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1. Protein engineering and preclinical development of a GM-CSF receptor antibody for the treatment of rheumatoid arthritis

Author

Inna Vainshtein, Matthew McCourt, C Drinkwater, Trevor Wilkinson, L Roskos, C Matthews, Mark A Sleeman, Paula Harrison, Dorothy A. Sims, Meina Liang, Bo Wang, Cohen Emma S, Ralph Minter, Lutz Jermutus, G Rees, I.K. Anderson, Phillip Monk, Andrew D. Nash, Laura Eghobamien, and L Fabri

Subjects
Pharmacology, Affinity maturation, biology, Antigen, Drug discovery, In vivo, GM-CSF Receptor, biology.protein, Potency, Antibody, Immunoglobulin G
Abstract

Background and Purpose For antibody therapies against receptor targets, in vivo outcomes can be difficult to predict because of target-mediated clearance or antigen ‘sink’ effects. The purpose of this work was to engineer an antibody to the GM-CSF receptor α (GM-CSFRα) with pharmacological properties optimized for chronic, s.c. treatment of rheumatoid arthritis (RA) patients. Experimental Approach We used an in silico model of receptor occupancy to guide the target affinity and a combinatorial phage display approach for affinity maturation. Mechanism of action and internalization assays were performed on the optimized antibody in vitro before refining the modelling predictions of the eventual dosing in man. Finally, in vivo pharmacology studies in cynomolgus monkeys were carried out to inform the predictions and support future clinical development. Key Results Antibody potency was improved 8600-fold, and the target affinity was reached. The refined model predicted pharmacodynamic effects at doses as low as 1 mg kg−1 and a study in cynomolgus monkeys confirmed in vivo efficacy at 1 mg kg−1 dosing. Conclusions and Implications This rational approach to antibody drug discovery enabled the isolation of a potent molecule compatible with chronic, s.c. self-administration by RA patients. We believe this general approach enables the development of optimal biopharmaceuticals.

Published
2012
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4. Pathway-based analysis of primary biliary cirrhosis genome-wide association studies

Author

Kar, Sp, Seldin, Mf, Chen, W, Lu, E, Hirschfield, Gm, Invernizzi, P, Heathcote, J, Cusi, D, Almasio, Pl, Alvaro, D, Andreone, P, Andriulli, A, Barlassina, C, Benedetti, A, Bernuzzi, F, Bianchi, I, Bragazzi, M, Brunetto, M, Bruno, S, Caliari, L, Casella, G, Coco, B, Colli, A, Colombo, M, Colombo, S, Cursaro, C, Croce, Ls, Crosignani, A, Donato, F, Elia, G, Fabris, L, Floreani, A, Galli, A, Grattagliano, I, Lazzari, R, Lleo, A, Macaluso, F, Marra, F, Marzioni, M, Mascia, E, Mattalia, A, Montanari, R, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, Picciotto, A, Podda, M, Portincasa, P, Prati, D, Raggi, C, Rosina, F, Rossi, S, Sogno, I, Spinzi, G, Strazzabosco, M, Tarallo, Sonia, Tarocchi, M, Tiribelli, C, Toniutto, P, Vinci, M, Zuin, M, Gershwin, Me, Siminovitch, Ka, Amos, Ci, Tarallo, S, Zuin, M., S. P., Kar, M. F., Seldin, W., Chen, E., Lu, G. M., Hirschfield, P., Invernizzi, J., Heathcote, D., Cusi, t. I., Pbc, P. L., Almasio, D., Alvaro, P., Andreone, A., Andriulli, C., Barlassina, A., Benedetti, F., Bernuzzi, I., Bianchi, M., Bragazzi, M., Brunetto, S., Bruno, L., Caliari, G., Casella, B., Coco, A., Colli, M., Colombo, S., Colombo, C., Cursaro, Croce', Saveria, A., Crosignani, F., Donato, G., Elia, L., Fabri, A., Floreani, A., Galli, I., Grattagliano, R., Lazzari, A., Lleo, F., Macaluso, F., Marra, M., Marzioni, E., Mascia, A., Mattalia, R., Montanari, L., Morini, F., Morisco, L., Muratori, P., Muratori, G., Niro, A., Picciotto, M., Podda, P., Portincasa, D., Prati, C., Raggi, F., Rosina, S., Rossi, I., Sogno, G., Spinzi, M., Strazzabosco, S., Tarallo, M., Tarocchi, Tiribelli, Claudio, P., Toniutto, M., Vinci, M., Zuin, M. E., Gershwin, K. A., Siminovitch, C. I., Amos, SP Kar, MF Seldin, W Chen, E Lu, GM Hirschfield, P Invernizzi, J Heathcote, D Cusi, the Italian PBC Genetics Study Group [.., P Andreone, L Muratori, P Muratori, ], ME Gershwin, KA Siminovitch, CI Amos, Kar, S, Seldin, M, Chen, W, Lu, E, Hirschfield, G, Invernizzi, P, Heathcote, J, Cusi, D, the Italian PBC Genetics Study, G, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Barlassina, C, Benedetti, A, Bernuzzi, F, Bianchi, I, Bragazzi, M, Brunetto, M, Bruno, S, Caliari, L, Casella, G, Coco, B, Colli, A, Colombo, M, Colombo, S, Cursaro, C, Croce, L, Crosignani, A, Donato, F, Elia, G, Fabris, L, Floreani, A, Galli, A, Grattagliano, I, Lazzari, R, Lleo, A, Macaluso, F, Marra, F, Marzioni, M, Mascia, E, Mattalia, A, Montanari, R, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G., P, A, Podda, M, Portincasa, P, Prati, D, Raggi, C, Rosina, F, Rossi, S, Sogno, I, Spinzi, G, Strazzabosco, M, Tarallo, S, Tarocchi, M, Tiribelli, C, Toniutto, P, Vinci, M, Zuin, M, Gershwin, M, Siminovitch, K, Amos, C, Kar, Sp, Seldin, Mf, Hirschfield, Gm, Almasio, Pl, Morisco, Filomena, Niro, G, Picciotto, A, Gershwin, Me, Siminovitch, Ka, Amos, Ci, and the Italian PBC Genetics Study, Group

