Institut De Recherches Cliniques De Montreal

Other

Adaerata, Limited Partnership

National Research Council of Canada

Institut National De La Recherche Scientifique

Clinical Research Institute of Montreal

Adaerata, Limited Partnershp

Nabil G Seidah

Michel Chretien

Michel Tremblay

Geneviève Dubuc

Jean Davignon

Lise Bernier

Jianbing Zhang

Steve Poirier

Robert Day

Guy Leclerc

Patrick Labonté

Gaétan Mayer

Mieczyslaw Marcinkiewicz

R&eacute;mi Martel

Tim Reudelhuber

Michel Chr&eacute;tien

Antibodies (e.g., sdAbs) binding to PCSK9 are described. Nucleic acids encoding such Abs, host cells expressing such Abs and pharmaceutical composition comprising same are described. The use of these PCSK9-binding Abs for lowering low-density lipoprotein-cholesterol (LDL-C) levels and for the treatment of cardiovascular disorders, is also described.

Single domain antibodies as inhibitors of PCSK9

A method for identifying a compound for preventing or treating a LDLR-associated disease, a VLDLR-associated disease or an ApoER2-associated disease, said method comprising determining whether: a) a level of expression of Annexin A2 nucleic acid or encoded polypeptide; b) a level of Annexin A2 activity; or c) a combination of a) and b), is increased in the presence of a test compound relative to in the absence of said test compound, wherein said increase is indicative that said test compound can be used for preventing or treating a LDLR-associated disease, a VLDLR-associated disease, an ApoER2-associated disease.

PCSK9 inhibitors and methods of use thereof

A chimera protein comprising in the following order: a signal peptide, a proprotein convertase subtilisin/kexin type 9 preproprotein (PCSK9) sequence consisting of amino acid residues at positions 35 to 696 of SEQ ID NO: 38, a transmembrane domain and a cytosolic domain, wherein said cytosolic (CT) domain comprises a sequence able to recycle the protein from the cellular membrane to endosomes.

Chimeric PCSK9 proteins, cells comprising same, and assays using same

A method for treating and/or preventing a proprotein convertase subtilisin/kexin type 9 preproprotein (PCSK9)-susceptible viral infection comprising increasing a PCSK9 activity and/or expression in a biological system infected by the virus, whereby the increased PCSK9 activity and/or expression treats and/or prevents the viral infection in the biological system. Methods of classifying subjects, methods of screening and kits therefore.

Methods of reducing a viral infection and kits therefore

Using RT-PCR and degenerate oligonucleotides derived from the active site residues of subtilisin-kexin-like serine proteinases, we have identified a highly conserved and phylogenetically ancestral human, rat and mouse type-I membrane-bound proteinase called subtilisin-kexin-isozyme-1 (SKI-1). Computer data bank searches reveals that human SKI-1 was previously cloned but with no identified function. A SKI-1 processed fragment is secreted in culture media in a soluble form. In vitro studies suggest that SKI-1 is a Ca-dependent serine proteinase exhibiting a wide pH optimum for cleavage of proBDNF. Peptides mimicking SKI-1 cleavages sites are also disclosed. SKI-1 prosegment has an ex vivo inhibitory effect on SKI-1 activity. The prosegment is also processed and secreted in culture media. One of its fragments is found tightly associated with the SKI-1 soluble form. Therapeutic applications for SKI-1 inhibitors are disclosed.

Mammalian Subtilisin/kexin isozyme SKI-1: a proprotein convertase with a unique cleavage specificity

The present invention relates to the cloning of human pro-protein converting enzyme 5 (PC5) CDNA isolated from human adrenal gland messenger RNA. Additionally, this invention relates to a method for reducing restenosis occurring at an injured vascular site comprising delivering to the injured site an antisense nucleic acid to suppress the expression of human PC5.

Pro-protein converting enzyme

This invention relates to a novel and seventh member of the subtilisin-kexin family isolated from rat, which has been named rPC7. The rat spleen cDNA has been totally sequenced. A shorter DNA sequence has been obtained for human, which corresponds to a portion of the catalytic region of a human pro-hormone convertase corresponding to the rat pro-hormone convertase. PC7 clearly distinguishes from the other mammalian members of the subtilisin-kexin family. Its tissue distribution is ubiquitous, but its presence is particularly remarkable in lymphoid tissues. It is present in LoVo cells that are able to cleave the HIV gp160 protein into active gp120/gp41 proteins and that are deficient in other effective pro-hormone convertases known up to date. Therefore, it is proposed that PC7 is a good candidate as a maturation enzyme responsible for the conversion of HIV gp160 protein in target CD.sup.+4 cells.

Mammalian pro-hormone convertase

The present invention relates to pro-hormone convertases and polypeptidic fragments thereof, nucleic acids encoding them, recombinant viruses expressing these convertases, polyclonal antibodies directed against the convertases, diagnostic kits for the detection and measurement of the convertase content in cell or tissue lysates, culture media or biological fluids by RIA. Diagnostic kits were also developped for detection or measurement of nucleic acids, preferably mRNAs, in cell or tissue lysates by hybridization. The invention also concerns oligonucleotides useful as probes or as primers for DNA synthesis. These oligonucleotides were included in the diagnostic kits as well as used for the obtention of specific fragments of the convertases which have served, together with native convertases, as antigens for the obtention of antibodies. The convertases were produced by mammalian cell lines transfected with the recombinant viruses and purified on affinity columns which are also an object of the invention. Processes for producing the native convertases, fragments thereof and antibodies are also described and claimed.

Development of research diagnostic and production tools for pro-hormone

There are disclosed the N-terminal fragment of human pro-opiomelanocortin, a glycopeptide composed of 76 amino acid residues, and a process for preparing same from human pituitary glands. The glycopeptide is useful in potentiating the effects of ACTH on steroidogenesis, in stimulating the production of aldosterone, as a diagnostic tool, as well as a reagent for determining its presence in biological fluids and tissues by immunochemical means.

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Verdun, Canada

Nabil G Seidah