Development of a Novel Long-Acting Antidiabetic FGF21 Mimetic by Targeted Conjugation to a Scaffold Antibody
Abstract
Fibroblast growth factor (FGF)21 improves insulin sensitivity, reduces body weight, and reverses hepatic steatosis in preclinical species. We generated long-acting FGF21 mimetics by site-specific conjugation of the protein to a scaffold antibody. Linking FGF21 through the C terminus decreased bioactivity, whereas bioactivity was maintained by linkage to selected internal positions. In mice, these CovX-Bodies retain efficacy while increasing half-life up to 70-fold compared with wild-type FGF21. A preferred midlinked CovX-Body, CVX-343, demonstrated enhanced in vivo stability in preclinical species, and a single injection improved glucose tolerance for 6 days in ob/ob mice. In diet-induced obese mice, weekly doses of CVX-343 reduced body weight, blood glucose, and lipids levels. In db/db mice, CVX-343 increased glucose tolerance, pancreatic β-cell mass, and proliferation. CVX-343, created by linkage of the CovX scaffold antibody to the engineered residue A129C of FGF21 protein, demonstrated superior preclinical pharmacodynamics by extending serum half-life of FGF21 while preserving full therapeutic functionality.
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Disrupting leptin signaling using ob/ob or db/db mice abrogates the beneficial effects of FGF21 in lowering body weight in response to extended FGF21 administration.
“In addition, disrupting leptin signaling using ob/ob or db/db mice abrogates the beneficial effects of FGF21 in lowering body weight in response to extended FGF21 administration (3, 45, 51, 67, 139).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [51]
The half-life of FGF21 is approximately 0.4-2 hours, depending on the species and method of delivery.
“The half-life of FGF21 is approximately 0.4–2 hours, depending on the species and method of delivery (51, 65, 142).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [51]
Cites
FGF-21 as a novel metabolic regulator
Kharitonenkov, A., Shiyanova, T. L., Koester, A., Ford, A. M., Micanovic, R., Galbreath, E. J., Sandusky, G. E., Hammond, L. J., Moyers, J. S., Owens, R. A., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23606 · Cited by 2,125 · see citing works
The FGF family: biology, pathophysiology and therapy
Beenken, A., & Mohammadi, M. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2792 · Cited by 1,945 · see citing works
Inagaki, T., Dutchak, P., Zhao, G., Ding, X., Gautron, L., Parameswara, V., Li, Y., Goetz, R., Mohammadi, M., Esser, V., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.003 · Cited by 1,504 · see citing works
Badman, M. K., Pissios, P., Kennedy, A. R., Koukos, G., Flier, J. S., & Maratos-Flier, E. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.002 · Cited by 1,495 · see citing works
FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis
Fisher, F. M., Kleiner, S., Douris, N., Fox, E. C., Mepani, R. J., Verdeguer, F., Wu, J., Kharitonenkov, A., Flier, J. S., Maratos-Flier, E., et al. (2012) · Genes & Development · doi:10.1101/gad.177857.111 · Cited by 1,478 · see citing works
Xu, J., Lloyd, D. J., Hale, C., Stanislaus, S., Chen, M., Sivits, G., Vonderfecht, S., Hecht, R., Li, Y.-S., Lindberg, R. A., et al. (2009) · Diabetes · doi:10.2337/db08-0392 · Cited by 1,151 · see citing works
Fibroblast Growth Factor 21 Corrects Obesity in Mice
Coskun, T., Bina, H. A., Schneider, M. A., Dunbar, J. D., Hu, C. C., Chen, Y., Moller, D. E., & Kharitonenkov, A. (2008) · Endocrinology · doi:10.1210/en.2008-0816 · Cited by 1,031 · see citing works
