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1. An adapted consensus protein design strategy for identifying globally optimal biotherapeutics

Author

Yanyun Liu, Kenny Tsang, Michelle Mays, Gale Hansen, Jeffrey Chiecko, Maureen Crames, Yangjie Wei, Weijie Zhou, Chase Fredrick, James Hu, Dongmei Liu, Douglas Gebhard, Zhong-Fu Huang, Akshita Datar, Anthony Kronkaitis, Kristina Gueneva-Boucheva, Daniel Seeliger, Fei Han, Saurabh Sen, Srinath Kasturirangan, Justin M. Scheer, Andrew E. Nixon, Tadas Panavas, Michael S. Marlow, and Sandeep Kumar

Subjects
Consensus protein design, biotherapeutics, bioinformatics, molecular modeling, developability, data science, Therapeutics. Pharmacology, RM1-950, Immunologic diseases. Allergy, RC581-607
Abstract

Biotherapeutic optimization, whether to improve general properties or to engineer specific attributes, is a time-consuming process with uncertain outcomes. Conversely, Consensus Protein Design has been shown to be a viable approach to enhance protein stability while retaining function. In adapting this method for a more limited number of protein sequences, we studied 21 consensus single-point variants from eight publicly available CD3 binding sequences with high similarity but diverse biophysical and pharmacological properties. All single-point consensus variants retained CD3 binding and performed similarly in cell-based functional assays. Using Ridge regression analysis, we identified the variants and sequence positions with overall beneficial effects on developability attributes of the CD3 binders. A second round of sequence generation that combined these substitutions into a single molecule yielded a unique CD3 binder with globally optimized developability attributes. In this first application to therapeutic antibodies, adapted Consensus Protein Design was found to be highly beneficial within lead optimization, conserving resources and minimizing iterations. Future implementations of this general strategy may help accelerate drug discovery and improve success rates in bringing novel biotherapeutics to market.

Published
2022
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2. Discovery Strategies to Maximize the Clinical Potential of T-Cell Engaging Antibodies for the Treatment of Solid Tumors

Author

Vladimir Voynov, Paul J. Adam, Andrew E. Nixon, and Justin M. Scheer

Subjects
T-cell engagers, bispecific antibodies, immunotherapy, oncology, antibody engineering, immunological synapse, Immunologic diseases. Allergy, RC581-607
Abstract

T-cell Engaging bispecific antibodies (TcEs) that can re-direct cytotoxic T-cells to kill cancer cells have been validated in clinical studies. To date, the clinical success with these agents has mainly been seen in hematologic tumor indications. However, an increasing number of TcEs are currently being developed to exploit the potent mode-of-action to treat solid tumor indications, which is more challenging in terms of tumor-cell accessibility and the complexity of the tumor microenvironment (TME). Of particular interest is the potential of TcEs as an immunotherapeutic approach for the treatment of non-immunogenic (often referred to as cold) tumors that do not respond to checkpoint inhibitors such as programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) antibodies. This has led to considerable discovery efforts for, firstly, the identification of tumor selective targeting approaches that can safely re-direct cytotoxic T-cells to cancer cells, and, secondly, bispecific antibodies and their derivatives with drug-like properties that promote a potent cytolytic synapse between T-cells and tumor cells, and in the most advanced TcEs, have IgG-like pharmacokinetics for dosing convenience. Based on encouraging pre-clinical data, a growing number of TcEs against a broad range of targets, and using an array of different molecular structures have entered clinical studies for solid tumor indications, and the first clinical data is beginning to emerge. This review outlines the different approaches that have been taken to date in addressing the challenges of exploiting the TcE mode-of-action for a broad range of solid indications, as well as opportunities for future discovery potential.

Published
2020
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3. Identification and characterization of an octameric PEG-protein conjugate system for intravitreal long-acting delivery to the back of the eye.

Author

Whitney Shatz, Philip E Hass, Nikhil Peer, Maciej T Paluch, Craig Blanchette, Guanghui Han, Wendy Sandoval, Ashley Morando, Kelly M Loyet, Vladimir Bantseev, Helen Booler, Susan Crowell, Amrita Kamath, Justin M Scheer, and Robert F Kelley

Subjects
Medicine, Science
Abstract

Innovative protein engineering and chemical conjugation technologies have yielded an impressive number of drug candidates in clinical development including >80 antibody drug conjugates, >60 bispecific antibodies, >35 Fc-fusion proteins and >10 immuno-cytokines. Despite these innovations, technological advances are needed to address unmet medical needs with new pharmacological mechanisms. Age-related eye diseases are among the most common causes of blindness and poor vision in the world. Many such diseases affect the back of the eye, where the inaccessibility of the site of action necessitates therapeutic delivery via intravitreal (IVT) injection. Treatments administered via this route typically have vitreal half-lives

Published
2019
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4. Antibodies with Weakly Basic Isoelectric Points Minimize Trade-offs between Formulation and Physiological Colloidal Properties

Author

Priyanka Gupta, Emily K. Makowski, Sandeep Kumar, Yulei Zhang, Justin M. Scheer, and Peter M. Tessier

Subjects
Immunoglobulin G, Drug Discovery, Antibodies, Monoclonal, Pharmaceutical Science, Molecular Medicine, Isoelectric Point, Complementarity Determining Regions, Article
Abstract

