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2. Nuclear localization signal-tagged systems: relevant nuclear import principles in the context of current therapeutic design.

Author

Goswami, Ritabrita, Gupta, Aarohi, Bednova, Olga, Coulombe, Gaël, Patel, Dipika, Rotello, Vincent M., and Leyton, Jeffrey V.

Subjects
NUCLEAR pore complex, TREATMENT effectiveness
Abstract

Nuclear targeting of therapeutics provides a strategy for enhancing efficacy of molecules active in the nucleus and minimizing off-target effects. 'Active' nuclear-directed transport and efficient translocations across nuclear pore complexes provide the most effective means of maximizing nuclear localization. Nuclear-targeting systems based on nuclear localization signal (NLS) motifs have progressed significantly since the beginning of the current millennium. Here, we offer a roadmap for understanding the basic mechanisms of nuclear import in the context of actionable therapeutic design for developing NLS-therapeutics with improved treatment efficacy. [ABSTRACT FROM AUTHOR]

Published
2024
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3. An affinity matured minibody for PET imaging of prostate stem cell antigen (PSCA)-expressing tumors

Author

Lepin, Eric J, Leyton, Jeffrey V, Zhou, Yu, Olafsen, Tove, Salazar, Felix B, McCabe, Katelyn E, Hahm, Scott, Marks, James D, Reiter, Robert E, and Wu, Anna M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Urologic Diseases, Biomedical Imaging, Prostate Cancer, Biotechnology, Amino Acid Sequence, Animals, Antibody Affinity, Antigens, Neoplasm, Cell Line, Tumor, GPI-Linked Proteins, Gene Expression Regulation, Neoplastic, Humans, Immunoglobulin Fragments, Male, Mice, Molecular Sequence Data, Mutation, Neoplasm Proteins, Positron-Emission Tomography, Prostatic Neoplasms, Radioactive Tracers, Imaging, Prostate, PSCA, Antibody, PET, Other Physical Sciences, Clinical Sciences, Nuclear Medicine & Medical Imaging, Clinical sciences
Abstract

PurposeProstate stem cell antigen (PSCA), a cell surface glycoprotein expressed in normal human prostate and bladder, is over-expressed in the majority of localized prostate cancer and most bone metastases. We have previously shown that the hu1G8 minibody, a humanized anti-PSCA antibody fragment (single-chain Fv-C(H)3 dimer, 80 kDa), can localize specifically and image PSCA-expressing xenografts at 21 h post-injection. However, the humanization and antibody fragment reformatting decreased its apparent affinity. Here, we sought to evaluate PET imaging contrast with affinity matured minibodies.MethodsYeast scFv display, involving four rounds of selection, was used to generate the three affinity matured antibody fragments (A2, A11, and C5) that were reformatted into minibodies. These three affinity matured anti-PSCA minibodies were characterized in vitro, and following radiolabeling with (124)I were evaluated in vivo for microPET imaging of PSCA-expressing tumors.ResultsThe A2, A11, and C5 minibody variants all demonstrated improved affinity compared to the parental (P) minibody and were ranked as follows: A2 > A11 > C5 > P. The (124)I-labeled A11 minibody demonstrated higher immunoreactivity than the parental minibody and also achieved the best microPET imaging contrast in two xenograft models, LAPC-9 (prostate cancer) and Capan-1 (pancreatic cancer), when evaluated in vivo.ConclusionOf the affinity variant minibodies tested, the A11 minibody that ranked second in affinity was selected as the best immunoPET tracer to image PSCA-expressing xenografts. This candidate is currently under development for evaluation in a pilot clinical imaging study.

Published
2010

8. 18th European Symposium on Radiopharmacy and Radiopharmaceuticals: Salzburg, Austria. 7-10 April 2016

Author

Radchenko, V., Engle, J. W., Roy, C., Griswold, J., Nortier, M. F., Birnbaum, E. R., Brugh, M., Mirzadeh, S., John, K. D., Fassbender, M. E., Zhai, Chuangyan, Franssen, Gerben M., Petrik, Milos, Laverman, Peter, Decristoforo, Clemens, Samia, Ait-Mohand, Véronique, Dumulon-Perreault, Brigitte, Guérin, Summer, D., Kroess, A., Rangger, C., Haas, H., Laverman, P., Gerben, F., von Guggenberg, E., Decristoforo, C., Bolzati, Cristina, Salvarese, Nicola, Refosco, Fiorenzo, Meléndez-Alafort, Laura, Carpanese, Debora, Rosato, Antonio, Saviano, Michele, Del Gatto, Annarita, Comegna, Daniela, Zaccaro, Laura, Billaud, Emilie, Ahamed, Muneer, Cleeren, Frederik, Shahbazali, Elnaz, Noël, Tim, Hessel, Volker, Verbruggen, Alfons, Bormans, Guy, Cleeren, F., Lecina, J., Koole, M., Verbruggen, A., Bormans, G., Lugatoa, B., Stucchia, S., Turollaa, E. A., Giulianoa, L., Toddea, S., Ferraboschib, P., Klok, R. P., Mooijer, M. P. J., Hendrikse, N. H., Windhorst, A. D., Collet, C., Petry, N., Chrétien, F., Karcher, G., Pellegrini-Moïse, N., Lamandé-Langle, S., Pfaff, Sarah, Philippe, Cecile, Mitterhauser, Markus, Hacker, Marcus, Wadsak, Wolfgang, Guérard, François, Lee, Yong-Sok, Gouard, Sébastien, Baidoo, Kwamena, Alliot, Cyrille, Chérel, Michel, Brechbiel, Martin W., Gestin, Jean-François, Lam, K., Chan, C., Reilly, R. M., Paillas, Salomé, Marshall, John, Pouget, Jean-Pierre, Sosabowski, Jane, Briard, Emmanuelle, Auberson, Yves P., Reilly, John, Healy, Mark, Sykes, David, Paulus, Andreas, Lichtenbelt, Wouter van Marken, Mottaghy, Felix, Bauwens, Matthias, Baranski, Ann-Christin, Schäfer, Martin, Bauder-Wüst, Ulrike, Haberkorn, Uwe, Eder, Matthias, Kopka, Klaus, Chaussard, M., Hosten, B., Vignal, N., Tsoupko-Sitnikov, V., Hernio, N., Hontonnou, F., Merlet, P., Poyet, J. L., Sarda-Mantel, L., Rizzo-Padoin, N., Cardinale, J., Schäfer, M., Benešová, M., Bauder-Wüst, U., Seibert, O., Giesel, F., Haberkorn, U., Eder, M., Kopka, K., Nematallah, Mansour, Michel, Paquette, Samia, Ait-Mohand, Véronique, Dumulon-Perreault, Roger, Lecomte, Brigitte, Guérin, Fernandez-Maza, L., Rivera-Marrero, S., Capote, A. Prats, Parrado-Gallego, A., Fernandez-Gomez, I., Balcerzyk, M., Sablon-Carrazana, M., Perera-Pintado, A., Merceron-Martinez, D., Acosta-Medina, E., Rodriguez-Tanty, C., Attili, Bala, Ahamed, Muneer, Bormans, Guy, Philippe, C., Zeilinger, M., Scherer, T., Fürnsinn, C., Dumanic, M., Wadsak, W., Hacker, M., Mitterhauser, M., Janssen, B., Vugts, D. J., Molenaar, G.T. T., Funke, U., Kruijer, P. S., Dollé, F., Bormans, G., Lammertsma, A. A., Windhorst, A. D., Vermeulen, Koen, Ahamed, Muneer, Schnekenburger, Michael, Froeyen, Mathy, Olberg, Dag Erlend, Diederich, Marc, Bormansa, Guy, Raaphorst, R. M., Luurtsema, G., Lammertsma, A. A., Elsinga, P. H., Windhorst, A D., Rotteveel, Lonneke, Funke, Uta, ten Dijke, Peter, Bogaard, Harm Jan, Lammertsma, Adriaan A., Windhorst, Albert D., Song, Lei, Able, Sarah, Falzone, Nadia, Kersemans, Veerle, Vallis, Katherine, Carta, Davide, Salvarese, Nicola, Sihver, Wiebke, Gao, Feng, Pietzsch, Hans Jürgen, Biondi, Barbara, Ruzza, Paolo, Refosco, Fiorenzo, Bolzati, Cristina, Haubner, Roland, Finkensted, Armin, Stegmair, Armin, Rangger, Christine, Decristoforo, Clemens, Zoller, Heinz, Virgolini, Irene J., Pooters, Ivo, Lotz, Maartje, Wierts, Roel, Mottaghy, Felix, Bauwens, Matthias, Forsback, Sarita, Jörgen, Bergman, Riikka, Kivelä, Karageorgou, M., Radović, M., Tsoukalas, C., Antic, B., Gazouli, M., Paravatou-Petsotas, M., Xanthopouls, S., Calamiotou, M., Stamopoulos, D., Vranješ-Durić, S., Bouziotis, P., Lunev, A. S., Larenkov, A. A., Petrosova, K. A., Klementyeva, O. E., Kodina, G. E., Kvernenes, O. H., Adamsen, T. C. H., Martin, René, Weidlich, Sebastian, Zerges, Anna-Maria, Gameiro, Cristiana, Lazarova, Neva, Müllera, Marco, Luurtsema, Gert, de Vries, Michèl, Ghyoot, Michel, van der Woude, Gina, Zijlma, Rolf, Dierckx, Rudi, Boersma, Hendrikus H., Elsinga, Philip H., Lambrecht, Fatma Yurt, Er, Ozge, Ince, Mine, Avci, Cıgır Biray, Gunduz, Cumhur, Sarı, Fatma Aslihan, Ocakoglu, Kasim, Er, Ozge, Ersoz, Onur Alp, Lambrecht, Fatma Yurt, Ince, Mine, Kayabasi, Cagla, Gunduz, Cumhur, Kniess, Torsten, Meister, Sebastian, Fischer, Steffen, Steinbach, Jörg, Ashfaq, Rabia, Iqbal, Saeed, ullah Khan, Irfan, Iglesias-Jerez, R., Martín-Banderas, L., Perera-Pintado, A., Borrego-Dorado, I., Farinha-Antunes, Ines, Kwizera, Chantal, Lacivita, Enza, Lucente, Ermelinda, Niso, Mauro, De Giorgio, Paola, Perrone, Roberto, Colabufo, Nicola A., Elsinga, Philip H., Leopoldo, Marcello, Vaulina, V. V., Fedorova, O. S., Orlovskaja, V. V., Chen, С. L., Li, G. Y., Meng, F. C., Liu, R. S., Wang, H. E., Krasikova, R. N., Meléndez-Alafort, Laura, Abozeid, Mohamed, Ferro-Flores, Guillermina, Negri, Anna, Bello, Michele, Uzunov, Nikolay, Paiusco, Martha, Esposito, Juan, Rosato, Antonio, Meléndez-Alafort, Laura, Bolzati, Cristina, Ferro-Flores, Guillermina, Salvarese, Nicola, Carpanese, Debora, Abozeid, Mohamed, Rosato, Antonio, Uzunov, Nikolay, Palmieri, L., Verbrugghen, T., Glassner, M., Hoogenboom, R., Staelens, S., Wyffels, L., Orlovskaja, V. V., Kuznetsova, O. F., Fedorova, O. S., Maleev, V. I., Belokon, Yu. N., Geolchanyan, A., Saghyan, A. S., Mu, L., Schibli, R., Ametamey, S. M., Krasikova, R. N., Revunov, Evgeny, Malmquist, Jonas, Johnström, Peter, Van Valkenburgh, Juno, Steele, Dalton, Halldin, Christer, Schou, Magnus, Osati, Samira, Paquette, Michel, Beaudoin, Simon, Ali, Hasrat, Guerin, Brigitte, Leyton, Jeffrey V., van Lier, Johan E., Di Iorio, V, Iori, M., Donati, C., Lanzetta, V., Capponi, P. C., Rubagotti, S., Dreger, T., Kunkel, F., Asti, M., Zhai, Chuangyan, Rangger, Christine, Summer, Dominik, Haas, Hubertus, Decristoforo, Clemens, Kijprayoon, Suphansa, Ruangma, Ananya, Ngokpol, Suthatip, Tuamputsha, Samart, Filp, Ulrike, Pees, Anna, Taddei, Carlotta, Pekošak, Aleksandra, Gee, Antony D., Poot, Alex J., Windhorst, Albert D., Gunay, Mine Silindir, Ozer, A. Yekta, Erdogan, Suna, Baysal, Ipek, Guilloteau, Denis, Chalon, Sylvie, Galli, Filippo, Artico, Marco, Taurone, Samanta, Bianchi, Enrica, Weintraub, Bruce D., Skudlinski, Mariusz, Signore, Alberto, Lepareur, Nicolas, Noiret, Nicolas, Hindré, François, Lacœuille, Franck, Benoist, Eric, Garin, Etienne, Trejo-Ballado, F., Zamora-Romo, E., Manrique-Arias, J. C., Gama-Romero, H M, Contreras-Castañon, G., Tecuapetla-Chantes, R. G., Avila-Rodriguez, M. A., Kvaternik, H., Hausberger, D., Zink, C., Rumpf, B., Aigner, R. M., Kvaternik, H., Hausberger, D., Rumpf, B., Aigner, R. M., Janković, Drina, Lakić, Mladen, Savić, Aleksandar, Ristić, Slavica, Nikolić, Nadežda, Vukadinović, Aleksandar, Sabo, Tibor J., Vranješ-Đurić, Sanja, Vranješ-Đurić, S., Radović, M., Janković, D., Nikolić, N., Goya, G. F., Calatayud, P., Spasojević, V., Antić, B., Goblet, David, Gameiro, Cristiana, Lazarova, Neva, Gameiro, Cristiana, Oxley, Ian, Abrunhosa, Antero, Kramer, Vasko, Vosjan, Maria, Spaans, Arnold, Vats, Kusum, Satpati, Drishty, Sarma, Haladhar D., Banerjee, Sharmila, Wojdowska, W., Pawlak, D. W., Parus, L. J., Garnuszek, P., Mikołajczak, R., Pijarowska-Kruszyna, J., Jaron, A., Kachniarz, A., Malkowski, B., Garnuszek, P., Mikolajczak, R., Ilem-Ozdemir, Derya, Caglayan-Orumlu, Oya, Asikoglu, Makbule, Ilem-Ozdemir, Derya, Caglayan-Orumlu, Oya, Asikoglu, Makbule, Eveliina, Arponen, Semi, Helin, Timo, Saarinen, Simo, Vauhkala, Esa, Kokkomäki, Pertti, Lehikoinen, De Simone, Mariarosaria, Pascali, Giancarlo, Carzoli, Ludovica, Quaglierini, Mauro, Telleschi, Mauro, Salvadori, Piero A., Lam, Phoebe, Aistleitner, Martina, Eichinger, Reinhard, Artner, Christoph, Nakka, Surendra, MC, Hemantha Kumara, Al-Qahtani, Mohammed, Al-Qahtani, Mohammed, Al-Malki, Yousif, Mambilima, N., Rubow, S. M., Berroterán-Infante, N., Hacker, M., Mitterhauser, M., Wadsak, W., Funke, Uta, Cleeren, Frederik, Lecina, Joan, Gallardo, Rodrigo, Verbruggen, Alfons M., Bormans, Guy, Ramos-Membrive, Rocío, Brotons, Ana, Quincoces, Gemma, Inchaurraga, Laura, de Redín, Inés Luis, Morán, Verónica, García-García, Berta, Irache, Juan Manuel, Peñuelas, Iván, Trabelsi, M., Cooper, M. S., Abella, Alejandra, Fuente, Teodomiro, Montellano, Antonio Jesús, Martínez, Teresa, Rabadan, Ruben, Meseguer-Olmo, Luis, Lehtiniemi, P., Yim, C., Mikkola, K., Nuutila, P., Solin, O., von Guggenberg, E., Rangger, C., Mair, C., Balogh, L., Pöstényi, Z., Pawlak, D., Mikołajczak, R., Socan, A., Peitl, P. Kolenc, Krošelj, M., Rangger, C., Decristoforo, C., Collet, C., Remy, S., Didier, R., Vergote, T., Karcher, G., Véran, N., Pawlak, D., Maurin, M., Garnuszek, P., Karczmarczyk, U., Mikołajczak, R., Fredericia, Pil, Severin, Gregory, Groesser, Torsten, Köster, Ulli, Jensen, Mikael, Leonte, R., Puicea, F. D., Raicu, A., Min, E. A., Serban, R., Manda, G., Niculae, D., Zerna, Marion, Schieferstein, Hanno, Müller, Andre, Berndt, Mathias, Yim, Cheng-Bin, Mikkola, Kirsi, Nuutila, Pirjo, Solin, Olof, Seifert, D., Ráliš, J., Lebeda, O., Selivanova, Svetlana V., Senta, Helena, Lavallée, Éric, Caouette, Lyne, Turcotte, Éric, Lecomte, Roger, Kochovska, Marina Zdraveska, Ivanovska, Emilija Janjevik, Jokic, Vesna Spasic, Ackova, Darinka Gjorgieva, Smilkov, Katarina, Makreski, Petre, Stafilov, Trajče, Janevik-Ivanovska, Emilija, Alemu, Aschalew, Muchira, Joel Munene, Wanjeh, David Mwanza, Janevik-Ivanovska, Emilija, Janevik-Ivanovska, Emilija, Zdravev, Zoran, Bhonsle, Uday, Alberto, Osso Júnior João, Duatti, Adriano, Angelovska, Bistra, Stojanovska, Zdenka, Sarafinovska, Zorica Arsova, Bosnakovski, Darko, Gorgieva-Ackova, Darinka, Smilkov, Katarina, Drakalska, Elena, Venkatesh, Meera, Gulaboski, Rubin, Colin, Didier J., Inkster, James A. H., Germain, Stéphane, Seimbille, Yann, Atiq-ur-Rehman, and Cayero-Otero