Kurosu, H., Choi, M., Ogawa, Y., Dickson, A. S., Goetz, R., Eliseenkova, A. V., Mohammadi, M., Rosenblatt, K. P., Kliewer, S. A., & Kuro-o, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704165200 · Cited by 748 · see citing works
The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21
Kharitonenkov, A., Wroblewski, V. J., Koester, A., Chen, Y.-F., Clutinger, C. K., Tigno, X. T., Hansen, B. C., Shanafelt, A. B., & Etgen, G. J. (2007) · Endocrinology · doi:10.1210/en.2006-1168 · Cited by 738 · see citing works
PEGylation of therapeutic proteins
Jevševar, S., Kunstelj, M., & Porekar, V. G. (2010) · Biotechnology Journal · doi:10.1002/biot.200900218 · Cited by 681 · see citing works
Thermogenic Activation Induces FGF21 Expression and Release in Brown Adipose Tissue
Hondares, E., Iglesias, R., Giralt, A., Gonzalez, F. J., Giralt, M., Mampel, T., & Villarroya, F. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.215889 · Cited by 623 · see citing works
βKlotho is required for metabolic activity of fibroblast growth factor 21
Ogawa, Y., Kurosu, H., Yamamoto, M., Nandi, A., Rosenblatt, K. P., Goetz, R., Eliseenkova, A. V., Mohammadi, M., & Kuro-o, M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701600104 · Cited by 617 · see citing works
Dutchak, P. A., Katafuchi, T., Bookout, A. L., Choi, J. H., Yu, R. T., Mangelsdorf, D. J., & Kliewer, S. A. (2012) · Cell · doi:10.1016/j.cell.2011.11.062 · Cited by 537 · see citing works
Wente, W., Efanov, A. M., Brenner, M. B., Kharitonenkov, A., Koster, A. M., Sandusky, G. E., Sewing, S., Treinies, I., Zitzer, H., & Gromada, J. (2006) · Diabetes · doi:10.2337/db05-1435 · Cited by 497 · see citing works
Introduction to current and future protein therapeutics: A protein engineering perspective
Carter, P. J. (2011) · Experimental Cell Research · doi:10.1016/j.yexcr.2011.02.013 · Cited by 467 · see citing works
Wei, W., Dutchak, P. A., Wang, X., Ding, X., Wang, X., Bookout, A. L., Goetz, R., Mohammadi, M., Gerard, R. D., Dechow, P. C., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1200797109 · Cited by 426 · see citing works
Hondares, E., Rosell, M., Gonzalez, F. J., Giralt, M., Iglesias, R., & Villarroya, F. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.02.001 · Cited by 377 · see citing works
Suzuki, M., Uehara, Y., Motomura-Matsuzaka, K., Oki, J., Koyama, Y., Kimura, M., Asada, M., Komi-Kuramochi, A., Oka, S., & Toru, T. (2008) · Molecular Endocrinology · doi:10.1210/me.2007-0313 · Cited by 345 · see citing works
Animal models of osteoporosis - necessity and limitations
Turner, A. S. (2001) · European Cells and Materials · doi:10.22203/ecm.v001a08 · Cited by 343 · see citing works
Xu, J., Stanislaus, S., Chinookoswong, N., Lau, Y. Y., Hager, T., Patel, J., Ge, H., Weiszmann, J., Lu, S.-C., Graham, M., et al. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00348.2009 · Cited by 340 · see citing works
FGF‐21/FGF‐21 receptor interaction and activation is determined by βKlotho
Kharitonenkov, A., Dunbar, J. D., Bina, H. A., Bright, S. W., Moyers, J. S., Zhang, C., Ding, L., Micanovic, R., Mehrbod, S. F., Knierman, M. D., et al. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21357 · Cited by 329 · see citing works
Berglund, E. D., Li, C. Y., Bina, H. A., Lynes, S. E., Michael, M. D., Shanafelt, A. B., Kharitonenkov, A., & Wasserman, D. H. (2009) · Endocrinology · doi:10.1210/en.2009-0221 · Cited by 297 · see citing works
Muise, E. S., Azzolina, B., Kuo, D. W., El-Sherbeini, M., Tan, Y., Yuan, X., Mu, J., Thompson, J. R., Berger, J. P., & Wong, K. K. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.044826 · Cited by 294 · see citing works
Brown Adipose Tissue Responds to Cold and Adrenergic Stimulation by Induction of FGF21