The widespread interest in antibody therapeutics has led to much focus on identifying antibody candidates with favorable developability properties. In particular, there is broad interest in identifying antibody candidates with highly repulsive self-interactions in standard formulations (e.g., low ionic strength buffers at pH 5-6) for high solubility and low viscosity. Likewise, there is also broad interest in identifying antibody candidates with low levels of non-specific interactions in physiological solution conditions (PBS, pH 7.4) to promote favorable pharmacokinetic properties. To what extent antibodies that possess both highly repulsive self-interactions in standard formulations and weak non-specific interactions in physiological solution conditions can be systematically identified remains unclear and is a potential impediment to successful therapeutic drug development. Here, we evaluate these two properties for 42 IgG1 variants based on the variable fragments (Fvs) from four clinical-stage antibodies and complementarity-determining regions from 10 clinical-stage antibodies. Interestingly, we find that antibodies with the strongest repulsive self-interactions in a standard formulation (pH 6 and 10 mM histidine) display the strongest non-specific interactions in physiological solution conditions. Conversely, antibodies with the weakest non-specific interactions under physiological conditions display the least repulsive self-interactions in standard formulations. This behavior can be largely explained by the antibody isoelectric point, as highly basic antibodies that are highly positively charged under standard formulation conditions (pH 5-6) promote repulsive self-interactions that mediate high colloidal stability but also mediate strong non-specific interactions with negatively charged biomolecules at physiological pH and vice versa for antibodies with negatively charged Fv regions. Therefore, IgG1s with weakly basic isoelectric points between 8 and 8.5 and Fv isoelectric points between 7.5 and 9 typically display the best combinations of strong repulsive self-interactions and weak non-specific interactions. We expect that these findings will improve the identification and engineering of antibody candidates with drug-like biophysical properties.

Published
2022
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6. Data from A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer

Author

Paul J. Adam, Justin M. Scheer, Andrew E. Nixon, Francesca Trapani, Craig Giragossian, Barbara Drobits-Handl, Vladimir Voynov, and Susanne Hipp

Abstract

Purpose:Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung carcinoma characterized by highly chemotherapy-resistant recurrence in the majority of patients. To effectively treat SCLC, we have developed a unique and novel IgG-like T-cell engaging bispecific antibody (ITE) that potently redirects T-cells to specifically lyse SCLC cells expressing Delta-like ligand 3 (DLL3), an antigen that is frequently expressed on the cell surface of SCLC cells, with no to very little detectable expression in normal tissues.Experimental Design:The antitumor activity and mode of action of DLL3/CD3 ITE was evaluated in vitro using SCLC cell lines and primary human effector cells and in vivo in an SCLC xenograft model reconstituted with human CD3+ T-cells.Results:Selective binding of DLL3/CD3 ITE to DLL3-positive tumor cells and T-cells induces formation of an immunological synapse resulting in tumor cell lysis and activation of T-cells. In a human T-cell engrafted xenograft model, the DLL3/CD3 ITE leads to an increase in infiltration of T-cells into the tumor tissue resulting in apoptosis of the tumor cells and tumor regression. Consistent with the mode of action, the DLL3/CD3 ITE treatment led to upregulation of PD-1, PD-L1, and LAG-3.Conclusions:This study highlights the ability of the DLL3/CD3 ITE to induce strictly DLL3-dependent T-cell redirected lysis of tumor cells and recruitment of T-cells into noninflamed tumor tissues leading to tumor regression in a preclinical in vivo model. These data support clinical testing of the DLL3/CD3 ITE in patients with SCLC.

Published
2023
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7. Supplemental Figures 1 - 8 from Antitumor Efficacy of a Bispecific Antibody That Targets HER2 and Activates T Cells

Author

Allen Ebens, Klara Totpal, Robert Kelley, Mark S. Dennis, Melissa R. Junttila, Justin M. Scheer, Bryan Irving, Andrew Polson, Christoph Spiess, Eric Stefanich, Gail Lewis Phillips, Elizabeth Luis, Judy Young, Guangmin Li, Mary Mathieu, Yijin Li, Bu-Er Wang, Diego Ellerman, Robyn Clark, Maria Hristopoulos, Jennifer Johnston, Ji Li, and Teemu T. Junttila

Abstract

Supplemental Fig. 1: Characteristics of T cell activation and killing induced by HER2-TDB. Supplemental Fig 2: Activation of T cells by HER2-TDB induces T cell proliferation. Supplemental Figure 3. Activity of HER2-TDB in NOD-SCID mice is dependent on human PBMCs. Supplemental Figure 4. TDB mediated killing by CD3-TG splenic T cells. Supplemental Figure 5. Effect of 4D5 on established mammary tumors in MMTV-huHER2 transgenic mice. CD3-TG T cells express both mouse and human CD3 on approximately 50% level of respective Balb/c mouse or human T cells. Supplemental Figure 6. Anti-tumor activity of HER2-TDB is T cell dependent. Supplemental Figure 7. T cells in CT26-HER2 tumors display CD69 activation marker. Supplemental Figure 8. CT-26-HER2 tumor infiltrating T cells express PD-1. CT-26-HER2 tumor cells express PD-L1.