Published
2016
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10. Solution-phase surface modification in intact poly(dimethylsiloxane) microfluidic channels

Author

Sui, Guodong, Wang, Jinyi, Lee, Chung-Cheng, Lu, Weixing, Lee, Stephanie P., Leyton, Jeffrey V., Wu, Anna M., and Tseng, Hsian-Rong

Subjects
Chemical tests and reagents -- Usage, Oxidation-reduction reaction -- Analysis, Dimethylpolysiloxane -- Chemical properties, Dimethylpolysiloxane -- Research, Polyethylene glycol -- Chemical properties, Polyethylene glycol -- Research, Chemistry
Abstract

An improved approach composed of an oxidation reaction in acidic [H.sub.2][O.sub.2] solution and a sequential silanization reaction using neat silane reagents for surface modification of poly(dimethylsiloxane) (PDMS) substrates was developed. This solution-phase approach is simple and convenient for some routine analytical applications in chemistry and biology laboratories and is designed for intact PDMS-based microfluidic devices, with no device postassembly required. Using this improved approach, two different functional groups, poly(ethylene glycol) (PEG) and amine (N[H.sub.2]), were introduced onto PDMS surfaces for passivation of nonspecific protein absorption and attachment of biomolecules, respectively. X-ray electron spectroscopy and temporal contact angle experiments were employed to monitor functional group transformation and dynamic characteristics of the PEG-grafted PDMS substrates; fluorescent protein solutions were introduced into the PEG-grafted PDMS microchannels to test their protein repelling characteristics. These analytical data indicate that the PEG-grafted PDMS surfaces exhibit improved short-term surface dynamics and robust long-term stability. The amino-grafted PDMS microchannels are also relatively stable and can be further activated for modifications with peptide, DNA, and protein on the surfaces of microfluidic channels. The resulting biomolecule-grafted PDMS microchannels can be utilized for cell immobilization and incubation, semiquantitative DNA hybridization, and immunoassay.

Published
2006

14. Proteomic-based evaluation of nuclear transport of NLS-tagged trastuzumab-emtansine with enhanced cytotoxic potency

Author

Lacasse, Vincent, Beaudoin, Simon, Jean, Steve, and Leyton, Jeffrey V.

Subjects
0303 health sciences, Endosome, Chemistry, Regulator, Computational biology, Importin, environment and public health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, medicine, NLS, Nuclear transport, Nucleus, Nuclear localization sequence, Function (biology), 030304 developmental biology
Abstract

Nuclear transport receptors (NTRs) are the only proteins able to transport large molecular weight payloads into the nucleus. A dominant area of molecular therapeutic research is the extension of the use of NTRs to target the nucleus for the development of pharmaceuticals or as tools for investigating fundamental biological questions. Although several examples of synthesized peptides harbouring nuclear localization signal (NLS) sequences conjugated to various payloads exist in the literature, the assumption has been that transport occurs by classical nuclear localization via the NTRs importin-α and importin-β. This assumption is relevant to nuclear-targeted therapeutics that aim for full potential clinical impact. In addition, fundamental research can benefit from unbiased approaches to investigate the role of NTRs. Herein, we report the construction of a novel NLS-modified agent composed of trastuzumab-emtansine (T-DM1) coupled to cell accumulator (Accum), a technology that enables monoclonal antibodies to escape endosome entrapment and accumulate conjugated payloads in the nucleus without abrogating affinity or specificity to target antigens. Accum harbours a classical NLS sequence from SV-40 large T-antigen. We demonstrate that routing T-DM1 to the nucleus successfully increased cytotoxic potency in the HER2-positive cell line SKBR3. More importantly, through the development of a novel bait-prey proteomic approach, we show that the non-classical NTR importin 7 and not importin-α/importin-β was required for the cytotoxicity effect. This result was validated by siRNA knock down. Our findings also indicate that by discovering an unanticipated NTR regulator of an NLS-modified agent, this study demonstrates the utility of combining an unbiased proteomic approach to probe NTR function in mammalian cell system and, is a foresight for future NLS-based development initiatives.