Chartoumpekis, D. V., Habeos, I. G., Ziros, P. G., Psyrogiannis, A. I., Kyriazopoulou, V. E., & Papavassiliou, A. G. (2011) · Molecular Medicine · doi:10.2119/molmed.2011.00075 · Cited by 252 · see citing works
Foltz, I. N., Hu, S., King, C., Wu, X., Yang, C., Wang, W., Weiszmann, J., Stevens, J., Chen, J. S., Nuanmanee, N., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004690 · Cited by 211 · see citing works
Wu, A.-L., Kolumam, G., Stawicki, S., Chen, Y., Li, J., Zavala-Solorio, J., Phamluong, K., Feng, B., Li, L., Marsters, S., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002669 · Cited by 184 · see citing works
Self-citationTherapeutic Fc-fusion proteins and peptides as successful alternatives to antibodies
Beck, A., & Reichert, J. M. (2011) · mAbs · doi:10.4161/mabs.3.5.17334 · Cited by 183 · see citing works
Mu, J., Pinkstaff, J. K., Li, Z., Skidmore, L. K., Li, N., Myler, H. A., Dallas-Yang, Q., Hays, A. A., Yao, J., Bussell, S., et al. (2011) · Diabetes · doi:10.2337/db11-0838 · Cited by 162 · see citing works
FGF21 N‐ and C‐termini play different roles in receptor interaction and activation
Yie, J., Hecht, R., Patel, J., Stevens, J., Wang, W., Hawkins, N., Steavenson, S., Smith, S., Winters, D., Fisher, S., et al. (2009) · FEBS Letters · doi:10.1016/j.febslet.2008.11.023 · Cited by 149 · see citing works
Different roles of N‐ and C‐ termini in the functional activity of FGF21
Micanovic, R., Raches, D. W., Dunbar, J. D., Driver, D. A., Bina, H. A., Dickinson, C. D., & Kharitonenkov, A. (2009) · Journal of Cellular Physiology · doi:10.1002/jcp.21675 · Cited by 146 · see citing works
Adams, A. C., Astapova, I. I., Fisher, F. M., Badman, M. K., Kurgansky, K. E., Flier, J. S., Hollenberg, A. N., & Maratos–Flier, E. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.c110.107375 · Cited by 141 · see citing works
Chemical generation of bispecific antibodies
Doppalapudi, V. R., Huang, J., Liu, D., Jin, P., Liu, B., Li, L., Desharnais, J., van Hagen, C., Levin, N. J., Shields, M. J., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016478108 · Cited by 124 · see citing works
Self-citationFibroblast Growth Factor-21 as a Therapeutic Agent for Metabolic Diseases
Kharitonenkov, A., & Shanafelt, A. B. (2008) · BioDrugs · doi:10.2165/00063030-200822010-00004 · Cited by 98 · see citing works
Huang, Z., Wang, H., Lu, M., Sun, C., Wu, X., Tan, Y., Ye, C., Zhu, G., Wang, X., Cai, L., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020669 · Cited by 51 · see citing works
Brommage, R. (2001) · PubMed · Cited by 44 · see citing works
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FGF/FGFR signaling in health and disease
Xie, Y., Su, N., Yang, J., Tan, Q., Huang, S., Jin, M., Ni, Z., Zhang, B., Zhang, D., Luo, F., et al. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00222-7 · Cited by 904 · see citing works
The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic
Geng, L., Lam, K. S. L., & Xu, A. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0386-0 · Cited by 607 · see citing works
Talukdar, S., Zhou, Y., Li, D., Rossulek, M., Dong, J., Somayaji, V., Weng, Y., Clark, R., Lanba, A., Owen, B. M., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.02.001 · Cited by 496 · see citing works
Self-citationTherapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23
Degirolamo, C., Sabbà, C., & Moschetta, A. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.9 · Cited by 424 · see citing works
FGF21 Regulates Sweet and Alcohol Preference
Talukdar, S., Owen, B. M., Song, P., Hernandez, G., Zhang, Y., Zhou, Y., Scott, W. T., Paratala, B., Turner, T., Smith, A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.008 · Cited by 342 · see citing works
Self-citationMetabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?