Published
2023
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8. Enhanced delivery of antibodies across the blood-brain barrier via TEMs with inherent receptor-mediated phagocytosis

Author

Suzanne Edavettal, Pilar Cejudo-Martin, Bidisha Dasgupta, Danlin Yang, Matthew D. Buschman, Derrick Domingo, Kristof Van Kolen, Pharavee Jaiprasat, Renata Gordon, Keith Schutsky, Brian Geist, Natalie Taylor, Camille Helene Soubrane, Elisabeth Van Der Helm, Ann LaCombe, Zemeda Ainekulu, Eilyn Lacy, Jason Aligo, Jason Ho, Yingbo He, Peter F. Lebowitz, James T. Patterson, Justin M. Scheer, and Sanjaya Singh

Subjects
Blood-Brain Barrier, Receptors, Transferrin, Biological Transport, General Medicine, Transcytosis, Antibodies
Abstract

The near impermeability of the blood-brain barrier (BBB) and the unique neuroimmune environment of the CNS prevents the effective use of antibodies in neurological diseases. Delivery of biotherapeutics to the brain can be enabled through receptor-mediated transcytosis via proteins such as the transferrin receptor, although limitations such as the ability to use Fc-mediated effector function to clear pathogenic targets can introduce safety liabilities. Hence, novel delivery approaches with alternative clearance mechanisms are warranted.Binders that optimized transport across the BBB, known as transcytosis-enabling modules (TEMs), were identified using a combination of antibody discovery techniques and pharmacokinetic analyses. Functional activity of TEMs were subsequently evaluated by imaging for the ability of myeloid cells to phagocytose target proteins and cells.We demonstrated significantly enhanced brain exposure of therapeutic antibodies using optimal transferrin receptor or CD98 TEMs. We found that these modules also mediated efficient clearance of tau aggregates and HER2+ tumor cells via a non-classical phagocytosis mechanism through direct engagement of myeloid cells. This mode of clearance potentially avoids the known drawbacks of FcγR-mediated antibody mechanisms in the brain such as the neurotoxic release of proinflammatory cytokines and immune cell exhaustion.Our study reports a new brain delivery platform that harnesses receptor-mediated transcytosis to maximize brain uptake and uses a non-classical phagocytosis mechanism to efficiently clear pathologic proteins and cells. We believe these findings will transform therapeutic approaches to treat CNS diseases.This research was funded by Janssen, Pharmaceutical Companies of JohnsonJohnson.