Published
2019

21. NLS-Cholic Acid Conjugation to IL-5Rα-Specific Antibody Improves Cellular Accumulation and In Vivo Tumor-Targeting Properties in a Bladder Cancer Model

Author

Paquette, Michel, primary, Beaudoin, Simon, additional, Tremblay, Mylene-Annie, additional, Jean, Steve, additional, Lopez, Angel F., additional, Lecomte, Roger, additional, Guérin, Brigitte, additional, Bentourkia, M’hamed, additional, Sabbagh, Robert, additional, and Leyton, Jeffrey V., additional

Published
2018
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22. 18Th European Symposium On Radiopharmacy And Radiopharmaceuticals

Author

Radchenko, V., Engle, J. W., Roy, C., Griswold, J., Nortier, M. F., Birnbaum, E. R., Brugh, M., Mirzadeh, S., John, K. D., Fassbender, M. E., Zhai, Chuangyan, Franssen, Gerben M., Petrik, Milos, Laverman, Peter, Decristoforo, Clemens, Samia, Ait-Mohand, Véronique, Dumulon-Perreault, Brigitte, Guérin, Summer, D., Kroess, A., Rangger, C., Haas, H., Laverman, P., Gerben, F., von Guggenberg, E., Decristoforo, C., Bolzati, Cristina, Salvarese, Nicola, Refosco, Fiorenzo, Meléndez-Alafort, Laura, Carpanese, Debora, Rosato, Antonio, Saviano, Michele, Del Gatto, Annarita, Comegna, Daniela, Zaccaro, Laura, Billaud, Emilie, Ahamed, Muneer, Cleeren, Frederik, Shahbazali, Elnaz, Noël, Tim, Hessel, Volker, Verbruggen, Alfons, Bormans, Guy, Cleeren, F., Lecina, J., Koole, M., Verbruggen, A., Bormans, G., Lugatoa, B., Stucchia, S., Turollaa, E. A., Giulianoa, L., Toddea, S., Ferraboschib, P., Klok, R. P., Mooijer, M. P. J., Hendrikse, N. H., Windhorst, A. D., Collet, C., Petry, N., Chrétien, F., Karcher, G., Pellegrini-Moïse, N., Lamandé-Langle, S., Pfaff, Sarah, Philippe, Cecile, Mitterhauser, Markus, Hacker, Marcus, Wadsak, Wolfgang, Guérard, François, Lee, Yong-Sok, Gouard, Sébastien, Baidoo, Kwamena, Alliot, Cyrille, Chérel, Michel, Brechbiel, Martin W., Gestin, Jean-François, Lam, K., Chan, C., Reilly, R. M., Paillas, Salomé, Marshall, John, Pouget, Jean-Pierre, Sosabowski, Jane, Briard, Emmanuelle, Auberson, Yves P., Reilly, John, Healy, Mark, Sykes, David, Paulus, Andreas, Lichtenbelt, Wouter van Marken, Mottaghy, Felix, Bauwens, Matthias, Baranski, Ann-Christin, Schäfer, Martin, Bauder-Wüst, Ulrike, Haberkorn, Uwe, Eder, Matthias, Kopka, Klaus, Chaussard, M., Hosten, B., Vignal, N., Tsoupko-Sitnikov, V., Hernio, N., Hontonnou, F., Merlet, P., Poyet, J. L., Sarda-Mantel, L., Rizzo-Padoin, N., Cardinale, J., Schäfer, M., Benešová, M., Bauder-Wüst, U., Seibert, O., Giesel, F., Haberkorn, U., Eder, M., Kopka, K., Nematallah, Mansour, Michel, Paquette, Roger, Lecomte, Fernandez-Maza, L., Rivera-Marrero, S., Capote, A. Prats, Parrado-Gallego, A., Fernandez-Gomez, I., Balcerzyk, M., Sablon-Carrazana, M., Perera-Pintado, A., Merceron-Martinez, D., Acosta-Medina, E., Rodriguez-Tanty, C., Attili, Bala, Philippe, C., Zeilinger, M., Scherer, T., Fürnsinn, C., Dumanic, M., Wadsak, W., Hacker, M., Mitterhauser, M., Janssen, B., Vugts, D. J., Molenaar, G.T. T., Funke, U., Kruijer, P. S., Dollé, F., Lammertsma, A. A., Vermeulen, Koen, Schnekenburger, Michael, Froeyen, Mathy, Olberg, Dag Erlend, Diederich, Marc, Bormansa, Guy, Raaphorst, R. M., Luurtsema, G., Elsinga, P. H., Windhorst, A D., Rotteveel, Lonneke, Funke, Uta, ten Dijke, Peter, Bogaard, Harm Jan, Lammertsma, Adriaan A., Windhorst, Albert D., Song, Lei, Able, Sarah, Falzone, Nadia, Kersemans, Veerle, Vallis, Katherine, Carta, Davide, Sihver, Wiebke, Gao, Feng, Pietzsch, Hans Jürgen, Biondi, Barbara, Ruzza, Paolo, Haubner, Roland, Finkensted, Armin, Stegmair, Armin, Rangger, Christine, Zoller, Heinz, Virgolini, Irene J., Pooters, Ivo, Lotz, Maartje, Wierts, Roel, Forsback, Sarita, Jörgen, Bergman, Riikka, Kivelä, Karageorgou, M., Radović, M., Tsoukalas, C., Antic, B., Gazouli, M., Paravatou-Petsotas, M., Xanthopouls, S., Calamiotou, M., Stamopoulos, D., Vranješ-Durić, S., Bouziotis, P., Lunev, A. S., Larenkov, A. A., Petrosova, K. A., Klementyeva, O. E., Kodina, G. E., Kvernenes, O. H., Adamsen, T. C. H., Martin, René, Weidlich, Sebastian, Zerges, Anna-Maria, Gameiro, Cristiana, Lazarova, Neva, Müllera, Marco, Luurtsema, Gert, de Vries, Michèl, Ghyoot, Michel, van der Woude, Gina, Zijlma, Rolf, Dierckx, Rudi, Boersma, Hendrikus H., Elsinga, Philip H., Lambrecht, Fatma Yurt, Er, Ozge, Ince, Mine, Avci, Cıgır Biray, Gunduz, Cumhur, Sarı, Fatma Aslihan, Ocakoglu, Kasim, Ersoz, Onur Alp, Kayabasi, Cagla, Kniess, Torsten, Meister, Sebastian, Fischer, Steffen, Steinbach, Jörg, Ashfaq, Rabia, Iqbal, Saeed, ullah Khan, Irfan, Iglesias-Jerez, R., Martín-Banderas, L., Borrego-Dorado, I., Farinha-Antunes, Ines, Kwizera, Chantal, Lacivita, Enza, Lucente, Ermelinda, Niso, Mauro, De Giorgio, Paola, Perrone, Roberto, Colabufo, Nicola A., Leopoldo, Marcello, Vaulina, V. V., Fedorova, O. S., Orlovskaja, V. V., Chen, С. L., Li, G. Y., Meng, F. C., Liu, R. S., Wang, H. E., Krasikova, R. N., Abozeid, Mohamed, Ferro-Flores, Guillermina, Negri, Anna, Bello, Michele, Uzunov, Nikolay, Paiusco, Martha, Esposito, Juan, Palmieri, L., Verbrugghen, T., Glassner, M., Hoogenboom, R., Staelens, S., Wyffels, L., Kuznetsova, O. F., Maleev, V. I., Belokon, Yu. N., Geolchanyan, A., Saghyan, A. S., Mu, L., Schibli, R., Ametamey, S. M., Revunov, Evgeny, Malmquist, Jonas, Johnström, Peter, Van Valkenburgh, Juno, Steele, Dalton, Halldin, Christer, Schou, Magnus, Osati, Samira, Paquette, Michel, Beaudoin, Simon, Ali, Hasrat, Guerin, Brigitte, Leyton, Jeffrey V., van Lier, Johan E., Di Iorio, V, Iori, M., Donati, C., Lanzetta, V., Capponi, P. C., Rubagotti, S., Dreger, T., Kunkel, F., Asti, M., Summer, Dominik, Haas, Hubertus, Kijprayoon, Suphansa, Ruangma, Ananya, Ngokpol, Suthatip, Tuamputsha, Samart, Filp, Ulrike, Pees, Anna, Taddei, Carlotta, Pekošak, Aleksandra, Gee, Antony D., Poot, Alex J., Gunay, Mine Silindir, Ozer, A. Yekta, Erdogan, Suna, Baysal, Ipek, Guilloteau, Denis, Chalon, Sylvie, Galli, Filippo, Artico, Marco, Taurone, Samanta, Bianchi, Enrica, Weintraub, Bruce D., Skudlinski, Mariusz, Signore, Alberto, Lepareur, Nicolas, Noiret, Nicolas, Hindré, François, Lacœuille, Franck, Benoist, Eric, Garin, Etienne, Trejo-Ballado, F., Zamora-Romo, E., Manrique-Arias, J. C., Gama-Romero, H M, Contreras-Castañon, G., Tecuapetla-Chantes, R. G., Avila-Rodriguez, M. A., Kvaternik, H., Hausberger, D., Zink, C., Rumpf, B., Aigner, R. M., Janković, Drina, Lakić, Mladen, Savić, Aleksandar, Ristić, Slavica, Nikolić, Nadežda, Vukadinović, Aleksandar, Sabo, Tibor J., Vranješ-Đurić, Sanja, Vranješ-Đurić, S., Janković, D., Nikolić, N., Goya, G. F., Calatayud, P., Spasojević, V., Antić, B., Goblet, David, Oxley, Ian, Abrunhosa, Antero, Kramer, Vasko, Vosjan, Maria, Spaans, Arnold, Vats, Kusum, Satpati, Drishty, Sarma, Haladhar D., Banerjee, Sharmila, Wojdowska, W., Pawlak, D. W., Parus, L. J., Garnuszek, P., Mikołajczak, R., Pijarowska-Kruszyna, J., Jaron, A., Kachniarz, A., Malkowski, B., Mikolajczak, R., Ilem-Ozdemir, Derya, Caglayan-Orumlu, Oya, Asikoglu, Makbule, Eveliina, Arponen, Semi, Helin, Timo, Saarinen, Simo, Vauhkala, Esa, Kokkomäki, Pertti, Lehikoinen, De Simone, Mariarosaria, Pascali, Giancarlo, Carzoli, Ludovica, Quaglierini, Mauro, Telleschi, Mauro, Salvadori, Piero A., Lam, Phoebe, Aistleitner, Martina, Eichinger, Reinhard, Artner, Christoph, Nakka, Surendra, MC, Hemantha Kumara, Al-Qahtani, Mohammed, Al-Malki, Yousif, Mambilima, N., Rubow, S. M., Berroterán-Infante, N., Lecina, Joan, Gallardo, Rodrigo, Verbruggen, Alfons M., Ramos-Membrive, Rocío, Brotons, Ana, Quincoces, Gemma, Inchaurraga, Laura, de Redín, Inés Luis, Morán, Verónica, García-García, Berta, Irache, Juan Manuel, Peñuelas, Iván, Trabelsi, M., Cooper, M. S., Abella, Alejandra, Fuente, Teodomiro, Montellano, Antonio Jesús, Martínez, Teresa, Rabadan, Ruben, Meseguer-Olmo, Luis, Lehtiniemi, P., Yim, C., Mikkola, K., Nuutila, P., Solin, O., Mair, C., Balogh, L., Pöstényi, Z., Pawlak, D., Socan, A., Peitl, P. Kolenc, Krošelj, M., Remy, S., Didier, R., Vergote, T., Véran, N., Maurin, M., Karczmarczyk, U., Fredericia, Pil, Severin, Gregory, Groesser, Torsten, Köster, Ulli, Jensen, Mikael, Leonte, R., Puicea, F. D., Raicu, A., Min, E. A., Serban, R., Manda, G., Niculae, D., Zerna, Marion, Schieferstein, Hanno, Müller, Andre, Berndt, Mathias, Yim, Cheng-Bin, Mikkola, Kirsi, Nuutila, Pirjo, Solin, Olof, Seifert, D., Ráliš, J., Lebeda, O., Selivanova, Svetlana V., Senta, Helena, Lavallée, Éric, Caouette, Lyne, Turcotte, Éric, Lecomte, Roger, Kochovska, Marina Zdraveska, Ivanovska, Emilija Janjevik, Jokic, Vesna Spasic, Ackova, Darinka Gjorgieva, Smilkov, Katarina, Makreski, Petre, Stafilov, Trajče, Janevik-Ivanovska, Emilija, Alemu, Aschalew, Muchira, Joel Munene, Wanjeh, David Mwanza, Zdravev, Zoran, Bhonsle, Uday, Alberto, Osso Júnior João, Duatti, Adriano, Angelovska, Bistra, Stojanovska, Zdenka, Sarafinovska, Zorica Arsova, Bosnakovski, Darko, Gorgieva-Ackova, Darinka, Drakalska, Elena, Venkatesh, Meera, Gulaboski, Rubin, Colin, Didier J., Inkster, James A. H., Germain, Stéphane, Seimbille, Yann, and Radyofarmasi