Asrih, M., & Jornayvaz, F. R. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.02.018 · Cited by 331 · see citing works
Fibroblast Growth Factor 21—Metabolic Role in Mice and Men
Staiger, H., Keuper, M., Berti, L., Hrabě de Angelis, M., & Häring, H.-U. (2017) · Endocrine Reviews · doi:10.1210/er.2017-00016 · Cited by 270 · see citing works
Schlein, C., Talukdar, S., Heine, M., Fischer, A. W., Krott, L. M., Nilsson, S. K., Brenner, M. B., Heeren, J., & Scheja, L. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.01.006 · Cited by 252 · see citing works
Self-citationStructures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling
Lee, S., Choi, J., Mohanty, J., Sousa, L. P., Tome, F., Pardon, E., Steyaert, J., Lemmon, M. A., Lax, I., & Schlessinger, J. (2018) · Nature · doi:10.1038/nature25010 · Cited by 236 · see citing works
Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis
BonDurant, L. D., & Potthoff, M. J. (2018) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064800 · Cited by 222 · see citing works
Tillman, E. J., & Rolph, T. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.601290 · Cited by 209 · see citing works
Inventing new medicines: The FGF21 story
Kharitonenkov, A., & Adams, A. C. (2014) · Molecular Metabolism · doi:10.1016/j.molmet.2013.12.003 · Cited by 198 · see citing works
Irisin ameliorates age‐associated sarcopenia and metabolic dysfunction
Guo, M., Yao, J., Li, J., Zhang, J., Wang, D., Zuo, H., Zhang, Y., Xu, B., Zhong, Y., Shen, F., et al. (2022) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13141 · Cited by 166 · see citing works
FGF21-based pharmacotherapy – potential utility for metabolic disorders
Gimeno, R. E., & Moller, D. E. (2014) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2014.03.001 · Cited by 163 · see citing works
New developments in the biology of fibroblast growth factors
Ornitz, D. M., & Itoh, N. (2022) · WIREs Mechanisms of Disease · doi:10.1002/wsbm.1549 · Cited by 143 · see citing works
Kim, A. M., Somayaji, V. R., Dong, J. Q., Rolph, T. P., Weng, Y., Chabot, J. R., Gropp, K. E., Talukdar, S., & Calle, R. A. (2017) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13023 · Cited by 145 · see citing works
Self-citationFibroblast Growth Factor Signaling in Metabolic Regulation
Nies, V. J. M., Sancar, G., Liu, W., van Zutphen, T., Struik, D., Yu, R. T., Atkins, A. R., Evans, R. M., Jonker, J. W., & Downes, M. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00193 · Cited by 135 · see citing works
Latest approaches for the treatment of obesity
Jackson, V. M., Breen, D. M., Fortin, J.-P., Liou, A., Kuzmiski, J. B., Loomis, A. K., Rives, M.-L., Shah, B., & Carpino, P. A. (2015) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2015.1044966 · Cited by 132 · see citing works
Zhang, F., Yu, L., Lin, X., Cheng, P., He, L., Li, X., Lu, X., Tan, Y., Yang, H., Cai, L., et al. (2015) · Molecular Endocrinology · doi:10.1210/me.2015-1155 · Cited by 130 · see citing works
Fibroblast growth factor 21: a regulator of metabolic disease and health span
Xie, T., & Leung, P. S. (2017) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00101.2017 · Cited by 121 · see citing works
FGF21 Revolutions: Recent Advances Illuminating FGF21 Biology and Medicinal Properties
Kharitonenkov, A., & DiMarchi, R. D. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.09.007 · Cited by 114 · see citing works
FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases
Sonoda, J., Chen, M. Z., & Baruch, A. (2017) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2017-0002 · Cited by 106 · see citing works
Dong, J. Q., Rossulek, M. I., Somayaji, V. R., Baltrukonis, D. J., Liang, Y., Hudson, K. J., Hernandez‐Illas, M., & Calle, R. A. (2015) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12676 · Cited by 100 · see citing works
Henriksson, E., & Andersen, B. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.601349 · Cited by 95 · see citing works
FGF21 in obesity and cancer: New insights
Lu, W., Li, X., & Luo, Y. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.11.026 · Cited by 92 · see citing works
Fibroblast Growth Factor 21 As an Emerging Therapeutic Target for Type 2 Diabetes Mellitus
So, W. Y., & Leung, P. S. (2016) · Medicinal Research Reviews · doi:10.1002/med.21390 · Cited by 85 · see citing works
Genetic Code Expansion: Inception, Development, Commercialization