Subjects
Male, Linkage disequilibrium, PRIMARY BILIARY CIRRHOSIS, Genome-wide association study, VARIANTS, Linkage Disequilibrium, Cohort Studies, ACTIVATION, Primary biliary cirrhosis, Gene Frequency, MED/12 - GASTROENTEROLOGIA, Databases, Genetic, SENSORS, Genetics (clinical), Genetics, Liver Cirrhosis, Biliary, Middle Aged, EPITHELIAL-MESENCHYMAL TRANSITION, hedgehog signaling, Hedgehog signaling pathway, Algorithm, Italy, DISEASES, Female, Algorithms, TRAITS, Human, Signal Transduction, Canada, Genotype, Immunology, EPITHELIAL-MESENCHYMAL TRANSITION, CELLS, ACTIVATION, GENE, IDENTIFICATION, RESPONSES, VARIANTS, DISEASES, SENSORS, TRAITS, autoimmune disease, Biology, Polymorphism, Single Nucleotide, linear combination test, Article, Autoimmune Diseases, Meta-Analysis as Topic, medicine, Humans, Genetic Predisposition to Disease, phosphatidylinositol signaling, KEGG, Allele frequency, Genetic association, IDENTIFICATION, medicine.disease, GENE, Multiple comparisons problem, PBC, genome wide association, CELLS, Cohort Studie, Genome-Wide Association Study, RESPONSES
Abstract

Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility (P

Published
2013

5. Insulin resistance and necroinflammation drives ductular reaction and epithelial-mesenchymal transition in chronic hepatitis C

Author

Massimiliano Cadamuro, Elisabetta Bugianesi, I. Pierantonelli, Luca Fabris, Giulio Marchesini, Maria Guido, Mario Strazzabosco, Antonio Benedetti, Gianluca Svegliati-Baroni, Graziella Faraci, Stefania Saccomanno, Luciano Trozzi, Svegliati Baroni, G, Faraci, G, Fabris, L, Saccomanno, S, Cadamuro, M, Pierantonelli, I, Trozzi, L, Bugianesi, E, Guido, M, Strazzabosco, M, Benedetti, A, Marchesini, G, G. Svegliati Baroni, G. Faraci, L. Fabri, S. Saccomanno, M. Cadamuro, I. Pierantonelli, L. Trozzi, E. Bugianesi, M. Guido, M. Strazzabosco, A. Benedetti, and G. Marchesini Reggiani

Subjects
Adult, Liver Cirrhosis, Male, Pathology, medicine.medical_specialty, Cirrhosis, Epithelial-Mesenchymal Transition, Fibrosi, Chronic liver injury, Vimentin, Insuline resistance, EMT, HCV, FSP-1, Chronic hepatitis C, Necrosis, Insulin resistance, Downregulation and upregulation, Fibrosis, MED/12 - GASTROENTEROLOGIA, medicine, Humans, Epithelial–mesenchymal transition, Hepatic stellate cell, biology, Anthropometry, business.industry, Gastroenterology, Glucose Tolerance Test, Hepatitis C, Chronic, Middle Aged, medicine.disease, Liver, biology.protein, Disease Progression, Female, Insulin Resistance, Hepatic fibrosis, business
Abstract

