAGA-JR11: OPS202 68Ga-NODAGA-JR11 (68Ga-OPS202) vs 68Ga-DOTA-TOC University of Basel Hospital, Switzerland (ClinicalTrials.gov NCT ) The theranostic pair 68Ga-DOTA-JR11 and 177Lu-DOTAJR11 (68Ga-/177Lu-OPS201) Memorial Sloan Kettering Cancer Center, New York, US (ClinicalTrials.gov NCT ) Larger-scale multicenter clinical trials are planned for 68GaNODAGA-JR11 (68Ga-OPS202) and 177Lu-DOTA-JR11 (177Lu-OPS201) OctreoPharm/IPSEN

37 Radiolabelled somatostatin receptor antagonists represent the recent most favorable innovation in molecular imaging and PRRT of NETs may well be the future of imaging and treatment of sstr-positive tumors

38 Prof. Helmut Maecke Dr. Rosalba Mansi Dr. Andreas Bauman Luigi Del Pozzo, MSc Prof. Damian Wild Dr. Guillaume Nicolas Dr. Felix Kaul

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