Manandhar, M., Chun, E., & Romesberg, F. E. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.0c11938 · Cited by 83 · see citing works
FGF19 and FGF21: In NASH we trust
Talukdar, S., & Kharitonenkov, A. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101152 · Cited by 82 · see citing works
Self-citationCirculating FGF21 Levels in Human Health and Metabolic Disease
Keuper, M., Häring, H., & Staiger, H. (2019) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-0879-2968 · Cited by 82 · see citing works
Yueh, M., He, F., Chen, C., Vu, C., Tripathi, A., Knight, R. D., Karin, M., Chen, S., & Tukey, R. H. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2017129117 · Cited by 77 · see citing works
Fibroblast growth factor 21, the endocrine FGF pathway and novel treatments for metabolic syndrome
Zhang, J., & Li, Y. (2013) · Drug Discovery Today · doi:10.1016/j.drudis.2013.10.021 · Cited by 73 · see citing works
Jin, L., Yang, R., Geng, L., & Xu, A. (2023) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-032322-093904 · Cited by 71 · see citing works
Babaknejad, N., Nayeri, H., Hemmati, R., Bahrami, S., & Esmaillzadeh, A. (2018) · Hormone and Metabolic Research · doi:10.1055/a-0623-2909 · Cited by 70 · see citing works
Fibroblast Growth Factor 21 Analogs for Treating Metabolic Disorders
Zhang, J., & Li, Y. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00168 · Cited by 70 · see citing works
Current status and future perspectives of FGF21 analogues in clinical trials
Chui, Z. S. W., Shen, Q., & Xu, A. (2024) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2024.02.001 · Cited by 68 · see citing works
Weng, Y., Chabot, J., Bernardo, B. L., Yan, Q., Zhu, Y., Brenner, M. B., Vage, C., Logan, A., Calle, R. A., & Talukdar, S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0119104 · Cited by 67 · see citing works
Self-citationFGF21 Administration Suppresses Retinal and Choroidal Neovascularization in Mice
Fu, Z., Gong, Y. Q., Liegl, R. G.-H., Wang, Z., Liu, C., Meng, S. S., Burnim, S. B., Saba, N. J., Fredrick, T. W., Morss, P., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.01.014 · Cited by 66 · see citing works
Self-citationPhan, P., Saikia, B. B., Sonnaila, S., Agrawal, S., Alraawi, Z., Kumar, T. K. S., & Iyer, S. (2021) · Cells · doi:10.3390/cells10092418 · Cited by 67 · see citing works
The role of fibroblast growth factor 21 in atherosclerosis
Kokkinos, J., Tang, S., Rye, K., & Ong, K. L. (2016) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2016.11.033 · Cited by 66 · see citing works
A link between hepatic glucose production and peripheral energy metabolism via hepatokines
Abdul-Wahed, A., Gautier‐Stein, A., Casteras, S., Soty, M., Roussel, D., Romestaing, C., Guillou, H., Tourette, J.-A., Plèche, N., Zitoun, C., et al. (2014) · Molecular Metabolism · doi:10.1016/j.molmet.2014.05.005 · Cited by 61 · see citing works
Struik, D., Dommerholt, M. B., & Jonker, J. W. (2019) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000599 · Cited by 61 · see citing works
Gilroy, C. A., Roberts, S., & Chilkoti, A. (2018) · Journal of Controlled Release · doi:10.1016/j.jconrel.2018.03.015 · Cited by 58 · see citing works
Xie, T., So, W. Y., Li, X. Y., & Leung, P. S. (2019) · Clinical Science · doi:10.1042/cs20190093 · Cited by 55 · see citing works
Chemically programmed antibodies
Rader, C. M. (2014) · Trends in biotechnology · doi:10.1016/j.tibtech.2014.02.003 · Cited by 50 · see citing works
Thompson, W. C., Zhou, Y., Talukdar, S., & Musante, C. J. (2016) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-016-9481-1 · Cited by 49 · see citing works
Self-citationBernardo, B. L., Lu, M. M., Bandyopadhyay, G. K., Li, P., Zhou, Y., Huang, J. S., Levin, N., Tomás, E., Calle, R. A., Erion, D. M., et al. (2015) · Scientific Reports · doi:10.1038/srep11382 · Cited by 46 · see citing works
Self-citationFGF-based drug discovery: advances and challenges
Chen, G., Chen, L., Li, X., & Mohammadi, M. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01125-w · Cited by 51 · see citing works
Self-citationFGF21 Mimetic Shows Therapeutic Promise
Reitman, M. L. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.08.014 · Cited by 47 · see citing works
Hepatic hormone FGF21 and its analogues in clinical trials
