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30 April 2019 Erice, Italy

Targeting ovarian cancer with anti-MISR2 radiolabeled maBS. Emmanuel Deshayes, MD, PhD INSERM U1194 Montpellier, France « Radiobiology and Targeted Radiotherapy Team ». 30 April 2019 Erice, Italy. Introduction. Targeted Radionuclide Therapy (TRT). Radionuclide. Vector. Target.

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30 April 2019 Erice, Italy

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  1. Targeting ovarian cancer with anti-MISR2 radiolabeled maBS Emmanuel Deshayes, MD, PhD INSERM U1194 Montpellier, France « Radiobiology and Targeted Radiotherapy Team » 30 April 2019 Erice, Italy

  2. Introduction Targeted Radionuclide Therapy (TRT) Radionuclide Vector Target Radioimmunotherapy (RIT) Use of antibodies (full or fragments)

  3. Introduction AIMOF THE WORK To develop a theranostic approach in ovarian cancer using radiolabeled mAbs Molecular Imaging In vivo imaging and quantitative assessment of target expression Radionuclide Therapy Patient specific dosimetry Absorbed dose estimation 177Lu 213Bi Isotope switch 50µm-100µm 50µm-1.1mm Radiolabeled mAbs for -SPECT (Indium-111) -PET (Zirconium-89) Same mAb Same target

  4. Introduction Ovarian Cancer • First cause of death from gynecologic malignancy • Bad prognosis: recurrence of 70% within 3 years in spite of optimal cytoreductive surgery • Dissemination of the disease in the peritoneal cavity (peritoneal carcinomatosis) is the main recurrence site • Need to develop new theranostic tools specifically directed against the residual disease 5 yearssurvival Siegel, Miller et al. 2016, Reid, Permuth et al. 2017

  5. Introduction Ovarian cancer : treatment • Complete surgical cytoreduction and adjuvant IV chemotherapy (carboplatine + paclitaxel) • Neoadjuvant chemotherapy when cytoreduction is not to be complete • Advanced stages: association with bevacizumab (anti-VEGF) • Aim of adjuvant treatments : treat microscopic residual disease to limit the risk of recurrence (mainly through peritoneal cavity) • Optimisation of way of delivery of chemotherapy : • Intraperitoneal : • Increase peritoneum/plasma ratio • HyperthermicInrtaperitoneal Chemotherapy (HIPEC) : • Synergistic effect of hyperthermia • Gain in overall survival & PFS • Morbidity (Huo, Richards et al. 2015, van Driel, Koole et al. 2018) « open HIPEC »

  6. Introduction A new target Müllerian Inhibiting Subtance Type II Receptor (MISRII) Anti-Müllerian Hormon Type 2 Receptor (AMHR2) • Transmembrane Glycoprotein with Ser/Thre activity • Expressed in ≈ 80% epithelial ovarian cancers, 90% GCT, 60% endometrial tumors • Other tumors: Breast, Prostate, Testicules • ≈ No expression in normal tissues MIS (AMH) MISR2 (AMHR2) Post-menopausalovarianepith Serousovarianadenocarcinoma Bakkum-Gamez, 2008, Gynecol. Oncol. Estupina et al. Oncotarget 2017; Kersual & Teulon, 2014, mAbs,

  7. Introduction Anti-MISR2 antibodies • Initially developed by the team (DrI.Teulon & Dr A. Pelegrin) • Production via mouse ascites using lymphocyte hybridization  • Murine (16F12/12G4) or humanized (3C23K) • High affinity (> nM) and specificity for human MISR2 • Internalization upon binding on MISR2 • Binds to MISRII independently from the natural ligand MIS • In vivo anti-tumor efficacy (SC, IP) On going phase I clinical trial with 3C23K (GM102) « First In Human Safety, Pharmacokinetics and Anti-tumoral Activity of GM102 in Gynecological advanced AMHR2 + Cancers» (NCT02978755). Kersual & Teulon, 2014, mAbs Estupina et al. Oncotarget 2017;

  8. Introduction Radioimmunotherapy & ovarian cancer

  9. Introduction The only phase III RIT in ovarian cancer: 90Y-HMFG1 Verheijen et al, JCO 2006 • Multicentric randomized (1:1) international trial • 447 patients • Adjuvant treatment after complete surgical cytoreduction • One single IP injection of 666 MBq/kg of 90Y-HMFG1 • Endpoints : overall survival and time to relapse No significant differences between treated and controled arms

  10. Introduction Verheijen et al, JCO 2006 The only phase III RIT in ovarian cancer: 90Y-HMFG1 Why it failed ? • “radioactive chemotherapy” ? • Body weighted injection ? • Level of expression of target on tumors ? • Intraperitoneal distribution of the radiopharmaceutical ? • Choice of isotope ? • Yttrium-90 : too long range ? • Dose insufficient ? • Fractionation ? • More than 10 years later, ovarian cancer still has a high rate of recurrence • Interest in new theranostic development targeting small residual disease after complete surgical cytoreduction

  11. Introduction Targeting microscopic residual disease after complete cytoreduction 213Bi 177Lu 100 Physical characteristics of radionuclides should be adapted 10 Dose (Gy) 1 0,1 Hindie, Zanotti-Fregonara et al. JNM, 2016 Pouget et al. Nat Rev Clin Oncol 2011

