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Research ArticleDrug Discovery and Translational Medicine

Pharmacologic Profile of the Adnectin BMS-962476, a Small Protein Biologic Alternative to PCSK9 Antibodies for Low-Density Lipoprotein Lowering

Tracy Mitchell, Ginger Chao, Doree Sitkoff, Fred Lo, Hossain Monshizadegan, Daniel Meyers, Simon Low, Katie Russo, Rose DiBella, Fabienne Denhez, Mian Gao, Joseph Myers, Gerald Duke, Mark Witmer, Bowman Miao, Siew P. Ho, Javed Khan and Rex A. Parker
Journal of Pharmacology and Experimental Therapeutics August 2014, 350 (2) 412-424; DOI: https://doi.org/10.1124/jpet.114.214221
Tracy Mitchell
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Ginger Chao
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Doree Sitkoff
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Fred Lo
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Hossain Monshizadegan
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Daniel Meyers
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Simon Low
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Katie Russo
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Rose DiBella
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Fabienne Denhez
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Mian Gao
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Joseph Myers
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Gerald Duke
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Mark Witmer
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Bowman Miao
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Siew P. Ho
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Javed Khan
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Rex A. Parker
Molecular Discovery Technologies (T.M., G.C., D.S., S.L., K.R., R.D., F.D., M.G., J.M., G.D., M.W., J.K.), Applied Genomics (S.P.H.), and Cardiovascular Discovery Biology (F.L., H.M., D.M., B.M., R.A.P.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Abstract

Proprotein convertase subtilisin kexin-9 (PCSK9) is an important pharmacological target for decreasing low-density lipoprotein (LDL) in cardiovascular disease, although seemingly inaccessible to small molecule approaches. Compared with therapeutic IgG antibodies currently in development, targeting circulating PCSK9 with smaller molecular scaffolds could offer different profiles and reduced dose burdens. This inspired genesis of PCSK9-binding Adnectins, a protein family derived from human fibronectin-10th-type III–domain and engineered for high-affinity target binding. BMS-962476, an ∼11-kDa polypeptide conjugated to polyethylene glycol to enhance pharmacokinetics, binds with subnanomolar affinity to human. The X-ray cocrystal structure of PCSK9 with a progenitor Adnectin shows ∼910 Å2 of PCSK9 surface covered next to the LDL receptor binding site, largely by residues of a single loop of the Adnectin. In hypercholesterolemic, overexpressing human PCSK9 transgenic mice, BMS-962476 rapidly lowered cholesterol and free PCSK9 levels. In genomic transgenic mice, BMS-962476 potently reduced free human PCSK9 (ED50 ∼0.01 mg/kg) followed by ∼2-fold increases in total PCSK9 before return to baseline. Treatment of cynomolgus monkeys with BMS-962476 rapidly suppressed free PCSK9 >99% and LDL-cholesterol ∼55% with subsequent 6-fold increase in total PCSK9, suggesting reduced clearance of circulating complex. Liver sterol response genes were consequently downregulated, following which LDL and total PCSK9 returned to baseline. These studies highlight the rapid dynamics of PCSK9 control over LDL and liver cholesterol metabolism and characterize BMS-962476 as a potent and efficacious PCSK9 inhibitor.

Footnotes

    • Received February 24, 2014.
    • Accepted June 9, 2014.
  • Use of the Advanced Photon Source was supported by the U S Department of Energy. Use of the IMCA-CAT beamline 17ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with the Center for Advanced Radiation Sources at the University of Chicago.

  • dx.doi.org/10.1124/jpet.114.214221.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 350 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 350, Issue 2
1 Aug 2014
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Research ArticleDrug Discovery and Translational Medicine

Structure and Pharmacodynamics of an Adnectin PCSK9 Inhibitor

Tracy Mitchell, Ginger Chao, Doree Sitkoff, Fred Lo, Hossain Monshizadegan, Daniel Meyers, Simon Low, Katie Russo, Rose DiBella, Fabienne Denhez, Mian Gao, Joseph Myers, Gerald Duke, Mark Witmer, Bowman Miao, Siew P. Ho, Javed Khan and Rex A. Parker
Journal of Pharmacology and Experimental Therapeutics August 1, 2014, 350 (2) 412-424; DOI: https://doi.org/10.1124/jpet.114.214221

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Research ArticleDrug Discovery and Translational Medicine

Structure and Pharmacodynamics of an Adnectin PCSK9 Inhibitor

Tracy Mitchell, Ginger Chao, Doree Sitkoff, Fred Lo, Hossain Monshizadegan, Daniel Meyers, Simon Low, Katie Russo, Rose DiBella, Fabienne Denhez, Mian Gao, Joseph Myers, Gerald Duke, Mark Witmer, Bowman Miao, Siew P. Ho, Javed Khan and Rex A. Parker
Journal of Pharmacology and Experimental Therapeutics August 1, 2014, 350 (2) 412-424; DOI: https://doi.org/10.1124/jpet.114.214221
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