Published
2021

9. Contributors

Author

Catherine Anne Abbott, Carmela R. Abraham, Hideki Adachi, Osao Adachi, Zach Adam, Michael W.W. Adams, Michael J. Adang, Ibrahim M. Adham, Patrizia Aducci, David A. Agard, Alexey A. Agranovsky, Tetsuya Akamatsu, Yoshinori Akiyama, Reidar Albrechtsen, Alí Alejo, Sean M. Amberg, Alexander Y. Amerik, Piti Amparyup, Felipe Andrade, Germán Andrés, Daniel M. Andrews, Robert K. Andrews, Toni M. Antalis, Colin S. Anthony, Naoya Aoki, Suneel S. Apte, Kazunari Arima, Gérard Arlaud, Raghuvir Krishnaswamy Arni, Pascal Arnoux, Nathan N. Aronson, Michel Arthur, Yasuhisa Asano, Paolo Ascenzi, Marina T. Assakura, David S. Auld, Veridiana de Melo Rodrigues Ávila, Francesc X. Avilés, William M. Awad, Anand K. Bachhawat, Shan Bai, Teaster T. Baird, S. Paul Bajaj, Susan C. Baker, Agnieszka Banbula, Alan J. Barrett, Jemima Barrowman, John D. Bartlett, Jörg W. Bartsch, Nikola Baschuk, Isolda P. Baskova, Jyotsna Batra, Karl Bauer, Ulrich Baumann, Wolfgang Baumeister, Cédric Bauvois, Alex Bayés, Anne Beauvais, Christoph Becker-Pauly, Tadhg P. Begley, Miklós Békés, Robert Belas, Daniah Beleford, Teruhiko Beppu, Ernst M. Bergmann, Bruno A. Bernard, Dominique Bernard, Michael C. Berndt, Giovanna Berruti, Colin Berry, Greg P. Bertenshaw, Christian Betzel, Chetana Bhaskarla, Manoj Bhosale, Gabriele Bierbaum, B. Bjarnason Jón, Michael Blaber, Michael J. Blackman, Alexander Blinkovsky, Jef D. Boeke, Matthew Bogyo, Stefan Bohn, Guy Boileau, Mike Boland, Tové C. Bolken, Judith S. Bond, Jan Bondeson, Javier Bordallo, Claudia Borelli, Tiago O. Botelho, Richard R. Bott, David G. Bourne, Niels Bovenschen, Ralph A. Bradshaw, Klaus Breddam, Keith Brew, Paul J. Brindley, Diane L. Brinkman, Collette Britton, Jeff R. Broadbent, Anne Broadhurst, Dieter Brómme, Murray Broom, Jeremy S. Brown, Mark A. Brown, Iris Bruchhaus, Barbara A. Burleigh, Kristin E. Burns, James F. Burrows, Michael J. Butler, David J. Buttle, Chelsea M. Byrd, Tony Byun, Sandrine Cadel, Conor R. Caffrey, Santiago Cal, Javier Caldentey, Thomas Candela, Clemente Capasso, Daniel R. Capriogilio, Vincenzo Carginale, Adriana Karaoglanovic Carmona, Vern B. Carruthers, Francis J. Castellino, Joseph J. Catanese, Bruce Caterson, George H. Caughey, Naimh X. Cawley, Tim E. Cawston, Juan José Cazzulo, Jijie Chai, Karl X. Chai, Olga Meiri Chaim, L.S. Chang, Julie Chao, Marie-Pierre Chapot-Chartier, Jean-Louis Charli, Paulette Charlier, Karen J. Chave, Jian-Min Chen, Jinq-May Chen, Li-Mei Chen, Ya-Wen Chen, Yu-Yen Chen, Bernard Chevrier, Jean-François Chich, Jeremy Chien, Suneeta Chimalapati, Ki Joon Cho, Kwan Yong Choi, Woei-Jer Chuang, Chin Ha Chung, Ivy Yeuk Wah Chung, Christine Clamagirand, Ian M. Clark, Adrian K. Clarke, Nicola E. Clarke, Steven Gerard Clarke, Philippe Clauziat, Judith A. Clements, Catherine Coffinier, Paul Cohen, Alain Colige, Anne Collignon, Sean D. Colloms, Andreas Conzelmann, Graham H. Coombs, Jakki C. Cooney, Jonathan B. Cooper, Max D. Cooper, Nikki A. Copeland, Graeme S. Cottrell, Joseph T. Coyle, Charles S. Craik, John W.M. Creemers, Daniela Cretu, Jenifer Croce, Keith J. Cross, Rosario Cueva, Sheng Cui, Luis Cunha, Simon Cutting, Christophe d’Enfert, Hugues D’Orchymont, Björn Dahlbäck, Shujia Dai, Ross E. Dalbey, John P. Dalton, Pam M. Dando, R.M. Daniel, Sergei M. Danilov, Donna E. Davies, Heloisa S. De Araujo, Teresa De los Santos, Viviana de Luca, Ingrid De Meester, Ana Karina de Oliveira, Eduardo Brandt de Oliveira, Pedro Lagerblad De Oliveira, Sarah de Vos, Jeroen Declercq, Wim Declercq, Ala-Eddine Deghmane, Niek Dekker, Sonia Del Prete, Marina Del Rosal, Bernard Delmas, Robert DeLotto, Ilya V. Demidyuk, Mark R. Denison, Jan M. Deussing, Lakshmi A. Devi, Eleftherios P. Diamandis, Isabel Diaz, Araceli Díaz-Perales, Bauke W. Dijkstra, Yan Ding, Jack E. Dixon, Johannes Dodt, Terje Dokland, Iztok Dolenc, Ningzheng Dong, Tran Cat Dong, Ying Dong, Mitesh Dongre, Mark Donovan, Timothy M. Dore, Loretta Dorstyn, Hong Dou, Zhicheng Dou, Annette M. Dougall, Marcin Drag, Edward G. Dudley, Ben M. Dunn, Bruno Dupuy, Maria Conceicāo Duque-Magalhāes, M. Asunción Durá, Yves Eeckhout, Vincent Eijsink, Arthur Z. Eisen, Azza Eissa, Sandra Eklund, Ziad M. Eletr, Vincent Ellis, Wolfgang Engel, Ervin G. Erdös, Teresa Escalante, David A. Estell, Michael Etscheid, Herbert J. Evans, Roger D. Everett, Alex C. Faesen, Falk Fahrenholz, Miriam Fanjul-Fernández, Christopher J. Farady, Georges Feller, Hong Feng, Kurt M. Fenster, Claude Férec, Silvia Ferrari, Barbara Fingleton, Jed F. Fisher, Paula M. Fives-Taylor, Loren G. Fong, F. Forneris, Brian M. Forster, Friedrich Forster, Simon J. Foster, Thierry Foulon, Stephen I. Foundling, Jay William Fox, Bruno Franzetti, Alejandra P. Frasch, Hudson H. Freeze, Jean-Marie Frère, Teryl K. Frey, Beate