Shao, W., & Jin, T. (2021) · Chronic Diseases and Translational Medicine · doi:10.1016/j.cdtm.2021.08.005 · Cited by 46 · see citing works
Zhang, J., & Li, Y. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.09.007 · Cited by 42 · see citing works
Fibroblast growth factor 21 in chronic kidney disease
Anuwatmatee, S., Tang, S., Wu, B. J., Rye, K., & Ong, K. L. (2017) · Clinica Chimica Acta · doi:10.1016/j.cca.2017.11.002 · Cited by 40 · see citing works
Beta-klotho in type 2 diabetes mellitus: From pathophysiology to therapeutic strategies
Hua, S., Liu, Q., Li, J., Fan, M., Yan, K., & Ye, D. (2021) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-021-09661-1 · Cited by 39 · see citing works
Claflin, K. E., Sullivan, A. I., Naber, M. C., Flippo, K. H., Morgan, D. A., Neff, T. J., Jensen-Cody, S. O., Zhu, Z., Zingman, L. V., Rahmouni, K., et al. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101564 · Cited by 37 · see citing works
Lee, D. V., Li, D., Yan, Q., Zhu, Y., Goodwin, B. J., Calle, R. A., Brenner, M. B., & Talukdar, S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0111767 · Cited by 38 · see citing works
Self-citationCharoenphandhu, N., Suntornsaratoon, P., Krishnamra, N., Sa‐nguanmoo, P., Tanajak, P., Wang, X., Liang, G., Li, X., Jiang, C., Chattipakorn, N., et al. (2016) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-016-0745-z · Cited by 38 · see citing works
Izaguirre, M., Gil, M. J., Monreal, I., Montecucco, F., Frühbeck, G., & Catalán, V. (2017) · Current Diabetes Reports · doi:10.1007/s11892-017-0866-3 · Cited by 37 · see citing works
Weng, Y., Ishino, T., Sievers, A., Talukdar, S., Chabot, J., Tam, A. S. P., Duan, W., Kerns, K. M., Sousa, E. A., He, T., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-22456-w · Cited by 33 · see citing works
Self-citationYadav, P., Khurana, A., Bhatti, J. S., Weiskirchen, R., & Navik, U. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106426 · Cited by 32 · see citing works
Fibroblast Growth Factors for Nonalcoholic Fatty Liver Disease: Opportunities and Challenges
Tian, H., Zhang, S., Liu, Y., Wu, Y., & Zhang, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24054583 · Cited by 32 · see citing works
Fibroblast growth factor 21: a promising therapeutic target in obesity-related diseases
Cheung, B. M. Y., & Deng, H. (2014) · Expert Review of Cardiovascular Therapy · doi:10.1586/14779072.2014.904745 · Cited by 32 · see citing works
Cheng, S. T. W., Li, S. Y. T., & Leung, P. S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20102517 · Cited by 31 · see citing works
Rational Design of a Humanized Glucagon‐Like Peptide‐1 Receptor Agonist Antibody
Zhang, Y., Zou, H., Wang, Y., Caballero, D., González, J., Chao, E., Welzel, G., Shen, W., Wang, D., Schultz, P. G., et al. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201410049 · Cited by 30 · see citing works
Yin, J., Bao, L., Tian, H., Wang, Q., Gao, X., & Yao, W. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13499 · Cited by 30 · see citing works
The role of FGF21 in type 1 diabetes and its complications
Zhang, J., Weng, W., Wang, K., Lu, X., Cai, L., & Sun, J. (2018) · International Journal of Biological Sciences · doi:10.7150/ijbs.25026 · Cited by 30 · see citing works
Paracrine-endocrine FGF chimeras as potent therapeutics for metabolic diseases
Zhao, L., Niu, J., Lin, H., Zhao, J., Liu, Y., Song, Z., Xiang, C., Wang, X., Yang, Y., Li, X., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.09.052 · Cited by 30 · see citing works
Chen, X. Y., Li, G. M., Dong, Q., & Peng, H. (2015) · Genetics and Molecular Research · doi:10.4238/2015.november.30.24 · Cited by 27 · see citing works
Role of fibroblast growth factor 21 in gestational diabetes mellitus: A mini‐review
Yuan, D., Wu, B. J., Henry, A., Rye, K., & Ong, K. L. (2018) · Clinical Endocrinology · doi:10.1111/cen.13881 · Cited by 26 · see citing works
Nutritional Regulation of Hepatic FGF21 by Dietary Restriction of Methionine
Fang, H., Stone, K. P., Forney, L. A., Wanders, D., & Gettys, T. W. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.773975 · Cited by 24 · see citing works
Hormonal factors in the control of the browning of white adipose tissue
Hu, J., & Christian, M. (2017) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2017-0017 · Cited by 22 · see citing works
Fibroblast growth factor 21: A “rheostat” for metabolic regulation?
