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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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“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]
In the citing paper
“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]
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Self-citation
Metadata
- 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
- Life Sciences › Immunology and Microbiology › Immunology › 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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