Fricke, Lloyd D. Fricker, Rafael Fridman, Christopher J. Froelich, Camilla Fröhlich, Hsueh-Liang Fu, Cynthia N. Fuhrmann, Satoshi Fujimura, Hiroshi Fujiwara, Jun Fukushima, Keiichi Fukuyama, Robert S. Fuller, Martin Fusek, Christine Gaboriaud, Christian Gache, Oleksandr Gakh, Peter Gal, Junjun Gao, Adolfo García-Sastre, Donald L. Gardiner, John A. Gatehouse, G.M. Gaucher, Francis Gauthier, Jean-Marie Ghuysen, Wade Gibson, Jennifer Gillies, Elzbieta Glaser, Fabian Glaser, Michael H. Glickman, Peter Goettig, Colette Goffin, Eiichi Gohda, Alfred L. Goldberg, Daniel E. Goldberg, Gregory I. Goldberg, Nathan E. Goldfarb, F. Xavier Gomis-Rüth, B. Gopal, Alexander E. Gorbalenya, Stuart G. Gordon, Mark D. Gorrell, Friedrich Götz, Theodoros Goulas, Cécile Gouzy-Darmon, K. Govind, Lászlo Gráf, Robert R. Granados, Melissa Ann Gräwert, Douglas A. Gray, Thomas P. Graycar, Jonathan A. Green, Luiza Helena Gremski, Michael Groll, Tania Yu Gromova, P. Gros, Marvin J. Grubman, Amy M. Grunden, Ágústa Gudmundsdóttir, Micheline Guinand, Djamel Gully, Alla Gustchina, José María Gutiérrez, Byung Hak Ha, Jesper Z. Haeggström, James H. Hageman, Johanna Haiko, Stephan Hailfinger, Hans Michael Haitchi, Ji Seon Han, Chantal Hanquez, Minoru Harada, Ikuko Hara-Nishimura, Marianne Harboe, Torleif Härd, David A. Harris, Ulrich Hassiepen, Shoji Hata, Akira Hattori, Rong-Qiao He, Albert J.R. Heck, Dirk F. Hendricks, Bernhard Henrich, Patrick Henriet, Andrés Hernández-Arana, Irma Herrera-Camacho, Gerhard Heussipp, Toshihiko Hibino, P.M. Hicks, Bradley I. Hillman, B. Yukihiro Hiraoka, Jun Hiratake, Yohei Hizukuri, Heng-Chien Ho, Ngo Thi Hoa, Mark Hochstrasser, Kathryn M. Hodge, Theo Hofmann, Thomas Hohn, John R. Hoidal, Joachim-Volker Höltje, Koichi J. Homma, John F. Honek, Vivian Y.H. Hook, John D. Hooper, Nigel M. Hooper, Kazuo Hosoi, Christopher J. Howe, Dennis E. Hruby, James J.-D. Hseih, Chun-Chieh Hsu, Tony T. Huang, Tur-Fu Huang, Yoann Huet, Clare Hughes, Jean-Emmanuel Hugonnet, Adrienne L. Huston, Oumaïma Ibrahim-Granet, Eiji Ichishima, Yukio Ikehara, Tadashi Inagami, Jessica Ingram, R.E. Isaac, Grazia Isaya, Clara E. Isaza, Shin-ichi Ishii, Amandine Isnard, Kiyoshi Ito, Koreaki Ito, Yoshifumi Itoh, Xavier Iturrioz, Sadaaki Iwanaga, Ralph W. Jack, Mel C. Jackson, Michael N.G. James, Jiří Janata, Claire Janoir, Hanna Janska, Ken F. Jarrell, Mariusz Jaskolski, Sheila S. Jaswal, Ying Y. Jean, Dieter E. Jenne, Young Joo Jeon, Ping Jiang, John E. Johnson, Michael D. Johnson, James A. Johnston, Amanda Jones, Elizabeth W. Jones, Carine Joudiou, Luiz Juliano, Hea-Jin Jung, Ray Jupp, Todd F. Kagawa, Hubert Kalbacher, Yayoi Kamata, Shuichi Kaminogawa, Yoshiyuki Kamio, Makoto Kaneda, Sung Gyun Kang, Sung Hwan Kang, Mary Kania, Tomasz Kantyka, Nobuyuki Kanzawa, Abdulkarim Y. Karim, Takafumi Kasumi, Hiroaki Kataoka, Hardeep Kaur, Shun-Ichiro Kawabata, Mari Kawaguchi, John Kay, Murat Kaynar, Kenneth C. Keiler, R.M. Kelly, Nathaniel T. Kenton, Michael A. Kerr, Kristof Kersse, Jukka Kervinen, Benedikt M. Kessler, Efrat Kessler, Timo K. Khoronen, Simon Kidd, Marjolein Kikkert, Mogens Kilian, Do-Hyung Kim, Doyoun Kim, Eunice EunKyeong Kim, In Seop Kim, Jung-Gun Kim, Kyeong Kyu Kim, Kyung Hyun Kim, Matthew S. Kimber, Yukio Kimura, Heidrun Kirschke, Yoshiaki Kiso, Colin Kleanthous, Jürgen R. Klein, Michael Klemba, Beata Kmiec, Hideyuki Kobayashi, Hiroyuki Kodama, Gerald Koelsch, Jan Kok, P.E. Kolattukody, Fabrice A. Kolb, Harald Kolmar, Yumiko Komori, Jan Konvalinka, Brice Korkmaz, Sergey V. Kostrov, Hans-Georg Kräusslich, Gabi Krczal, Lawrence F. Kress, Magnüs Már Kristjánsson, Tomáš Kučera, Sayali S. Kukday, Hidehiko Kumagai, Sharad Kumar, Malika Kumarasiri, Takashi Kumazaki, Beate M. Kümmerer, Kouji Kuno, Markku Kurkinen, Eva Kutejová, Marie Kveiborg, Agnieszka Kwarciak, Liisa Laakkonen, Nikolaos E. Labrou, Gavin D. Laing, Gayle Lamppa, Thomas Langer, Richard A. Laursen, Richard A. Lawrenson, Matthew D. Layne, Bernard F. Le Bonniec, María C. Leal, Ronald M. Lechan, David H. Lee, Irene Lee, Jae Lee, Kye Joon Lee, Soohee Lee, Xiaobo Lei, Jonathan Leis, Ellen K. LeMosy, Thierry Lepage, Stephen H. Leppla, Adam Lesner, Ivan A.D. Lessard, Guy Lhomond, Huilin Li, Shu-Ming Li, Weiguo Li, Ta-Hsiu Liao, Robert C. Liddington, Toby Lieber, H.R. Lijnen, Christopher D. Lima, Chen-Yong Lin, Gang Lin, Ming T. Lin, Xinli Lin, Yee-Shin Lin, L.L. Lindsay, William N. Lipscomb, John W. Little, Ching-Chuan Liu, Chuan-ju Liu, Mark O. Lively, Nurit Livnat-Levanon, Per O. Ljungdahl, Catherine Llorens-Cortes, Peter Lobel, Y. Peng Loh, Jouko Lohi, G.P. Lomonossoff, Yvan Looze, Carlos López-Otin, Landys Lopez-Quezada, Alex Loukas, Long-Sheng Lu, Áke Lundwall, Liu-Ying Luo, Andrei Lupas, Dawn S. Luthe, Nicholas J. Lynch, Peter J. Lyons, Vivian L. MacKay, Jesica