Subjects
Meeting Abstracts
Abstract

OP03 Selective extraction of medically-related radionuclides from proton-irradiated thorium targets, V. Radchenko, J.W. Engle, C. Roy, J. Griswold, M.F. Nortier, E.R. Birnbaum, M. Brugh, S. Mirzadeh, K. D. John, M.E. Fassbender, OP04 Comparison of [68Ga]FSC(succ-RGD)3 and [68Ga]NODAGA-RGD for PET imaging of αvβ3 integrin expression, Chuangyan Zhai, Gerben M. Franssen, Milos Petrik, Peter Laverman, Clemens Decristoforo, OP05 A new NPY-Y1R targeting peptide for breast cancer PET imaging, Ait-Mohand Samia, Dumulon-Perreault Véronique, Guérin Brigitte, OP06 The influence of multivalency on CCK 2 receptor targeting, D. Summer, A. Kroess, C. Rangger, H. Haas, P. Laverman, F. Gerben, E. von Guggenberg, C.Decristoforo, OP07 SPECT Imaging of αvβ3 Expression by [99mTc(N)PNP43]- Bifunctional Chimeric RGD Peptide not Cross-Reacting with αvβ5, Cristina Bolzati, Nicola Salvarese, Fiorenzo Refosco, Laura Meléndez-Alafort, Debora Carpanese, Antonio Rosato, Michele Saviano, Annarita Del Gatto, Daniela Comegna, Laura Zaccaro, OP09 New dienophiles for the inverse-electron-demand Diels-Alder reaction and for pretargeted PET imaging, Emilie Billaud, Muneer Ahamed, Frederik Cleeren, Elnaz Shahbazali, Tim Noël, Volker Hessel, Alfons Verbruggen and Guy Bormans, OP10 New complexing agent for Al18F-labelling of heat-sensitive biomolecules: Synthesis and preclinical evaluation of Al18F-RESCA1-HAS, Cleeren F, Lecina J, Koole M, Verbruggen A and Bormans G, OP11 A novel versatile precursor efficient for F-18 radiolabelling via click-chemistry, B. Lugatoa, S. Stucchia, E.A. Turollaa, L. Giulianoa, S.Toddea, P. Ferraboschib, OP12 A general applicable method to quantify unidentified UV impurities in radiopharmaceuticals, R.P. Klok, M.P.J. Mooijer, N.H. Hendrikse, A.D. Windhorst, OP13 Development of [18F]Fluoro-C-glycosides to radiolabel peptides, Collet C., Petry N., Chrétien F., Karcher G., Pellegrini-Moïse N., Lamandé-Langle S., OP14 A Microfluidic Approach for the 68Ga-labeling of PSMAHBED-CC and NODAGA-RGD, Sarah Pfaff, Cecile Philippe, Markus Mitterhauser, Marcus Hacker, Wolfgang Wadsak, OP16 Surprising reactivity of astatine in the nucleophilic substitution of aryliodonium salts: application to the radiolabeling of antibodies, François Guérard, Yong-Sok Lee, Sébastien Gouard, Kwamena Baidoo, Cyrille Alliot, Michel Chérel, Martin W. Brechbiel, Jean-François Gestin, OP17 64Cu-NOTA-pertuzumab F(ab')2 fragments, a second-generation probe for PET imaging of the response of HER2-positive breast cancer to trastuzumab (Herceptin), Lam K, Chan C, Reilly RM, OP18 Development of radiohalogenated analogues of a avb6-specific peptide for high LET particle emitter targeted radionuclide therapy of cancer, Salomé Paillas, John Marshall, Jean-Pierre Pouget, Jane Sosabowski, OP19 Ligand Specific Efficiency (LSE) as a guide in tracer optimization, Emmanuelle Briard, Yves P. Auberson, John Reilly, Mark Healy, David Sykes, OP23 The radiosynthesis of an 18F-labeled triglyceride, developed to visualize and quantify brown adipose tissue activity, Andreas Paulus, Wouter van Marken Lichtenbelt,Felix Mottaghy, Matthias Bauwens, OP24 Influence of the fluorescent dye on the tumor targeting properties of dual-labeled HBED-CC based PSMA inhibitors, Baranski, Ann-Christin, Schäfer, Martin, Bauder-Wüst, Ulrike, Haberkorn, Uwe, Eder, Matthias, Kopka, Klaus, OP25 [18F]MEL050 as a melanin PET tracer : fully automated radiosynthesis and evaluation for the detection of pigmented melanoma in mice pulmonary metastases, Chaussard M, Hosten B, Vignal N, Tsoupko-Sitnikov V, Hernio N, Hontonnou F, Merlet P, Poyet JL, Sarda-Mantel L, Rizzo-Padoin N, OP26 Design and Preclinical Evaluation of Novel Radiofluorinated PSMA Targeting Ligands Based on PSMA-617, J. Cardinale, M. Schäfer, M. Benešová, U. Bauder-Wüst, O. Seibert, F. Giesel, U. Haberkorn, M. Eder, K. Kopka, OP27 A novel radiolabeled peptide for PET imaging of prostate cancer: 64Cu-DOTHA2-PEG-RM26, Mansour Nematallah, Paquette Michel, Ait-Mohand Samia, Dumulon-Perreault Véronique, Lecomte Roger, Guérin Brigitte, OP29 Biodistribution of [18F]Amylovis®, a new radiotracer PET imaging of β-amyloid plaques, Fernandez-Maza L, Rivera-Marrero S, Prats Capote A, Parrado-Gallego A, Fernandez-Gomez I, Balcerzyk M, Sablon-Carrazana M, Perera-Pintado A, Merceron-Martinez D, Acosta-Medina E, Rodriguez-Tanty C, OP30 Synthesis and preclinical evaluation of [11C]-BA1 PET tracer for the imaging of CSF-1R, Bala Attili, Muneer Ahamed, Guy Bormans, OP31 In vivo imaging of the MCHR1 in the ventricular system via [18F]FE@SNAP, C. Philippe, M. Zeilinger, T. Scherer, C. Fürnsinn, M. Dumanic, W. Wadsak, M. Hacker, M. Mitterhauser, OP32 Synthesis of the first carbon-11 labelled P2Y12 receptor antagonist for imaging the anti-inflammatory phenotype of activated microglia, B. Janssen, D.J. Vugts, G.T. Molenaar, U. Funke, P.S. Kruijer, F. Dollé, G. Bormans, A.A. Lammertsma, A.D. Windhorst, OP33 Radiosynthesis of a selective HDAC6 inhibitor [11C]KB631 and in vitro and ex vivo evaluation, Koen Vermeulen, Muneer Ahamed, Michael Schnekenburger, Mathy Froeyen, Dag Erlend Olberg, Marc Diederich, Guy Bormansa, OP34 Improving metabolic stability of fluorine-18 labelled verapamil analogues, Raaphorst RM, Luurtsema G, Lammertsma AA, Elsinga PH, Windhorst AD, OP36 Development of a novel PET tracer for the activin receptor-like kinase 5, Lonneke Rotteveel, Uta Funke, Peter ten Dijke, Harm Jan Bogaard, Adriaan A. Lammertsma, Albert D. Windhorst, OP37 SPECT imaging and biodistribution studies of 111In-EGF-Au-PEG nanoparticles in vivo, Lei Song, Sarah Able, Nadia Falzone, Veerle Kersemans, Katherine Vallis, OP38 Melanoma targeting with [99mTc(N)(PNP3)]-labeled NAPamide derivatives: preliminary pharmacological studies, Davide Carta, Nicola Salvarese, Wiebke Sihver, Feng Gao, Hans Jürgen Pietzsch, Barbara Biondi, Paolo Ruzza, Fiorenzo Refosco, Cristina Bolzati, OP39 [68Ga]NODAGA-RGD: cGMP synthesis and data from a phase I clinical study, Roland Haubner, Armin Finkensted, Armin Stegmair, Christine Rangger, Clemens Decristoforo, Heinz Zoller, Irene J. Virgolin, OP44 Implementation of a GMP-grade radiopharmacy facility in Maastricht, Ivo Pooters, Maartje Lotz, Roel Wierts, Felix Mottaghy, Matthias Bauwens, OP45 Setting up a GMP production of a new radiopharmaceutical, Forsback, Sarita, Bergman Jörgen, Kivelä Riikka, OP48 In vitro and in vivo evaluation of 68-gallium labeled Fe3O4-DPD nanoparticles as potential PET/MRI imaging agents, M. Karageorgou, M. Radović, C. Tsoukalas, B. Antic, M. Gazouli, M. Paravatou-Petsotas, S. Xanthopouls, M. Calamiotou, D. Stamopoulos, S. Vranješ-Durić, P. Bouziotis, OP49 Fast PET imaging of inflammation using 68Ga-citrate with Fe-containing salts of hydroxy acids, A. S. Lunev, A. A. Larenkov, K.A. Petrosova, O. E. Klementyeva, G. E. Kodina, PP01 Installation and validation of 11C-methionine synthesis, Kvernenes, O.H., Adamsen, T.C.H., PP02 Fully automated synthesis of 68Ga-labelled peptides using the IBA Synthera® and Synthera® Extension modules, René Martin, Sebastian Weidlich, Anna-Maria Zerges, Cristiana Gameiro, Neva Lazarova, Marco Müllera, PP03 GMP compliant production of 15O-labeled water using IBA 18 MeV proton cyclotron, Gert Luurtsema, Michèl de Vries, Michel Ghyoot, Gina van der Woude, Rolf Zijlma, Rudi Dierckx, Hendrikus H. Boersma, Philip H. Elsinga, PP04 In vitro Nuclear Imaging Potential of New Subphthalocyanine and Zinc Phthalocyanine, Fatma Yurt Lambrecht, Ozge Er, Mine Ince, Cıgır Biray Avci, Cumhur Gunduz, Fatma Aslihan Sarı, PP05 Synthesis, Photodynamic Therapy Efficacy and Nuclear Imaging Potential of Zinc Phthalocyanines, Kasim Ocakoglu, Ozge Er, Onur Alp Ersoz, Fatma Yurt Lambrecht, Mine Ince, Cagla Kayabasi, Cumhur Gunduz, PP06 Radio-U(H)PLC – the Search on the Optimal Flow Cell for the γ-Detector, Torsten Kniess, Sebastian Meister, Steffen Fischer, Jörg Steinbach, PP07 Radiolabeling, characterization & biodistribution study of cysteine and its derivatives with Tc99m, Rabia Ashfaq, Saeed Iqbal, Atiq-ur-Rehman, Irfan ullah Khan, PP08 Radiolabelling of poly (lactic-co.glycolic acid) (PLGA) nanoparticles with 99mTC, R Iglesias-Jerez, Cayero-Otero, L. Martín-Banderas, A. Perera-Pintado, I. Borrego-Dorado, PP09 Development of [18F]PD-410 as a non-peptidic PET radiotracer for gastrin releasing peptide receptors, Ines Farinha-Antunes, Chantal Kwizera, Enza Lacivita, Ermelinda Lucente, Mauro Niso, Paola De Giorgio, Roberto Perrone, Nicola A. Colabufo, Philip H. Elsinga, Marcello Leopoldo, PP10 An improved nucleophilic synthesis of 2-(3,4-dimethoxyphenyl)-6-(2-[18F]fluoroethoxy) benzothiazole ([18F]FEDMBT), potential diagnostic agent for breast cancer imaging by PET, V.V. Vaulina, O.S. Fedorova, V.V. Orlovskaja, ?