Merck Sharp + Dohme Corp.

Merck Sharpe & Dohme Corp.

Joseph C Santoro

Ayesha Sitlani

Yan Li

Pingyu Zhong

Feng Dong

Rose M Cubbon

Holly A Hammond

Jon H Condra

Kevin Caili Wang

Jeffrey T Blue

Laurence B Peterson

Shilpa Pandit

Denise K Nawrocki

Dana D Wood

Henryk Mach

Sonia M Gregory

Peter Peizhi Luo

Timothy McCabe

Heidi Pixley

Laura Orsatti

Heidi Yoder

Peizhi (Peter) Luo

Timothy S Fisher

Timothy Mccabe

Antagonists of human proprotein convertase subtilisin-kexin type 9 ('PCSK9') are disclosed. The disclosed antagonists are effective in the inhibition of PCSK9 function and, accordingly, present desirable antagonists for use in the treatment of conditions associated with PCSK9 activity. The present invention also discloses nucleic acid encoding said antagonists, vectors, host cells, and compositions comprising the antagonists. Methods of making PCSK9-specific antagonists as well as methods of using the antagonists for inhibiting or antagonizing PCSK9 function are also disclosed and form important additional aspects of the present disclosure.

1B20 PCSK9 antagonists

1D05 PCSK9 antagonists

The present invention provides a method for detecting autoprocessed, secreted PCSK9, a protein involved in cholesterol homeostasis, and for effectively identifying compounds that inhibit autocleavage and secretion from cells. The disclosed method involves the insertion of an epitope tag into a PCSK9 expression construct immediately C-terminal to the pro domain ending at an amino acid residue corresponding to Q152 of human PCSK9. Upon autoprocessing, the epitope tag is exposed and capable of recognition by anti-epitope antibodies or other suitable identification system, allowing for the selective and exclusive identification and/or quantification of processed PCSK9. The present disclosure thus advances the goal of providing enabling technology to the art for the effective identification of therapeutics effective in combating coronary heart disease.

Method for detecting autoprocessed, secreted PCSK9

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Belle Mead, NJ, United States of America

Joseph C Santoro