M. Levingston Macleod, Viktor Magdolen, Jean-Luc Mainardi, Kauko K. Mäkinen, Jeremy P. Mallari, Surya P. Manandhar, Fajga R. Mandelbaum, Anne M. Manicone, Johanna Mansfeld, Joseph Marcotrigiano, Michael Mares, Gemma Marfany, Francis S. Markland, Judith Marokházi, Hélène Marquis, Robert A. Marr, Enzo Martegani, Erik W. Martin, Manuel Martinez, L. Miguel Martins, Masato Maruyama, Masugi Maruyama, Sususmu Maruyama, Takeharu Masaki, Ramin Massoumi, Rency T. Mathew, Lynn M. Matrisian, Yoshihiro Matsuda, Osamu Matsushita, Marco Matuschek, Anna Matušková, Krisztina Matúz, Cornelia Mauch, Michael R. Maurizi, Lorenz M. Mayr, Dewey G. McCafferty, J. Ken McDonald, James H. McKerrow, David McMillan, Robert P. Mecham, Darshini P. Mehta, Chris Meisinger, Alan Mellors, Roger G. Melton, Jeffrey A. Melvin, Robert Ménard, Luis Menéndez-Arias, Milene C. Menezes, Andrew Mesecar, Stéphane Mesnage, Diane H. Meyer, Gregor Meyers, Susan Michaelis, Karolina Michalska, Wojciech P. Mielicki, Igor Mierau, Galina V. Mikoulinskaia, Charles G. Miller, Lydia K. Miller, John Mills, Kenneth V. Mills, Jinrong Min, Michel-Yves Mistou, Yoshio Misumi, Shin-ichi Miyoshi, Shigehiko Mizutani, Shahriar Mobashery, Satsuki Mochizuki, William L. Mock, Frank Möhrlen, Nathalie Moiré, Paul E. Monahan, Angela Moncada-Pazos, Véronique Monnet, Michel Monod, Cesare Montecucco, Laura Morelli, Sumiko Mori, Takashi Morita, James H. Morrissey, Richard J. Morse, John S. Mort, Uffe H. Mortensen, Rory E. Morty, Joel Moss, Hidemasa Motoshima, Jeremy C. Mottram, Ana M. Moura-da-Silva, Mary Beth Mudgett, Egbert Mundt, Kazuo Murakami, Mario Tyago Murakami, Kimiko MurakamiMurofoshi, Sawao Murao, Gillian Murphy, M.R.N. Murthy, Tatsushi Muta, Elmarie Myburgh, Nino Mzhavia, A.H.M. Nurun Nabi, Hideaki Nagase, Michael W. Nagle, Dorit K. Nägler, Rajesh R. Naik, Divya B. Nair, Toshiki Nakai, Yoshitaka Nakajima, Yukio Nakamura, Hitoshi Nakatogawa, Toru Nakayama, Natalia N. Nalivaeva, Dipankar Nandi, Maria Clara Leal Nascimento-Silva, Kim Nasmyth, Carl F. Nathan, Fernando Navarro-García, Dayane Lorena Naves, Danny D. Nedialkova, Keir C. Neuman, Jeffrey-Tri Nguyen, Ky-Anh Nguyen, Gabriela T. Niemirowicz, Toshiaki Nikai, Eiichiro Nishi, Wataru Nishii, Makoto Nishiyama, Yasuhiro Nishiyama, Masatoshi Noda, Seiji Nomura, Shigemi Norioka, Desire M.M. Nsangou, Amornrat O’Brien, Michael B. O’Connor, Kohei Oda, Irina V. Odinokova, Joyce Oetjen, Teru Ogura, Dennis E Ohman, Yoshinori Ohsumi, Mukti Ojha, Akinobu Okabe, Yasunori Okada, Keinosuke Okamoto, Kenji Okuda, Nobuaki Okumura, Takashi Okuno, Kjeld Oleson, Priscila Oliveira de Giuseppe, Martin Olivier, Yasuko Ono, Stephen Oroszlan, Nobuyuki Ota, Michael Ovadia, Jiyang O-Wang, Claus Oxvig, Jeremy C.L. Packer, Sergio Padilla-López, Mark Paetzel, Michael J. Page, Andrea Page-McCaw, Mark J.I. Paine, Byoung Chul Park, Eunyong Park, John E. Park, Pyong Woo Park, Sung Goo Park, Kirk L. Parkin, William C Parks, Thaysa Paschoalin, Annalisa Pastore, Alexander Nikolich Patananan, Sudhir Paul, Henry L. Paulson, Ulrich von Pawel-Rammingen, David A. Pearce, Mark S. Pearson, Duanqing Pei, Gunnar Pejler, Alan D. Pemberton, Jianhao Peng, Julien Pernier, Jan-Michael Peters, Thorsten Pfirrmann, Viet-Laï Pham, Iva Pichová, Darren Pickering, Christophe Piesse, David Pignol, Robert N. Pike, Lothaire Pinck, Hubert Pirkle, Henry C. Pitot, Andrew G. Plaut, Hidde Ploegh, László Polgár, Corrine Porter, Rolf Postina, Jan Potempa, Knud Poulsen, Scott D. Power, Rex. F. Pratt, Gerd Prehna, Gilles Prévost, Alexey V. Pshezhetsky, Mohammad A. Qasim, Feng Qian, Jiazhou Qiu, Víctor Quesada, Evette S. Radisky, Stephen D. Rader, Kavita Raman, Andrew J. Ramsay, Derrick E. Rancourt, Najju Ranjit, Narayanam V. Rao, Kiira Ratia, Neil D. Rawlings, Robert B. Rawson, Vijay Reddy, Colvin M. Redman, Maria Elena Regonesi, Andreas S. Reichert, Antonia P. Reichl, Han Remaut, S. James Remington, Martin Renatus, David Reverter, Eric C. Reynolds, Mohamed Rholam, Charles M. Rice, Todd W. Ridky, Howard Riezman, D.C. Rijken, Marie-Christine Rio, Alison Ritchie, Janine Robert-Baudouy, Mark W. Robinson, Michael Robinson, Adela Rodriguez-Romero, Renata Santos Rodriques, John C. Rogers, Camilo Rojas, Floyd E. Romesberg, David J. Roper, Nora Rosas-Murrieta, A.M. Rose, Philip J. Rosenthal, J. Rosing, Ornella Rossetto, Véronique Rossi, Richard A. Roth, Hanspeter Rottensteiner, Andrew D. Rowan, Mikhail Rozanov, Alexandra Rucavado, Andrea Ruecker, Françoise Rul, Till Rümenapf, Ilaria Russo, Martin D. Ryan, Elena Sacco, J. Evan Sadler, W. Saenger, Hans-Georg Sahl, Mohammed Sajid, Masayoshi Sakaguchi, Fumio Sakiyama, Maria L. Salas, Maria Cristina O. Salgado, Guy S. Salvesen, Edith Sánchez, Eladio F. Sanchez, Qing-Xiang Amy Sang, Krishnan Sankaran, Susanta K. Sarkar, Michael