�.L. Chen, G.Y. Li, F.C. Meng, R.S. Liu, H.E. Wang, R.N. Krasikova, PP11 Internal radiation dose assessment of radiopharmaceuticals prepared with accelerator-produced 99mTc, Laura Meléndez-Alafort, Mohamed Abozeid, Guillermina Ferro-Flores, Anna Negri, Michele Bello, Nikolay Uzunov, Martha Paiusco, Juan Esposito, Antonio Rosato, PP12 A specialized five-compartmental model software for pharmacokinetic parameters calculation, Laura Meléndez-Alafort, Cristina Bolzati, Guillermina Ferro-Flores, Nicola Salvarese, Debora Carpanese, Mohamed Abozeid, Antonio Rosato, Nikolay Uzunov, PP13 Molecular imaging of the pharmacokinetic behavior of low molecular weight 18F-labeled PEtOx in comparison to 89Zr-labeled PEtOx, Palmieri L, Verbrugghen T, Glassner M, Hoogenboom R, Staelens S, Wyffels L, PP14 Towards nucleophilic synthesis of the α-[18F]fluoropropyl-L-dihydroxyphenylalanine, V. V. Orlovskaja, O. F. Kuznetsova, O. S. Fedorova, V. I. Maleev, Yu. N. Belokon, A. Geolchanyan, A. S. Saghyan, L. Mu, R. Schibli, S. M. Ametamey, R. N. Krasikova, PP15 A convenient one-pot synthesis of [18F]clofarabine, Revunov, Evgeny, Malmquist, Jonas, Johnström, Peter, Van Valkenburgh, Juno, Steele, Dalton, Halldin, Christer, Schou, Magnus, PP16 BODIPY-estradiol conjugates as multi-modality tumor imaging agents, Samira Osati,Michel Paquette,Simon Beaudoin,Hasrat Ali,Brigitte Guerin, Jeffrey V. Leyton, Johan E. van Lier, PP17 Easy and high yielding synthesis of 68Ga-labelled HBED-PSMA and DOTA-PSMA by using a Modular-Lab Eazy automatic synthesizer, Di Iorio V, Iori M, Donati C, Lanzetta V, Capponi PC, Rubagotti S, Dreger T, Kunkel F, Asti M, PP18 Synthesis and evaluation of fusarinine C-based octadentate bifunctional chelators for zirconium-89 labelling, Chuangyan Zhai, Christine Rangger, Dominik Summer, Hubertus Haas, Clemens Decristoforo, PP19 Fully automated production of [18F]NaF using a re-configuring FDG synthesis module., Suphansa Kijprayoon, Ananya Ruangma, Suthatip Ngokpol, Samart Tuamputsha, PP20 Extension of the Carbon-11 Small Labeling Agents Toolbox and Conjugate Addition, Ulrike Filp, Anna Pees, Carlotta Taddei, Aleksandra Pekošak, Antony D. Gee, Alex J. Poot, Albert D. Windhorst, PP21 In vitro studies on BBB penetration of pramipexole encapsulated theranostic liposomes for the therapy of Parkinson’s disease, Mine Silindir Gunay, A. Yekta Ozer, Suna Erdogan, Ipek Baysal, Denis Guilloteau, Sylvie Chalon, PP22 Factors affecting tumor uptake of 99mTc-HYNIC-VEGF165, Filippo Galli, Marco Artico, Samanta Taurone, Enrica Bianchi, Bruce D. Weintraub, Mariusz Skudlinski, Alberto Signore, PP23 Rhenium-188: a suitable radioisotope for targeted radiotherapy, Nicolas Lepareur, Nicolas Noiret, François Hindré, Franck Lacœuille, Eric Benoist, Etienne Garin, PP24 Preparation of a broad palette of 68Ga radiopharmaceuticals for clinical applications, Trejo-Ballado F, Zamora-Romo E, Manrique-Arias JC, Gama-Romero HM, Contreras-Castañon G, Tecuapetla-Chantes RG, Avila-Rodriguez MA, PP25 68Ga-peptide preparation with the use of two 68Ge/68Ga-generators, H. Kvaternik, D. Hausberger, C. Zink, B. Rumpf, R. M. Aigner, PP26 Assay of HEPES in 68Ga-peptides by HPLC, H. Kvaternik, D. Hausberger, B. Rumpf, R. M. Aigner, PP27 Preparation, in vitro and in vivo evaluation of a 99mTc(I)-Diethyl Ester (S,S)-Ethylenediamine- N,N´-DI-2-(3-Cyclohexyl) Propionic acid as a target-specific radiopharmaceutical, Drina Janković, Mladen Lakić, Aleksandar Savić, Slavica Ristić, Nadežda Nikolić, Aleksandar Vukadinović, Tibor J. Sabo, Sanja Vranješ-Đurić, PP28 90Y-labeled magnetite nanoparticles for possible application in cancer therapy, S. Vranješ-Đurić, M. Radović, D. Janković, N. Nikolić, G. F. Goya, P. Calatayud, V. Spasojević, B. Antić, PP29 Simplified automation of the GMP production of 68Ga-labelled peptides, David Goblet, Cristiana Gameiro, Neva Lazarova, PP30 Combining commercial production of multi-products in a GMP environment with Clinical & R&D activities, Cristiana Gameiro, Ian Oxley, Antero Abrunhosa, Vasko Kramer, Maria Vosjan, Arnold Spaans, PP31 99mTc(CO)3-labeling and Comparative In-Vivo Evaluation of Two Clicked cRGDfK Peptide Derivatives, Kusum Vats, Drishty Satpati, Haladhar D Sarma, Sharmila Banerjee, PP32 Application of AnaLig resin for 99mTc separation from molybdenum excess, Wojdowska W., Pawlak D.W., Parus L. J., Garnuszek P., Mikołajczak R., PP33 Constraints for selection of suitable precursor for one-step automated synthesis of [18F]FECNT, the dopamine transporter ligand, Pijarowska-Kruszyna J, Jaron A, Kachniarz A, Malkowski B, Garnuszek P, Mikolajczak R, PP34 Gamma scintigraphy studies with 99mTc- amoxicillin sodium in bacterially infected and sterile inflamed rats, Derya Ilem-Ozdemir, Oya Caglayan-Orumlu, Makbule Asikoglu, PP35 Preparation of 99mTc- Amoxicillin Sodium Lyophilized Kit, Derya Ilem-Ozdemir, Oya Caglayan-Orumlu, Makbule Asikoglu, PP36 Outfits of Tracerlan FXC-PRO for 11C-Labeling, Arponen Eveliina, Helin Semi, Saarinen Timo, Vauhkala Simo, Kokkomäki Esa, Lehikoinen Pertti, PP37 Microfluidic synthesis of ω-[18F]fluoro-1-alkynes, Mariarosaria De Simone, Giancarlo Pascali, Ludovica Carzoli, Mauro Quaglierini, Mauro Telleschi, Piero A. Salvadori, PP38 Automated 18F-flumazenil production using chemically resistant disposable cassettes, Phoebe Lam, Martina Aistleitner, Reinhard Eichinger, Christoph Artner, PP39 The effect of the eluent solutions (TBAHCO3, Kryptand K2.2.2) on the radiochemical yields of 18F-Fluoromethylcholine, Surendra Nakka, Hemantha Kumara MC, Al-Qahtani Mohammed, PP40 [68Ga]Radiolabeling of short peptide that has a PET imaging potentials, Al-Qahtani, Mohammed, Al-Malki, Yousif, PP41 Is validation of radiochemical purity analysis in a public hospital in a developing country possible?, N Mambilima, SM Rubow, PP42 Improved automated radiosynthesis of [18F]FEPPA, N. Berroterán-Infante, M. Hacker, M. Mitterhauser, W. Wadsak, PP43 Synthesis and initial evaluation of Al18F-RESCA1-TATE for somatostatin receptor imaging with PET, Uta Funke, Frederik Cleeren, Joan Lecina, Rodrigo Gallardo, Alfons M. Verbruggen, Guy Bormans, PP44 Radiolabeling and SPECT/CT imaging of different polymer-decorated zein nanoparticles for oral administration, Rocío Ramos-Membrive, Ana Brotons, Gemma Quincoces, Laura Inchaurraga, Inés Luis de Redín, Verónica Morán, Berta García-García, Juan Manuel Irache, Iván Peñuelas, PP45 An analysis of the quality of 68Ga-DOTANOC radiolabelling over a 3 year period, Trabelsi, M., Cooper M.S., PP46 In vivo biodistribution of adult human mesenchymal stem cells I (MSCS-ah) labeled with 99MTC-HMPAO administered via intravenous and intra-articular in animal model. Preliminary results, Alejandra Abella, Teodomiro Fuente, Antonio Jesús Montellano, Teresa Martínez, Ruben Rabadan, Luis Meseguer-Olmo, PP47 Synthesis of [18F]F-exendin-4 with high specific activity, Lehtiniemi P, Yim C, Mikkola K, Nuutila P, Solin O, PP48 Experimental radionuclide therapy with 177Lu-labelled cyclic minigastrin and human dosimetry estimations, von Guggenberg E, Rangger C, Mair C, Balogh L, Pöstényi Z, Pawlak D, Mikołajczak R, PP49 Synthesis of radiopharmaceuticals for cell radiolabelling using anion exchange column, Socan A, Kolenc Peitl P, Krošelj M, Rangger C, Decristoforo C, PP50 [68Ga]peptide production on commercial synthesiser mAIO, Collet C., Remy S., Didier R,Vergote T.,Karcher G., Véran N., PP51 Dry kit formulation for efficient radiolabeling of 68Ga-PSMA, D. Pawlak, M. Maurin, P. Garnuszek, U. Karczmarczyk, R. Mikołajczak, PP52 Development of an experimental method using Cs-131 to evaluate radiobiological effects of internalized Auger-electron emitters, Pil Fredericia, Gregory Severin, Torsten Groesser, Ulli Köster, Mikael Jensen, PP53 Preclinical comparative evaluation of NOTA/NODAGA/DOTA CYCLO-RGD peptides labelled with Ga-68, R. Leonte, F. D. Puicea, A. Raicu, E. A. Min, R. Serban, G. Manda, D. Niculae, PP54 Synthesizer- and Kit-based preparation of prostate cancer imaging agent 68Ga-RM2, Marion Zerna, Hanno Schieferstein, Andre Müller, Mathias Berndt, PP55 Synthesis of pancreatic beta cell-specific [18F]fluoro-exendin-4 via strain-promoted aza-dibenzocyclooctyne/azide cycloaddition, Cheng-Bin Yim, Kirsi Mikkola, Pirjo Nuutila, Olof Solin, PP56 Automated systems for radiopharmacy, D. Seifert, J. Ráliš, O. Lebeda, PP57 Simple, suitable for everyday routine use quality control method to assess radionuclidic purity of cyclotron-produced 99mTc, Svetlana V. Selivanova, Helena Senta, Éric Lavallée, Lyne Caouette, Éric Turcotte, Roger Lecomte, PP58 Effective dose estimation using Monte Carlo simulation for patients undergoing radioiodine therapy, Marina Zdraveska Kochovska, Emilija Janjevik Ivanovska, Vesna Spasic Jokic, PP59 Chemical analysis of the rituximab radioimmunoconjugates in lyophilized formulations intended for oncological applications, Darinka Gjorgieva Ackova, Katarina Smilkov, Petre Makreski, Trajče Stafilov, Emilija Janevik-Ivanovska, PP61 The need and benefits of established radiopharmacy in developing African countries, Aschalew Alemu, Joel Munene Muchira, David Mwanza Wanjeh, Emilija Janevik-Ivanovska, PP62 University Master Program of Radiopharmacy – step forward for Good Radiopharmacy Education, Emilija Janevik-Ivanovska, Zoran Zdravev, Uday Bhonsle, Osso Júnior João Alberto, Adriano Duatti, Bistra Angelovska, Zdenka Stojanovska, Zorica Arsova Sarafinovska, Darko Bosnakovski, Darinka Gorgieva-Ackova, Katarina Smilkov, Elena Drakalska, Meera Venkatesh, Rubin Gulaboski, PP63 Synthesis and preclinical validations of a novel 18F-labelled RGD peptide prepared by ligation of a 2-cyanobenzothiazole with 1,2-aminothiol to image angiogenesis., Didier J. Colin, James A. H. Inkster, Stéphane Germain, Yann Seimbille