She, Q.-Y., Bao, J., Wang, H.-Z., Liang, H., Huang, W., Wu, J., Zhong, Y.-W., Ling, H., Li, A., & Qin, S.-L. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155166 · Cited by 22 · see citing works
Bioanalytical Approaches to Assess The Proteolytic Stability of Therapeutic Fusion Proteins
Pearson, J. T., & Rock, D. A. (2015) · Bioanalysis · doi:10.4155/bio.15.217 · Cited by 21 · see citing works
Tillman, E. J., Brock, W. J., & Rolph, T. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15725 · Cited by 22 · see citing works
Nielsen, M. H., Gillum, M. P., Vrang, N., Jelsing, J., Hansen, H. H., Feigh, M., & Oró, D. (2023) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00157.2022 · Cited by 20 · see citing works
Molecular and Materials Engineering for Delivery of Peptide Drugs to Treat Type 2 Diabetes
Varanko, A. K., & Chilkoti, A. (2019) · Advanced Healthcare Materials · doi:10.1002/adhm.201801509 · Cited by 21 · see citing works
Giragossian, C., Vage, C., Li, J., Pelletier, K. B., Piche‐Nicholas, N., Rajadhyaksha, M., Liras, J. L., Logan, A., Calle, R. A., & Weng, Y. (2015) · Drug Metabolism and Disposition · doi:10.1124/dmd.114.061713 · Cited by 20 · see citing works
Current understanding and controversies on the clinical implications of fibroblast growth factor 21
Badakhshi, Y., & Jin, T. (2020) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408363.2020.1864278 · Cited by 20 · see citing works
Emerging roles of fibroblast growth factor 21 in critical disease
Fang, Y., Li, Y., Yang, F., Wu, G., & Jiang, X. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.1053997 · Cited by 20 · see citing works
Insulin sensitizes FGF21 in glucose and lipid metabolisms via activating common AKT pathway
Yu, D., Ye, X., Wu, Q., Li, S., Yang, Y., He, J., Liu, Y., Zhang, X., Yuan, Q., Liu, M., et al. (2015) · Endocrine · doi:10.1007/s12020-015-0801-9 · Cited by 19 · see citing works
Fibroblast growth factors 19 and 21 in acute liver damage
Shan, Z., Álvarez‐Sola, G., Uriarte, I., Arechederra, M., Fernández‐Barrena, M. G., Berasain, C., Ju, C., & Avila, M. A. (2018) · Annals of Translational Medicine · doi:10.21037/atm.2018.05.26 · Cited by 18 · see citing works
Emerging targets and potential therapeutic agents in non-alcoholic fatty liver disease treatment
Yang, Y., Zhao, Y., Li, W., Wu, Y., Wang, X., Wang, Y., Liu, T.-M., Ye, T., Xie, Y., Cheng, Z., et al. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112311 · Cited by 17 · see citing works
Zarei, M., Pujol, E., Quesada‐López, T., Villarroya, F., Barroso, E., Vázquez, S., Pizarro‐Delgado, J., Palomer, X., & Vázquez‐Carrera, M. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14678 · Cited by 17 · see citing works
Homogeneously modified immunoglobulin domains for therapeutic application
Liu, T., Du, J., Luo, X., Schultz, P. G., & Wang, F. (2015) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2015.06.007 · Cited by 15 · see citing works
FAP finds FGF21 easy to digest
Gillum, M. P., & Potthoff, M. J. (2016) · Biochemical Journal · doi:10.1042/bcj20160004 · Cited by 14 · see citing works
Pancreatic Tumorigenesis: Oncogenic KRAS and the Vulnerability of the Pancreas to Obesity
Luo, Y., Li, X., Ma, J., Abbruzzese, J. L., & Lu, W. (2021) · Cancers · doi:10.3390/cancers13040778 · Cited by 14 · see citing works
Dorval, L., Knapp, B. I., Majekodunmi, O. A., Eliseeva, S. I., & Bidlack, J. M. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108858 · Cited by 13 · see citing works
Modulation of adipose tissue thermogenesis as a method for increasing energy expenditure
Sammons, M. F., & Price, D. A. (2013) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2013.12.016 · Cited by 12 · see citing works
Development of Zalfermin, a Long-Acting Proteolytically Stabilized FGF21 Analog
Sass‐Ørum, K., Tagmose, T. M., Olsen, J., Sjölander, A., Wahlund, P., Han, D., Vegge, A., Reedtz‐Runge, S., Wang, Z., Gao, X., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00391 · Cited by 10 · see citing works