OBJECTIVE: To study the mechanism(s) linking insulin resistance (IR) to hepatic fibrosis and the role of the epithelial component in tissue repair and fibrosis in chronic hepatitis C (CHC). DESIGN: Prospective observational study. SETTING: Tertiary care academic centre. PATIENTS: 78 consecutive patients with CHC. MAIN OUTCOME MEASURES: IR, calculated by the oral glucose insulin sensitivity during oral glucose tolerance test; necroinflammatory activity and fibrosis, defined according to Ishak's score; steatosis, graded as 0 (66%). To evaluate the role of the epithelial component in tissue repair and fibrosis, the expansion of the ductular reaction (DR) was calculated by keratin-7 (CK7) morphometry. Nuclear expression of Snail, downregulation of E-cadherin and expression of fibroblast specific protein-1 (FSP1) and vimentin by CK7-positive cells were used as markers of epithelial-mesenchymal transition in DR elements. RESULTS: IR, the degree of necroinflammation and expansion of the DR (stratified as reactive ductular cells (RDCs), hepatic progenitor cells and intermediate hepatobiliary cells according to morphological criteria) were all associated with the stage of fibrosis. Nuclear Snail expression, E-cadherin downregulation and vimentin upregulation were observed in RDCs. By dual immunofluorescence for CK7 and FSP1, the number of RDCs undergoing epithelial-mesenchymal transition progressively increased together with the necroinflammatory score. By multivariate analysis, total inflammation and insulin resistance were the only factors significantly predicting the presence of advanced fibrosis (Ishak score ≥3) and the expansion of RDCs. CONCLUSION: This study indicates that IR is associated with the degree of necroinflammatory injury in CHC and contributes to hepatic fibrosis by stimulating the expansion of RDCs that express epithelial-mesenchymal transition markers.