  12. Objectives Aim of the work • To treat with radioimmunotherapy residual disease post cytoreductive surgery (small volume tumors : 1-3 mm) by : • Developing new anti-MISR2 radiopharmaceuticals • Find the best way of delivery • To develop some companion tools

  13. Materials and methods Radioimmunoconjugates Important steps : bioconjugaison, radiolabeling & immuno-affinity check

  14. Materials and methods Tumor xenograft models • Athymic nude mice • Cell line AN3CA (MISR2+ endometrial human cancer) • Xenografts : • Sub-cutaneous (SC) : proof of concept • Intra-peritoneal (IP) : model of peritoneal carcinomatosis SC IP

  15. Materials and methods ‘BriefIntraPeritonealRadioImmunotherapy’ (BIP-RIT) Similar to « closed HIPEC », but with radiopharmaceuticals Inflow Waste 30’ WashingwithNaCl (25 mL) IP high activities Outflow Outflow • Well tolerated • Low systemic diffusion • High tumor/blood ratio BIP-RIT Boudousqet al. J Nucl Med 2010 Boudousq et al. Plos One 2013

  16. Materials and methods Assessement of therapeutic efficacy Nodule 1 • On sub-cutaneous (SC) xenograft model : • Caliper • On intra-peritoneal (IP)xenograft model • Dissection at various time points to estimate peritoneal tumor mass Total tumor mass = sum of all nodules mass

  17. Materials and methods Biodistribution : % IA vs % Ra ? Biodistributionis the concentration of radiopharmaceuticals at different time points in organs IP-RIT X MBq t0 t1 t2 t3 t4 % injected activity per gram of tissue ? MBq BIP-RIT Washing Y MBq t0 t1 t2 t3 t4 BIP-RIT with washing procedure : take into account residual activity (%RA) rather than injected activity (%IA) in biodistribution studies Residual activity = sum of activity in the whole animal after washing

  18. Materials and methods Dosimetric studies • Data from biodistribution studies • Based on MIRD formalism • Absorbed doses (Gy) Gy.Bq-1.s • Cumulated Activity : temporal variations : • Pharmacokinetics • Physical decay S Factor: physical characteristics of the radionuclide & geometrical features of the model

  19. Materials and methods SPECT/CT 177Lu-16F12 Gamma Particle PET/CT 89Zr-16F12

  20. Results : proof of concept Sub-cutaneous Models AN3CA cell lines, treatments by IP-RIT * 177Lu-16F12 SPECT/CT 24h p.i. Anti-MISR2 177Lu-16F12 is efficient after IP injection in control tumor growth on SC xenograft model 20

  21. Results : Comparison of way of injection (IP/BIP) & radionuclide (213Bi/177Lu) Deshayes et al. JNM, 2018 Biodistribution 177Lu-16F12 BIP-RIT IP-RIT SPECT/CT

  22. Results : Comparison of way of injection (IP/BIP) & radionuclide (213Bi/177Lu) Deshayes et al. JNM, 2018 Therapeutic efficacy 177Lu-16F12 NaCl BIP-RIT IP-RIT RIT p = 0,034 p = 0,034 213Bi-16F12

  23. Results : Comparison of way of injection (IP/BIP) & radionuclide (213Bi/177Lu) Deshayes et al. JNM, 2018 Toxicity • IP 177Lu-16F12 Transient & reversible toxicity • No toxicity with IP/BIP 213Bi-16F12 or BIP 177Lu-16F12

  24. Results : Comparison of way of injection (IP/BIP) & radionuclide (213Bi/177Lu) Dosimetry 213Bi-16F12 177Lu-16F12

  25. Results : Comparison of way of injection (IP/BIP) & radionuclide (213Bi/177Lu) Dosimetry 213Bi-16F12 177Lu-16F12 Dosimetricdatas in agreement with therapeutic effects and toxicities.

  26. Results : imaging PET/CT imaging 24h 48h72h 96h 89Zr-DFO-16F12

  27. Conclusion With anti-MISR2 radiolabeled mAbs : • BIP-RIT shows a favorable biodistribution and dosimetricprofil whatever the type of isotope is used : 177Lu or 213Bi (low systemic diffusion and favorable tumor over blood ratio) • 213Bi-16F12 appears well suited to target small residual disease of peritoneal carcinomatosis : • Therapeutic efficacy • No significant toxicity • Different results are concordant with absorbed doses • 89Zr-16F12 may be suitable for theranostic applications

  28. Perspectives • Transfer BIP-RIT with 213Bi-16F12 to clinic Unsealed sources in the operating room • Humanization of 16F12

  29. Acknowledgements Radiobiology & TRT Team (U1194) Jean Pierre Pouget Isabelle Navarro-Teulon Catherine Lozza Vincent Boudousq Samuel Sevestre Alexandre Pichard Riad Ladjohouonlou Pierre Le Fur Muriel Busson Institut des TransUraniens Karlsruhe, Germany Frank Bruchertseifer Alfred Morgenstern Nuclearmedecinedepartment ICM Val d’Aurelle Pierre Olivier Kotzki Marie-Claude Eberle Sophie Guillemard Lore Santoro Laurence Calas Cyril Fersing Biostatistique ICM/IRCM Marta Jarlier BartsCancer Institute University of London, UK Roxana Kashani Joanna Koch Jane Sosabowski Julie Foster CRCINA Nantes, FRANCE Nicolas Chouin

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