Published
2016

24. Targeting IL-5Rα with antibody-conjugates reveals a strategy for imaging and therapy for invasive bladder cancer

Author

Paquette, Michel, primary, Vilera-Perez, Luis-Guillermo, additional, Beaudoin, Simon, additional, Ekindi-Ndongo, Nadia, additional, Boudreaut, Pierre-Luc, additional, Bonin, Marc-Andre, additional, Battista, Marie-Claude, additional, Bentourkia, M'hamed, additional, Lopez, Angel F., additional, Lecomte, Roger, additional, Marsault, Eric, additional, Guérin, Brigitte, additional, Sabbagh, Robert, additional, and Leyton, Jeffrey V., additional

Published
2017
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35. The human polynucleotide kinase/phosphatase (hPNKP) inhibitor A12B4C3 radiosensitizes human myeloid leukemia cells to Auger electron-emitting anti-CD123 111In-NLS-7G3 radioimmunoconjugates.

Author

Zereshkian, Arman, Leyton, Jeffrey V., Cai, Zhongli, Bergstrom, Dane, Weinfeld, Michael, and Reilly, Raymond M.

Subjects
*MYELOID leukemia, *LEUKEMIA treatment, *NUCLEIC acids, *PHOSPHATASE inhibitors, *RADIATION-sensitizing agents, *RADIATION immunology, *BIOCONJUGATES, *STEM cells
Abstract

Introduction: Leukemia stem cells (LSCs) are believed to be responsible for initiating and propagating acute myeloid leukemia (AML) and for causing relapse after treatment. Radioimmunotherapy (RIT) targeting these cells may improve the treatment of AML, but is limited by the low density of target epitopes. Our objective was to study a human polynucleotide kinase/phosphatase (hPNKP) inhibitor that interferes with DNA repair as a radiosensitizer for the Auger electron RIT agent, 111In-NLS-7G3, which recognizes the CD123+/CD131- phenotype uniquely displayed by LSCs. Methods: The surviving fraction (SF) of CD123+/CD131- AML-5 cells exposed to 111In-NLS-7G3 (33–266 nmols/L; 0.74MBq/μg) or to γ-radiation (0.25-5Gy) was determined by clonogenic assays. The effect of A12B4C3 (25 μmols/L) combined with 111In-NLS-7G3 (16–66 nmols/L) or with γ-radiation (0.25–2Gy) on the SF of AML-5 cells was assessed. The density of DNA double-strand breaks (DSBs) in the nucleus was measured using the γ-H2AX assay. Cellular dosimetry was estimated based on the subcellular distribution of 111In-NLS-7G3 measured by cell fractionation. Results: Binding of 111In-NLS-7G3 to AML-5 cells was reduced by 2.2-fold in the presence of an excess (1μM) of unlabeled NLS-7G3, demonstrating specific binding to the CD123+/CD131- epitope. 111In-NLS-7G3 reduced the SF of AML-5 cells from 86.1±11.0% at 33 nmols/L to 10.5±3.6% at 266 nmols/L. Unlabeled NLS-7G3 had no significant effect on the SF. Treatment of AML-5 cells with γ-radiation reduced the SF from 98.9±14.9% at 0.25Gy to 0.03±0.1% at 5Gy. A12B4C3 combined with 111In-NLS-7G3 (16–66 nmols/L) enhanced the cytotoxicity up to 1.7-fold compared to treatment with radioimmunoconjugates alone and was associated with a 1.6-fold increase in DNA DSBs in the nucleus. A12B4C3 enhanced the cytotoxicity of γ-radiation (0.25–0.5Gy) on AML-5 cells by up to 1.5-fold, and DNA DSBs were increased by 1.7-fold. Exposure to 111In-NLS-7G3 (66 nmols/L) delivered up to 0.6Gy to AML-5 cells. Conclusions: We conclude that A12B4C3 radiosensitized AML cells to the DNA damaging effects of 111In-NLS-7G3. Combination treatment may increase the effectiveness for Auger electron RIT of AML targeting the LSC subpopulation. [ABSTRACT FROM AUTHOR]

Published
2014
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36. Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development.

Author

Hammood, Manar, Craig, Andrew W., and Leyton, Jeffrey V.

Subjects
ANTIBODY-drug conjugates, ENDOCYTOSIS, EXOCYTOSIS, CANCER treatment, BIOLOGY, LYSOSOMES
Abstract

Biologically-based therapies increasingly rely on the endocytic cycle of internalization and exocytosis of target receptors for cancer therapies. However, receptor trafficking pathways (endosomal sorting (recycling, lysosome localization) and lateral membrane movement) are often dysfunctional in cancer. Antibody-drug conjugates (ADCs) have revitalized the concept of targeted chemotherapy by coupling inhibitory antibodies to cytotoxic payloads. Significant advances in ADC technology and format, and target biology have hastened the FDA approval of nine ADCs (four since 2019). Although the links between aberrant endocytic machinery and cancer are emerging, the impact of dysregulated internalization processes of ADC targets and response rates or resistance have not been well studied. This is despite the reliance on ADC uptake and trafficking to lysosomes for linker cleavage and payload release. In this review, we describe what is known about all the target antigens for the currently approved ADCs. Specifically, internalization efficiency and relevant intracellular sorting activities are described for each receptor under normal processes, and when complexed to an ADC. In addition, we discuss aberrant endocytic processes that have been directly linked to preclinical ADC resistance mechanisms. The implications of endocytosis in regard to therapeutic effectiveness in the clinic are also described. Unexpectedly, information on endocytosis is scarce (absent for two receptors). Moreover, much of what is known about endocytosis is not in the context of receptor-ADC/antibody complexes. This review provides a deeper understanding of the pertinent principles of receptor endocytosis for the currently approved ADCs. [ABSTRACT FROM AUTHOR]

Published
2021
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37. The Chemistry Behind ADCs.

Author

Kostova, Vesela, Désos, Patrice, Starck, Jérôme-Benoît, Kotschy, Andras, Leyton, Jeffrey V., and Barok, Mark

Subjects
ANTIBODY-drug conjugates, CONTROLLED release drugs, NANOMEDICINE, PHARMACEUTICAL chemistry, DRUG marketing
Abstract

Combining the selective targeting of tumor cells through antigen-directed recognition and potent cell-killing by cytotoxic payloads, antibody-drug conjugates (ADCs) have emerged in recent years as an efficient therapeutic approach for the treatment of various cancers. Besides a number of approved drugs already on the market, there is a formidable follow-up of ADC candidates in clinical development. While selection of the appropriate antibody (A) and drug payload (D) is dictated by the pharmacology of the targeted disease, one has a broader choice of the conjugating linker (C). In the present paper, we review the chemistry of ADCs with a particular emphasis on the medicinal chemistry perspective, focusing on the chemical methods that enable the efficient assembly of the ADC from its three components and the controlled release of the drug payload. [ABSTRACT FROM AUTHOR]

Published
2021
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38. Improving Receptor-Mediated Intracellular Access and Accumulation of Antibody Therapeutics—The Tale of HER2.

Author

Leyton, Jeffrey V.

Subjects
*ANTIBODY-drug conjugates, *IMMUNOGLOBULINS, *THERAPEUTICS, *CELL tumors, *LYSOSOMES
Abstract

Therapeutic anti-HER2 antibodies and antibody–drug conjugates (ADCs) have undoubtedly benefitted patients. Nonetheless, patients ultimately relapse—some sooner than others. Currently approved anti-HER2 drugs are expensive and their cost-effectiveness is debated. There is increased awareness that internalization and lysosomal processing including subsequent payload intracellular accumulation and retention for ADCs are critical therapeutic attributes. Although HER2 preferential overexpression on the surface of tumor cells is attractive, its poor internalization and trafficking to lysosomes has been linked to poor therapeutic outcomes. To help address such issues, this review will comprehensively detail the most relevant findings on internalization and cellular accumulation for approved and investigational anti-HER2 antibodies and ADCs. The improved clarity of the HER2 system could improve antibody and ADC designs and approaches for next-generation anti-HER2 and other receptor targeting agents. [ABSTRACT FROM AUTHOR]

Published
2020
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40. Solution-Phase Surface Modification in Intact Poly(dimethylsiloxane) Microfluidic Channels.