Published
2011

6. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis

Author

Massimo Zuin, Antonio Benedetti, Pierluigi Toniutto, Vincenzo Palmieri, Peter K. Gregersen, Cristina Rigamonti, Christopher I. Amos, Paolo Muratori, Barbara Coco, Francesca Bernuzzi, Piero Luigi Almasio, Renzo Montanari, Maurizia Rossana Brunetto, Fabio Macciardi, Andrea Galli, Pietro Andreone, Cameron N. Ghent, Yue Lu, Luca Fabris, Gideon M. Hirschfield, Marzia Margotti, Michael Ransom, Ilaria Bianchi, Agostino Colli, Carlo Selmi, Giancarlo Spinzi, Lory Saveria Crocè, S. Bruno, Gang Xie, Mario Strazzabosco, Claudio Tiribelli, Xiangdong Liu, Grazia Anna Niro, E. Jenny Heathcote, Russell Shigeta, Katherine A. Siminovitch, Elisabetta Borghesio, Nicola Caporaso, M. Eric Gershwin, Andrew Mason, Maria Vinci, Mauro Podda, Robert P. Myers, Fabio Marra, Cleofe Prisco, Lorenzo Morini, Roman Kosoy, Alberto Mattalia, Michael F. Seldin, Chun Xu, Maria Consiglia Bragazzi, Piero Portincasa, Roberta Lazzari, Giovanni Casella, Sonia Rossi, Marco Marzioni, Silvia Colombo, Domenico Alvaro, Luigi Muratori, Sara Lupoli, Carlo Ferrari, Annette Lee, Annarosa Floreani, Yan Lu, Floriano Rosina, Angelo Andriulli, Massimo Colombo, Antonio Picciotto, Kevork M. Peltekian, Ana Lleo, Alessandro Pisano, Pietro Invernizzi, Liu, X, Invernizzi, P, Lu, Y, Kosoy, R, Bianchi, I, Podda, M, Xu, C, Xie, G, Macciardi, F, Selmi, C, Lupoli, S, Shigeta, R, Ransom, M, Lleo, A, Lee, AT, Mason, AL, Myers, RP, Peltekian, KM, Ghent, CN, Bernuzzi, F, Zuin, M, Rosina, F, Borghesio, E, Floreani, A, Lazzari, R, Niro, G, Andriulli, A, Muratori, L, Muratori, P, Almasio, PL, Andreone, P, Margotti, M, Brunetto, M, Coco, B, Alvaro, D, Bragazzi, MC, Marra, F, Pisano, A, Rigamonti, C, Colombo, M, Marzioni, M, Benedetti, A, Fabris, L, Strazzabosco, M, Portincasa, P, Palmieri, VO, Tiribelli, C, Croce, L, Bruno, S, Rossi, S, Vinci, M, Prisco, C, Mattalia, A, Toniutto, P, Picciotto, A, Galli, A, Ferrari, C, Colombo, S, Casella, G, Morini, L, Caporaso, N, Colli, A, Spinzi, G, Montanari, R, Gregersen, PK, Heathcote, EJ, Hirschfield, GM, Siminovitch, KA, Amos, CI, Gershwin, ME, Seldin, MF, Lee, At, Mason, Al, Myers, Rp, Peltekian, Km, Ghent, Cn, Almasio, Pl, Bragazzi, Mc, Palmieri, Vo, Caporaso, Nicola, Gregersen, Pk, Heathcote, Ej, Hirschfield, Gm, Siminovitch, Ka, Amos, Ci, Gershwin, Me, Seldin, M. F., Lee, A, Mason, A, Myers, R, Peltekian, K, Ghent, C, Almasio, P, Bragazzi, M, Palmieri, V, Gregersen, P, Heathcote, E, Hirschfield, G, Siminovitch, K, Amos, C, Gershwin, M, Seldin, M, X., Liu, P., Invernizzi, Y., Lu, R., Kosoy, I., Bianchi, M., Podda, C., Xu, G., Xie, F., Macciardi, C., Selmi, S., Lupoli, R., Shigeta, M., Ransom, A., Lleo, A. T., Lee, A. L., Mason, R. P., Myer, K. M., Peltekian, C. N., Ghent, F., Bernuzzi, M., Zuin, F., Rosina, E., Borghesio, A., Floreani, R., Lazzari, G., Niro, A., Andriulli, L., Muratori, P., Muratori, P. L., Almasio, P., Andreone, M., Margotti, M., Brunetto, B., Coco, D., Alvaro, M. C., Bragazzi, F., Marra, A., Pisano, C., Rigamonti, M., Colombo, M., Marzioni, A., Benedetti, L., Fabri, M., Strazzabosco, P., Portincasa, V. O., Palmieri, Tiribelli, Claudio, Croce', Saveria, S., Bruno, S., Rossi, M., Vinci, C., Prisco, A., Mattalia, P., Toniutto, A., Picciotto, A., Galli, C., Ferrari, S., Colombo, G., Casella, L., Morini, N., Caporaso, A., Colli, G., Spinzi, R., Montanari, P. K., Gregersen, E. J., Heathcote, G. M., Hirschfield, K. A., Siminovitch, C. I., Amo, M. E., Gershwin, M. F., Seldin, Liu X, Invernizzi P, Lu Y, Kosoy R, Bianchi I, Podda M, Xu C, Xie G, Macciardi F, Selmi C, Lupoli S, Shigeta R, Ransom M, Lleo A, Lee AT, Mason AL, Myers RP, Peltekian KM, Ghent CN, Bernuzzi F, Zuin M, Rosina F, Borghesio E, Floreani A, Lazzari R, Niro G, Andriulli A, Muratori L, Muratori P, Almasio PL, Andreone P, Margotti M, Brunetto M, Coco B, Alvaro D, Bragazzi MC, Marra F, Pisano A, Rigamonti C, Colombo M, Marzioni M, Benedetti A, Fabris L, Strazzabosco M, Portincasa P, Palmieri VO, Tiribelli C, Croce L, Bruno S, Rossi S, Vinci M, Prisco C, Mattalia A, Toniutto P, Picciotto A, Galli A, Ferrari C, Colombo S, Casella G, Morini L, Caporaso N, Colli A, Spinzi G, Montanari R, Gregersen PK, Heathcote EJ, Hirschfield GM, Siminovitch KA, Amos CI, Gershwin ME, and Seldin MF.

Subjects
Liver Cirrhosis, Oncology, Canada, medicine.medical_specialty, Cirrhosis, European Continental Ancestry Group, LOCI, PRIMARY BILIARY CIRRHOSIS, GENOME WIDE ASSOCIATION, Genome-wide association study, Locus (genetics), genetics, Genome, Genome-Wide Association Study, Humans, Interferon Regulatory Factors, Liver Cirrhosi, Biology, Biliary, Meta-Analysis as Topic, Odds Ratio, White People, Article, Alleles, Canada, European Continental Ancestry Group, primary biliary cirrhosi, Primary biliary cirrhosis, Meta-Analysis as Topic, MED/12 - GASTROENTEROLOGIA, IL12A, Internal medicine, Odds Ratio, Genetics, medicine, Humans, Allele, genome, genetics, Genome, Genome-Wide Association Study, Humans, Interferon Regulatory Factors, Liver Cirrhosis, Alleles, primary biliary cirrhosis, genome-wide meta-analyses, Liver Cirrhosis, Biliary, Biliary, Odds ratio, medicine.disease, Interferon Regulatory Factors, Cohort, Genome-Wide Association Study
Abstract

A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 × 10−11, odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 × 10−10, OR = 1.63) and 17q12-21 (P = 1.7 × 10−10, OR = 1.38).

Published
2010

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