FGF21 Analogues and MASLD: A Summary of Preclinical and Clinical Data
Boutari, C., Triantafyllou, A., Papalavrentios, L., Goulis, I., & Sinakos, E. (2025) · Current Pharmaceutical Design · doi:10.2174/0113816128374854250709050425 · Cited by 10 · see citing works
Research progress on the role of FGF21 in insulin resistance
Zhang, H., Zhu, R., Sun, Q., & Du, L. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1619462 · Cited by 10 · see citing works
Lee, D., Nakai, A., Miwa, Y., Negishi, K., Tomita, Y., & Kurihara, T. (2023) · PeerJ · doi:10.7717/peerj.14611 · Cited by 9 · see citing works
Novel Therapeutic Proteins and Peptides
Buchanan, A. G., & Revell, J. D. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-416603-5.00008-0 · Cited by 9 · see citing works
Fibroblast Growth Factor 21 Mimetics for Treating Atherosclerosis
Kwok, K. H. M., & Lam, K. S. L. (2017) · Endocrinology and Metabolism · doi:10.3803/enm.2017.32.2.145 · Cited by 9 · see citing works
Kim, D., Lee, J., Bae, I., Kim, M., Huh, Y., Choi, J., Bae, S., Choi, I. Y., Kim, H. H., & Kim, D. K. (2020) · Biologicals · doi:10.1016/j.biologicals.2020.11.005 · Cited by 9 · see citing works
Fibroblast Growth Factors: Roles and Emerging Therapeutic Applications
Ternier, G., Shahzad, K., Edirisinghe, O., Okoto, P. S., Alraawi, Z., Sonnaila, S., Phan, P., Adams, P. D., & Thallapuranam, S. (2025) · Current Drug Targets · doi:10.2174/0113894501351461250301072444 · Cited by 9 · see citing works
Ho, M., Zhang, C., Moon, I., Biernacka, J. M., Coombes, B. J., Ngo, Q., Skillon, C., Skime, M. K., Oesterle, T., Croarkin, P. E., et al. (2023) · Molecular Metabolism · doi:10.1016/j.molmet.2023.101798 · Cited by 8 · see citing works
Lack of Day/Night variation in fibroblast growth factor 21 levels in young healthy men
Foo, J., Aronis, K. N., Chamberland, J. P., & Mantzoros, C. S. (2014) · International Journal of Obesity · doi:10.1038/ijo.2014.215 · Cited by 8 · see citing works
Wu, F., Zhang, Y., Tang, Y., Kang, Y., Li, Y., Hu, X., Liu, J., Tian, X., & Lu, Z. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.123932 · Cited by 7 · see citing works
Treating metabolic dysfunction‐associated steatohepatitis: The fat‐trimming FGF21 approach
Li, X., Rao, Z., Hu, W., Lu, W., & Luo, Y. (2024) · Obesity Reviews · doi:10.1111/obr.13861 · Cited by 6 · see citing works
Hou, H.-W., Bishop, C. A., Huckauf, J., Broer, I., Klaus, S., Nausch, H., & Buyel, J. F. (2022) · Frontiers in Plant Science · doi:10.3389/fpls.2022.998596 · Cited by 5 · see citing works
Juan, Z., Liu, X., Yue, J., Zhang, S., Li, L., & Wei, H. (2024) · Frontiers in Veterinary Science · doi:10.3389/fvets.2024.1429639 · Cited by 5 · see citing works
Self-citation
- Authors
- Huang, J., Ishino, T., Chen, G., Rolzin, P., Osothprarop, T. F., Retting, K., Li, L., Jin, P., Matin, M. J., Huyghe, B., Talukdar, S., Bradshaw, C. W., Palanki, M., Violand, B. N., Woodnutt, G., Lappe, R. W., Ogilvie, K., & Levin, N.
- Affiliations
- Pfizer (United States) (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 346
- Issue
- 2
- Pages
- 270-280
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2029880965
- Cited by
- 121
- References
- 36
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 8 · 2023: 5 · 2022: 9 · 2021: 8 · 2020: 11 · 2019: 7 · 2018: 9 · 2017: 11 · 2016: 9 · 2015: 19 · 2014: 9 · 2013: 3
- FWCI
- 5.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- FGF21, protein conjugation, long-acting drugs, protein half-life extension, insulin sensitivity, glucose tolerance, obesity, type 2 diabetes, ob/ob mice, db/db mice, hepatic steatosis
- MeSH terms
- Animals, Antibodies, Body Weight, Cysteine, Delayed-Action Preparations, Diabetes Mellitus, Energy Metabolism, Fibroblast Growth Factors, Humans, Hypoglycemic Agents, Immunoglobulin Fab Fragments, Lysine, Macaca fascicularis, Male, Mice, Obese, Recombinant Proteins, Rats, Sprague-Dawley, Molecular Mimicry, 3T3-L1 Cells, Insulin-Secreting Cells, Mice, Rats
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