P. Sarras, Yoshikiyo Sasagawa, Araki Satohiko, Eric Sauvage, Loredana Saveanu, H.S. Savithri, Hitoshi Sawada, R. Gary Sawers, Isobel A. Scarisbrick, Andreas Schaller, Justin M. Scheer, Friedrich Scheiflinger, Cordelia Schiene-Fischer, Uwe Schlomann, Manfred Schlösser, Alvin H. Schmaier, Walter K. Schmidt, Anette Schneemann, Rick G. Schnellmann, Henning Scholze, Lutz Schomburg, Wilhelm J. Schwaeble, Christopher J. Scott, Rosaria Scudiero, Atsuko Sehara-Fujisawa, Nabil G. Seidah, Motoharu Seiki, Junichi Sekiguchi, Andrea Senff-Ribeiro, Ihn Sik Seong, Mihaela Serpe, Solange M.T. Serrano, Peter Setlow, Tina Shahian, M. Shanks, Feng Shao, Steven D. Shapiro, Navneet Sharma, Lindsey N. Shaw, Aimee Shen, Lei Shen, Roger F. Sherwood, Yun-Bo Shi, Hitoshi Shimoi, Yoichiro Shimura, A.D. Shirras, Viji Shridhar, Jinal K. Shukla, Ene Siigur, Jüri Siigur, Natalie C. Silmon de Monerri, Robert B. Sim, James P. Simmer, William H. Simmons, Jaspreet Singh, Alison Singleton, Tatiana D. Sirakova, Titia K. Sixma, Tim Skern, Randal A. Skidgel, Jeffrey Slack, David E. Sleat, Barbara S. Slusher, Janet L. Smith, Matthew A. Smith, Mark J. Smyth, Erik J. Snijder, Solmaz Sobhanifar, Kenneth Söderhaäll, Istvan Sohar, Peter Sonderegger, Marcos Henrique Ferreira Sorgine, Hiroyuki Sorimachi, Karen E. Soukhodolets, Tatiana de Arruda Campos Brasil de Souza, Tamás Sperka, Shiranee Sriskandan, Joseph W. St. Geme, Raymond J. St. Leger, Peter Staib, James L. Steele, Bjarki Stefansson, Christian Steinkühler, Leisa M. Stenberg, Johan Stenflo, Henning R. Stennicke, Valentin M. Stepanov, Olga A. Stepnaya, Frank Steven, Richard L. Stevens, Kenneth J. Stevenson, Mathieu St-Louis, Christopher C. Stobart, Walter Stöcker, Andrew C. Storer, Norbert Sträter, Ellen G. Strauss, James H. Strauss, Kvido Stříšovský, Natalie C.J. Strynadka, Edward D. Sturrock, Dan Su, Xiao-Dong Su, Paz Suárez-Rendueles, Traian Sulea, Venkatesh Sundararajan, Ryoji Suno, Carolyn K. Suzuki, Fumiaki Suzuki, Hideyuki Suzuki, Nobuhiro Suzuki, Stephen Swenson, Rose L. Szabady, Pal Bela Szecsi, Lászlo Szilágyi, Muhamed-Kheir Taha, Eizo Takahashi, Kenji Takahashi, Toshiro Takai, Atsushi Takeda, Soichi Takeda, Jeremy J.R.H. Tame, Tomohiro Tamura, Fulong Tan, Keiji Tanaka, Carmen Tanase, Jordan Tang, Martha M. Tanizaki, Egbert Tannich, Guido Tans, Anthony L. Tarentino, Anchalee Tassanakajon, Hiroki Tatsumi, Norbert Tautz, Erin Bassford Taylor, Pedro Filipe Teixeira, Bhanu Prakash V.L. Telugu, Markus F. Templin, Shigeyuki Terada, Uchikoba Tetsuya, C. Thacker, Maulik Thaker, Heinz-Jürgen Thiel, Nicole Thielens, Gonzales Thierry, Karine Thivierge, Mark D. Thomas, Margot Thome, Mary K. Thorsness, Peter E. Thorsness, Natalie J. Tigue, Sokol V. Todi, Birgitta Tomkinson, Fiorella Tonello, Liang Tong, H.S. Toogood, Paolo Tortora, József Tözsèr, Luiz Rodolpho Travassos, James Travis, Dilza Trevisan-Silva, Francesca Trinchella, Neil N. Trivedi, Carol M. Troy, Harald Tschesche, Yu-Lun Tseng, Masafumi Tsujimoto, Anthony T. Tu, Kathleen E. Tumelty, Boris Turk, Dusan Turk, Vito Turk, Anthony J. Turner, Tetsuya Uchikoba, Takayuki Ueno, Alejandro P. Ugalde, Veli-Jukka Uitto, Sinisa Urban, Olivier Valdenaire, Adrian Valli, Jozef Van Beeumen, Bertus Van den Burg, Renier A.L. Van der Hoorn, Jan Maarten van Dijl, Peter Van Endert, Bram J. Van Raam, Harold E. Van Wart, Tom Vanden Berghe, Peter Vandenabeele, Margo Vanoni, Silvio Sanches Veiga, William H. Velander, Gloria Velasco, Josep Vendrell, I. István Venekei, Vaclav Vetvicka, F.-Nora Vögtle, Waldemar Vollmer, Kei Wada, Fred W. Wagner, Sun Nyunt Wai, Timothy Wai, Shane Wainwright, Kenneth W. Walker, Stephen J. Walker, Jean Wallach, Linda L. Walling, Peter N. Walsh, Hai-Yan Wang, Hengbin Wang, Jianwei Wang, Peng Wang, Ping Wang, Michael Wassenegger, Kunihiko Watanabe, Helen Webb, Joseph M. Weber, Niklas Weber, Daniel R. Webster, Shuo Wei, Rodney A. Welch, James A. Wells, Herbert Wenzel, Ingrid E. Wertz, Ulla W. Wewer, Alison R. Whyteside, Sherwin Wilk, Jean-Marc Wilkin, Claudia Wilmes, Jakob R. Winther, David S. Wishart, Alexander Wlodawer, J. Fred Woessner, Michael S. Wolfe, Wilson Wong, Roger Woodgate, Gerry Wright, Jiunn-Jong Wu, Qingyu Wu, Magdalena Wysocka, Chao Xu, Zhenghong Xu, Kinnosuke Yahori, Shoji Yamada, Nozomi Yamaguchi, Shinji Yamaguchi, Yoshio Yamakawa, Hiroki Yamamoto, Ikao Yana, Maozhou Yang, Na Yang, Chenjuan Yao, Tingting Yao, Noriko Yasuda, Toshimasa Yasuhara, Shigeki Yasumasu, Edward T.H. Yeh, Irene Yiallouros, Jiang Yin, Hiroo Yonezawa, Soon Ji Yoo, Tadashi Yoshimoto, Michael W. Young, Stephen G. Young, Nousheen Zaidi, Ludmila L. Zavalova, Peter Zavodszky, Aidong Zhang, Xianming Zhang, Yi-Zheng Zhang, Dominick Zheng, Guangming Zhong, Rong Zhong, Yuan Zhou, Zhaohui Sunny Zhou, Michael Zick, Paola Zigrino, and Andrei A. Zimin