Author

Guodong Sui, Jinyi Wang, Chung-Cheng Lee, Weixing Lu, Lee, Stephanie P., Leyton, Jeffrey V., Wu, Anna M., and Hsian-Rong Tseng

Subjects
*OXIDATION, *MICROFLUIDICS, *CRYOSCOPY, *SOLUTION (Chemistry), *FUNCTIONAL groups, *MOLECULAR biology, *ORGANIC chemistry, *SURFACE chemistry, *IMMUNOASSAY
Abstract

An improved approach composed of an oxidation reaction in acidic H2O2 solution and a sequential silanization reaction using neat silane reagents for surface modification of poly(dimethylsiloxane) (PDMS) substrates was developed. This solution-phase approach is simple and convenient for some routine analytical applications in chemistry and biology laboratories and is designed for intact PDMS-based microfluidic devices, with no device postassembly required. Using this improved approach, two different functional groups, poly(ethylene glycol) (PEG) and amine (NH2), were introduced onto PDMS surfaces for passivation of nonspecific protein absorption and attachment of biomolecules, respectively. X-ray electron spectroscopy and temporal contact angle experiments were employed to monitor functional group transformation and dynamic characteristics of the PEG-grafted PDMS substrates; fluorescent protein solutions were introduced into the PEG-grafted PDMS microchannels to test their protein repelling characteristics. These analytical data indicate that the PEG-grafted PDMS surfaces exhibit improved short-term surface dynamics and robust long-term stability. The amino-grafted PDMS microchannels are also relatively stable and can be further activated for modifications with peptide, DNA, and protein on the surfaces of microfluidic channels. The resulting biomolecule-grafted PDMS microchannels can be utilized for cell immobilization and incubation, semiquantitative DNA hybridization, and immunoassay. [ABSTRACT FROM AUTHOR]

Published
2006
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41. NLS-cholic acid conjugation to IL-5Rα-specific antibody improves cellular accumulation and in vivo tumor-targeting properties in a bladder cancer model

Author

Steve Jean, Simon Beaudoin, Mylene-Annie Tremblay, Angel F. Lopez, Robert Sabbagh, Roger Lecomte, Brigitte Guérin, Michel Paquette, M'hamed Bentourkia, Jeffrey V. Leyton, Paquette, Michel, Beaudoin, Simon, Tremblay, Mylene-Annie, Jean, Steve, Lopez, Angel F, Lecomte, Roger, Guérin, Brigitte, Bentourkia, M'Hamed, Sabbagh, Robert, and Leyton, Jeffrey V

Subjects
0301 basic medicine, Immunoconjugates, Endosome, antibody conjugate, media_common.quotation_subject, Biomedical Engineering, Pharmaceutical Science, Bioengineering, Cholic Acid, Mice, SCID, 03 medical and health sciences, Drug Delivery Systems, 0302 clinical medicine, Mice, Inbred NOD, In vivo, Cell Line, Tumor, Interleukin-5 Receptor alpha Subunit, medicine, Animals, Humans, NLS, Tissue Distribution, Internalization, Receptor, media_common, Pharmacology, Bladder cancer, Chemistry, Organic Chemistry, technology, industry, and agriculture, interleukin 5 receptor alpha, medicine.disease, cholic acid, 030104 developmental biology, Copper Radioisotopes, Urinary Bladder Neoplasms, Cell culture, Positron-Emission Tomography, 030220 oncology & carcinogenesis, Cancer research, Intracellular, Biotechnology
Abstract

Receptor-mediated internalization followed by trafficking and degradation of antibody-conjugates (ACs) via the endosomal-lysosomal pathway is the major mechanism for delivering molecular payloads inside target tumor cells. Although a mainstay for delivering payloads with clinically approved ACs in cancer treatment and imaging, tumor cells are often able to decrease intracellular payload concentrations and thereby reduce the effectiveness of the desired application. Thus, increasing payload intracellular accumulation has become a focus of attention for designing next-generation ACs. We developed a composite compound (ChAcNLS) that enables ACs to escape endosome entrapment and route to the nucleus resulting in the increased intracellular accumulation as an interleukin-5 receptor α-subunit (IL-5Rα)-targeted agent for muscle invasive bladder cancer (MIBC). We constructed ⁶⁴Cu-A14-ChAcNLS, ⁶⁴Cu-A14-NLS, and ⁶⁴Cu-A14 and evaluated their performance by employing mechanistic studies for endosome escape coupled to nuclear routing and determining whether this delivery system results in improved ⁶⁴Cu cellular accumulation. ACs consisting of ∼20 ChAcNLS or NLS moieties per ⁶⁴Cu-A14 were prepared in good yield, high monomer content, and maintaining high affinity for IL-5Rα. Confocal microscopy analysis demonstrated ChAcNLS mediated efficient endosome escape and nuclear localization. ⁶⁴Cu-A14-ChAcNLS increased ⁶⁴Cu cellular accumulation in HT-1376 and HT-B9 cells relative to ⁶⁴Cu-A14 and ⁶⁴Cu-A14-NLS. In addition, we tested ⁶⁴Cu-A14-ChAcNLS in vivo to evaluate its tissue distribution properties and, ultimately, tumor uptake and targeting. A model of human IL-5Rα MIBC was developed by implanting NOD/SCID mice with subcutaneous HT-1376 or HT-B9MIBC tumors, which grow containing high and low IL-5Rα-positive tumor cell densities, respectively. ACs were intravenously injected, and daily blood sampling, biodistribution at 48 and 96 h, and positron emission tomography (PET) at 24 and 48 h were performed. Region of interest (ROI) analysis was also performed on reconstructed PET images. Pharmacokinetic analysis and biodistribution studies showed that ⁶⁴Cu-A14-ChAcNLS had faster clearance rates from the blood and healthy organs relative to ⁶⁴Cu-A14. However, ⁶⁴Cu-A14-ChAcNLS maintained comparable tumor accumulation relative to ⁶⁴Cu-A14. This resulted in ⁶⁴Cu-A14-ChAcNLS having superior tumor/normal tissue ratios at both 48 and 96 h biodistribution time points. Visualization of AC distribution by PET and ROI analysis confirmed that ⁶⁴Cu-A14-ChAcNLS had improved targeting of MIBC tumor relative to ⁶⁴Cu-A14. In addition, ⁶⁴Cu-A14 modified with only NLS had poor tumor targeting. This was a result of poor tumor uptake due to extremely rapid clearance. Thus, the overall findings in this model of human IL-5Rα-positive MIBC describe an endosome escape-nuclear localization cholic-acid-linked peptide that substantially enhances AC cellular accumulation and tumor targeting. Refereed/Peer-reviewed

Published
2018

42. Targeting IL-5Rα with antibody-conjugates reveals a strategy for imaging and therapy for invasive bladder cancer

Author

Luis-Guillermo Vilera-Perez, Michel Paquette, Robert Sabbagh, Pierre-Luc Boudreaut, Brigitte Guérin, Nadia Ekindi-Ndongo, Roger Lecomte, Angel F. Lopez, Marie-Claude Battista, Jeffrey V. Leyton, Marc-André Bonin, M'hamed Bentourkia, Eric Marsault, Simon Beaudoin, Paquette, Michel, Vilera-Perez, Luis-Guillermo, Beaudoin, Simon, Ekindi-Ndongo, Nadia, Boudreaut, Pierre-Luc, Bonin, Marc-Andre, Battista, Marie-Claude, Bentourkia, M'hamed, Lopez, Angel F, Lecomte, Roger, Marsault, Eric, Guérin, Brigitte, Sabbagh, Robert, and Leyton, Jeffrey V

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, Pathology, medicine.medical_specialty, medicine.drug_class, media_common.quotation_subject, Immunology, PET imaging, antibody-drug conjugates, Monoclonal antibody, lcsh:RC254-282, IL-5Ra, 03 medical and health sciences, invasive bladdercancer, 0302 clinical medicine, In vivo, medicine, Immunology and Allergy, il-5rα, Internalization, media_common, Original Research, Bladder cancer, medicine.diagnostic_test, business.industry, invasive bladder cancer, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Vinblastine, Immunoconjugate, 030104 developmental biology, Oncology, Positron emission tomography, 030220 oncology & carcinogenesis, pet imaging, Cancer research, Immunohistochemistry, business, lcsh:RC581-607, medicine.drug
Abstract

Despite the high interest and concern due to an increasing incidence and death rate, patients who develop muscle invasive bladder cancer (MIBC) have few options available. However, the past decade has produced many candidate bladder tumor-specific markers but further development of these markers is still needed for creating effective targeted medications to solve this urgent need. Interleukin-5 receptor α-subunit (IL-5Rα) has recently been reported to be involved in MIBC progression. Thus, we aimed to validate IL-5Rα as a target for antibody-conjugates to better manage patients with MIBC. Patients were recruited and their tumors were processed for IL-5Rα immunohistochemical analysis. NOD/SCID mice were also heterotopically implanted with the human MIBC HT-1376 and HT-B9 cell lines and established xenografts immunohistochemically evaluated for IL-5Rα and compared against patient tumors. Using the mAb A14, an antibody-drug conjugate (ADC) and a radiolabeled immunoconjugate (RIC) were developed by conjugating to vinblastine and to the positron emitter copper-64 ( 64 Cu), respectively. As a proof-of-concept for ADC and RIC efficacy, in vitro cytotoxicity and in vivo positron emission tomography (PET) imaging in tumor-bearing mice were performed, respectively. In addition, as rapid internalization and accumulation are important components for effective antibody-conjugates, we evaluated these aspects in response to IL-5 and 64 Cu-A14 treatments. Our findings suggest that although IL-5Rα protein expression is preferentially increased in MIBC, it is rapid IL-5Rα-mediated internalization allowing vinblastine-A14 to have cytotoxic activity and 64 Cu-A14 to detect MIBC tumors in vivo. This is the first report to elucidate the potential of IL-5Rα as an attractive MIBC target for antibody-conjugate applications. Refereed/Peer-reviewed

Published
2017

43. A Novel Proteomic Method Reveals NLS Tagging of T-DM1 Contravenes Classical Nuclear Transport in a Model of HER2-Positive Breast Cancer.

Author

Lacasse V, Beaudoin S, Jean S, and Leyton JV

Abstract

The next breakthrough for protein therapeutics is effective intracellular delivery and accumulation within target cells. Nuclear localization signal (NLS)-tagged therapeutics have been hindered by the lack of efficient nuclear localization due to endosome entrapment. Although development of strategies for tagging therapeutics with technologies capable of increased membrane penetration has resulted in proportional increased potency, nonspecific membrane penetration limits target specificity and, hence, widespread clinical success. There is a long-standing idea that nuclear localization of NLS-tagged agents occurs exclusively via classical nuclear transport. In the present study, we modified the antibody-drug conjugate trastuzumab-emtansine (T-DM1) with a classical NLS linked to cholic acid (cell accumulator [Accum]) that enables modified antibodies to escape endosome entrapment and increase nuclear localization efficiency without abrogating receptor targeting. In parallel, we developed a proteomics-based method to evaluate nuclear transport. Accum-modified T-DM1 significantly enhanced cytotoxic efficacy in the human epidermal growth factor receptor 2 (HER2)-positive SKBR3 breast cancer system. We discovered that efficacy was dependent on the nonclassical importin-7. Our evaluation reveals that when multiple classical NLS tagging occurs, cationic charge build-up as opposed to sequence dominates and becomes a substrate for importin-7. This study results in an effective target cell-specific NLS therapeutic and a general approach to guide future NLS-based development initiatives., (© 2020 The Author(s).)

Published
2020
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44. CD16 + NK-92 and anti-CD123 monoclonal antibody prolongs survival in primary human acute myeloid leukemia xenografted mice.