Published
2013
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10. Crystal structures of a ligand-free and malonate-bound human caspase-1: implications for the mechanism of substrate binding

Author

Michael J, Romanowski, Justin M, Scheer, Tom, O'Brien, and Robert S, McDowell

Subjects
Models, Molecular, Aspartic Acid, Caspase 1, Mutation, Humans, Hydrogen Bonding, Crystallography, X-Ray, Ligands, Dimerization, Malonates, Recombinant Proteins
Abstract

Caspase-1, a mediator of the posttranslational processing of IL-1beta and IL-18, requires an aspartic acid in the P1 position of its substrates. The mechanisms of caspase-1 activation remain poorly understood despite numerous structures of the enzyme complexed with aspartate-based inhibitors. Here we report a crystal structure of ligand-free caspase-1 that displays dramatic rearrangements of loops defining the active site to generate a closed conformation that is incompatible with substrate binding. A structure of the enzyme complexed with malonate shows the protein in its open (active-site ligand-bound) conformation in which malonate reproduces the hydrogen bonding network observed in structures with covalent inhibitors. These results illustrate the essential function of the obligatory aspartate recognition element that opens the active site of caspase-1 to substrates and may be the determinant responsible for the conformational changes between ligand-free and -bound forms of the enzyme, and suggest a new approach for identifying novel aspartic acid mimetics.

Published
2004

13. Reorienting the Fab domains of trastuzumab results in potent HER2 activators.

Author

Justin M Scheer, Wendy Sandoval, J Michael Elliott, Lily Shao, Elizabeth Luis, Sock-Cheng Lewin-Koh, Gabriele Schaefer, and Richard Vandlen

Subjects
Medicine, Science
Abstract

The structure of the Fab region of antibodies is critical to their function. By introducing single cysteine substitutions into various positions of the heavy and light chains of the Fab region of trastuzumab, a potent antagonist of HER2, and using thiol chemistry to link the different Fabs together, we produced a variety of monospecific F(ab')(2)-like molecules with activities spanning from activation to inhibition of breast tumor cell growth. These isomers (or bis-Fabs) of trastuzumab, with varying relative spatial arrangements between the Fv-regions, were able to either promote or inhibit cell-signaling activities through the PI3K/AKT and MAPK pathways. A quantitative phosphorylation mapping of HER2 indicated that the agonistic isomers produced a distinct phosphorylation pattern associated with activation. This study suggests that antibody geometric isomers, found both in nature and during synthetic antibody development, can have profoundly different biological activities independent of their affinities for their target molecules.

Published
2012
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