Author

Williams BA, Wang XH, Leyton JV, Maghera S, Deif B, Reilly RM, Minden MD, and Keating A

Subjects
Animals, GPI-Linked Proteins antagonists & inhibitors, GPI-Linked Proteins metabolism, Humans, Interleukin-3 Receptor alpha Subunit metabolism, K562 Cells, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Proteins metabolism, Receptors, IgG metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents, Immunological pharmacology, Interleukin-3 Receptor alpha Subunit antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Neoplasm Proteins antagonists & inhibitors, Receptors, IgG antagonists & inhibitors
Abstract

Patients with acute myeloid leukemia (AML) often relapse after initial therapy because of persistence of leukemic stem cells that frequently express the IL-3 receptor alpha chain CD123. Natural killer (NK) cell-based therapeutic strategies for AML show promise and we explore the NK cell lines, NK-92 and CD16 + NK-92, as a treatment for AML. NK-92 has been tested in phase I clinical trials with minimal toxicity; irradiation prior to infusion prevents risk of engraftment. The CD16 negative NK-92 parental line was genetically modified to express the high affinity Fc gamma receptor, enabling antibody-dependent cell-mediated cytotoxicity, which we utilized in combination with an anti-CD123 antibody to target leukemic stem cells. NK-92 was preferentially cytotoxic against leukemic stem and progenitor cells compared with bulk leukemia in in vitro assays, while CD16 + NK-92 in combination with an anti-CD123 mAb mediated antibody-dependent cell-mediated cytotoxicity against CD123 + leukemic targets. Furthermore, NK-92 infusions (with or without prior irradiation) improved survival in a primary AML xenograft model. Mice xenografted with primary human AML cells had a superior survival when treated with irradiated CD16 + NK-92 cells and an anti-CD123 monoclonal antibody (7G3) versus treatment with irradiated CD16 + NK-92 cells combined with an isotype control antibody. In this proof-of-principle study, we show for the first time that a CD16 + NK-92 cell line combined with an antibody that targets a leukemic stem cell antigen can lead to improved survival in a relevant pre-clinical model of AML., (Copyright © 2018 Ferrata Storti Foundation.)

Published
2018
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45. The human polynucleotide kinase/phosphatase (hPNKP) inhibitor A12B4C3 radiosensitizes human myeloid leukemia cells to Auger electron-emitting anti-CD123 ¹¹¹In-NLS-7G3 radioimmunoconjugates.

Author

Zereshkian A, Leyton JV, Cai Z, Bergstrom D, Weinfeld M, and Reilly RM

Subjects
Animals, Antibodies, Monoclonal chemistry, Cell Line, Tumor, Cell Survival drug effects, Cell Survival radiation effects, Clone Cells drug effects, Clone Cells pathology, Clone Cells radiation effects, Coordination Complexes chemistry, DNA Damage, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Humans, Immunoconjugates chemistry, Intracellular Space drug effects, Intracellular Space radiation effects, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells pathology, Neoplastic Stem Cells radiation effects, Pyrroles chemistry, Radiation-Sensitizing Agents chemistry, Radiation-Sensitizing Agents pharmacology, Radiometry, Antibodies, Monoclonal immunology, Coordination Complexes immunology, DNA Repair Enzymes antagonists & inhibitors, Electrons, Immunoconjugates pharmacology, Interleukin-3 Receptor alpha Subunit immunology, Leukemia, Myeloid pathology, Phosphotransferases (Alcohol Group Acceptor) antagonists & inhibitors, Pyrroles pharmacology
Abstract

Introduction: Leukemia stem cells (LSCs) are believed to be responsible for initiating and propagating acute myeloid leukemia (AML) and for causing relapse after treatment. Radioimmunotherapy (RIT) targeting these cells may improve the treatment of AML, but is limited by the low density of target epitopes. Our objective was to study a human polynucleotide kinase/phosphatase (hPNKP) inhibitor that interferes with DNA repair as a radiosensitizer for the Auger electron RIT agent, ¹¹¹In-NLS-7G3, which recognizes the CD123⁺/CD131⁻ phenotype uniquely displayed by LSCs., Methods: The surviving fraction (SF) of CD123⁺/CD131⁻ AML-5 cells exposed to ¹¹¹In-NLS-7G3 (33-266 nmols/L; 0.74MBq/μg) or to γ-radiation (0.25-5Gy) was determined by clonogenic assays. The effect of A12B4C3 (25 μmols/L) combined with ¹¹¹In-NLS-7G3 (16-66 nmols/L) or with γ-radiation (0.25-2Gy) on the SF of AML-5 cells was assessed. The density of DNA double-strand breaks (DSBs) in the nucleus was measured using the γ-H2AX assay. Cellular dosimetry was estimated based on the subcellular distribution of ¹¹¹In-NLS-7G3 measured by cell fractionation., Results: Binding of (111)In-NLS-7G3 to AML-5 cells was reduced by 2.2-fold in the presence of an excess (1μM) of unlabeled NLS-7G3, demonstrating specific binding to the CD123⁺/CD131⁻ epitope. ¹¹¹In-NLS-7G3 reduced the SF of AML-5 cells from 86.1 ± 11.0% at 33 nmols/L to 10.5 ± 3.6% at 266 nmols/L. Unlabeled NLS-7G3 had no significant effect on the SF. Treatment of AML-5 cells with γ-radiation reduced the SF from 98.9 ± 14.9% at 0.25Gy to 0.03 ± 0.1% at 5 Gy. A12B4C3 combined with ¹¹¹In-NLS-7G3 (16-66 nmols/L) enhanced the cytotoxicity up to 1.7-fold compared to treatment with radioimmunoconjugates alone and was associated with a 1.6-fold increase in DNA DSBs in the nucleus. A12B4C3 enhanced the cytotoxicity of γ-radiation (0.25-0.5Gy) on AML-5 cells by up to 1.5-fold, and DNA DSBs were increased by 1.7-fold. Exposure to ¹¹¹In-NLS-7G3 (66 nmols/L) delivered up to 0.6Gy to AML-5 cells., Conclusions: We conclude that A12B4C3 radiosensitized AML cells to the DNA damaging effects of ¹¹¹In-NLS-7G3. Combination treatment may increase the effectiveness for Auger electron RIT of AML targeting the LSC subpopulation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Published
2014
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46. Positron emission tomographic imaging of iodine 124 anti-prostate stem cell antigen-engineered antibody fragments in LAPC-9 tumor-bearing severe combined immunodeficiency mice.

Author

Fonge H and Leyton JV

Subjects
Animals, Antibodies chemistry, GPI-Linked Proteins immunology, Male, Mice, Mice, SCID, Antibodies immunology, Antigens, Neoplasm immunology, Iodine Radioisotopes, Neoplasm Proteins immunology, Positron-Emission Tomography methods, Prostatic Neoplasms diagnosis
Abstract

The humanized antibody (hu1G8) has been shown to localize to prostate stem cell antigen (PSCA) and image PSCA-positive xenografts. We previously constructed hu1G8 anti-PSCA antibody fragments and tested them for tumor targeting and the ability to image prostate cancer at early and late time points postinjection by positron emission tomography (PET). We now then compare the PET imaging and the radioactivity accumulation properties in prostate cancer tumors and nontarget tissues to determine the superior 124I-labeled hu1G8 antibody format. 124I-labeled diabody, minibody, scFv-Fc, scFv-Fc double mutant (DM), and parental IgG were administered into severe combined immunodeficiency (SCID) mice bearing LAPC-9 xenografts and followed by whole-body PET imaging of mice at preselected time points. Regions of interest were manually drawn around tumor and nontarget tissues and evaluated for radioactivity accumulation. The 124I-hu1G8 IgG has its best time point for tumor high-contrast imaging at 168 hours postinjection. The 124I-hu1G8 minibody at 44 hours postinjection results in superior tumor high-contrast imaging compared to the other antibody formats. The 124I-hu1G8 minibody at 44 hours postinjection also has comparable percent tumor radioactivity compared to 124I-hu1G8 IgG at 168 hours postinjection. The 124I-hu1G8 minibody is the best engineered hu1G8 antibody format for imaging prostate cancer.

Published
2013

47. ¹¹¹In-Bn-DTPA-nimotuzumab with/without modification with nuclear translocation sequence (NLS) peptides: an Auger electron-emitting radioimmunotherapeutic agent for EGFR-positive and trastuzumab (Herceptin)-resistant breast cancer.

Author

Fasih A, Fonge H, Cai Z, Leyton JV, Tikhomirov I, Done SJ, and Reilly RM

Subjects
Animals, Antibodies, Monoclonal, Humanized pharmacology, Breast Neoplasms metabolism, Cell Line, Tumor, DNA Damage radiation effects, Drug Resistance, Neoplasm, ErbB Receptors immunology, Female, Humans, Immunoconjugates therapeutic use, Mice, Nuclear Localization Signals, Pentetic Acid therapeutic use, Tissue Distribution, Trastuzumab, Antibodies, Monoclonal, Humanized therapeutic use, Breast Neoplasms radiotherapy, ErbB Receptors metabolism, Immunoglobulin G therapeutic use, Indium Radioisotopes therapeutic use, Pentetic Acid analogs & derivatives, Radioimmunotherapy
Abstract

Increased expression of epidermal growth factor receptors (EGFR) in breast cancer (BC) is often associated with trastuzumab (Herceptin)-resistant forms of the disease and represents an attractive target for novel therapies. Nimotuzumab is a humanized IgG(1) monoclonal antibody that is in clinical trials for treatment of EGFR-overexpressing malignancies. We show here that nimotuzumab derivatized with benzylisothiocyanate diethylenetriaminepentaacetic acid for labelling with the subcellular range Auger electron-emitter, (111)In and modified with nuclear translocation sequence (NLS) peptides ((111)In-NLS-Bn-DTPA-nimotuzumab) was bound, internalized and transported to the nucleus of EGFR-positive BC cells. Emission of Auger electrons in close proximity to the nucleus caused multiple DNA double-strand breaks which diminished the clonogenic survival (CS) of MDA-MB-468 cells that have high EGFR density (2.4 × 10(6) receptors/cell) to less than 3 %. (111)In-Bn-DTPA-nimotuzumab without NLS peptide modification was sevenfold less effective for killing MDA-MB-468 cells. (111)In-Bn-DTPA-nimotuzumab with/without NLS peptide modification were equivalently cytotoxic to MDA-MB-231 and TrR1 BC cells that have moderate EGFR density (5.4 × 10(5) or 4.2 × 10(5) receptors/cell, respectively) reducing their CS by twofold. MDA-MB-231 cells have intrinsic trastuzumab resistance due to low HER2 density, whereas TrR1 cells have acquired resistance despite HER2 overexpression. Biodistribution and microSPECT/CT imaging revealed that (111)In-NLS-Bn-DTPA-nimotuzumab exhibited more rapid elimination from the blood and lower tumour uptake than (111)In-Bn-DTPA-nimotuzumab. Tumour uptake of the radioimmunoconjugates in mice with MDA-MB-468 xenografts was high (8-16 % injected dose/g) and was blocked by administration of an excess of unlabelled nimotuzumab, demonstrating EGFR specificity. We conclude that (111)In-Bn-DTPA-nimotuzumab with/without NLS peptide modification are promising Auger electron-emitting radioimmunotherapeutic agents for EGFR-positive BC, but (111)In-Bn-DTPA-nimotuzumab may be preferred due to its higher tumour uptake in vivo.

Published
2012
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