Isländischer reporter

isländischer reporter

Juni In letzter Minute gelingt EM-Neuling Island der Siegtreffer gegen Österreich. Danach kennt der Jubel keine Grenzen. Ein isländischer. Auch nach dem historischen Sieg über England bei der Fußball-EM ist ein Isländer in aller Munde: Reporter Guðmundur Benediktsson, der völlig heiser, nach. Juni Im Achtelfinale gegen England fiebert der isländische Reporter wieder leidenschaftlich mit - und kriegt sich nach dem Abpfiff gar nicht mehr ein.

Isländischer Reporter Video

Island: Huh! Zehntausende empfangen isländisches Nationalteam nach ihrer Rückkehr aus Frankreich

It took me a while to realize he was a man, there was just something about it that made me assume Einar was female. The other characters are ok and even provide some comic relief.

By the end, I was drawn into the story, but it is not one of my favourite series. Aug 11, Lynn Weber rated it liked it Shelves: I particularly liked the protagonist of this mystery, a middle-aged journalist who is quirky and funny and outgoing, not the gruff, noir-tinged figure of most police procedurals.

Jan 11, Suspense Magazine added it. Icelandic newspaper reporter Einar has failed at pretty much everything that matters: Now he has been assigned to the northern city of Akureyri, far from bustling Rekyjavik as a last chance to keep his job with the Evening News.

Here the former crime reporter must—to his chagrin—turn his talents to penning stories about high school play productions and lost dogs…or at least until the first body pops up.

So begins this Nordic knot of a story where the Icelandic newspaper reporter Einar has failed at pretty much everything that matters: So begins this Nordic knot of a story where the strands and strains of daily modern Icelandic life weave together to create a perplexing pattern of envy, greed, and lust.

Einar follows these strands, one by one and through every twist and turn as he unravels the mystery confronting him. Meanwhile, at the other end of the economic scale, powerful and politically connected industrialists make clear their interests in keeping, to all outward appearances, everything neat and tidy.

In the end, a line from the play performed sums up the crucial crux of this tangled tale: Ich bin aber froh darum. Es hat ein bisschen gedauert, bis ich reingekommen bin, aber nachher hat mir das Buch ziemlich gut gefallen.

Es ist aber m. Nov 25, Booknblues rated it really liked it Shelves: Season of the Witch By Arni Thorarinsson 3 stars pp. The protagonist, Einar is a journalist who covers crime.

Starting with the fourth of a series, one misses some of the back story of the protagonist and must fill in the where possible. It appears the Einar used to bend his elbow a bit but is now trying to dry up.

He is an intrepid investigator and that is what makes him interesting. The story is intricate and interesting.

I did have some problems with the resolution and the use of justice. I suppose each reader will have to answer if this satisfies their moral code.

I do think that this was interesting enough and promising to read more of the series, when they become available in English. Jul 18, Marije rated it it was ok.

I think I expected more dramatic Icelandic nature, to lose myself in the dark, desolate beauty and grimness of the northern wild. But it was hard to get more than names and places from this book.

It was as if I was reading a book-adaptation of a movie. Telling instead of showing is not always a bad thing, but in this case it is. Dec 07, Carol Jean rated it liked it.

Chatty Icelandic murder mystery with a newspaper reporter protagonist. Amusing and entertaining, but not terribly involving, somehow. Juoni hatara, liikaa sivuja.

Jun 07, Lora rated it liked it. The mystery kept me guessing, the characters were interesting and there were some interesting observations and bits about Icelandic culture.

I would definitely read future translations by this author, even though this one had some minor flaws. One chapter felt a bit disjointed, and in a couple places the author mentioned a new chara The mystery kept me guessing, the characters were interesting and there were some interesting observations and bits about Icelandic culture.

One chapter felt a bit disjointed, and in a couple places the author mentioned a new character in such a way as I thought it was an existing character I had forgotten about.

The time period was not mentioned but presumed to be the same as the publication date of This is important because so much has changed technology since its publication, and that has some bearing on our understanding of the plot.

Nothing outstanding but I did rather enjoy reading this - the central voice was very clear. May 22, Jane Segal rated it really liked it Shelves: This book takes place in a remote northern city; the amateur sleuth is a journalist who must unravel the quaint city facade to solve several local murders.

Great background and character development. Jan 30, Heather rated it liked it Shelves: It was worthwhile for me due to my Iceland obsession, but I would recommend anyone go out of the way to read this one unless the obsession is mutual.

Jun 08, Buchdoktor rated it really liked it Shelves: Das Handwerkliche Bei amazon-crossing erscheint "Seasons of the witch" als Paperback, das in Format und Seitenlayout den deutschen Klappenbroschuren entspricht.

Mar 10, Linda Branham Greenwell rated it really liked it Shelves: A recovering alcoholic newspaper reporter, Einar is sent to a small town in the northern Iceland for a second chance and a new start.

His main assignment is to write human interest stories, but soon Einar finds himself delving into into some mysterious events that are happening in the small town.

I found the first approximately 90 pages to not be very interesting - more background on the characters - but then it picks up and became a very good story.

Interesting, but not usually for the expected reasons. So I cannot say I have a great conceptual framework into which to place this book.

But it looked interesting enough and was titled "Season of the Witch"--at the time, I was buying books with that title.

And when it comes though most clearly at the end seems way out of place. The book, for example, is in constant dialogue with a century-old Icelandic saga.

There are obvious points of contact, and the author brings them out, but I suspect I am missing some of the weight of the connections simply because I am unfamiliar with the referenced material.

And there is something going on with pets throughout the whole story--birds and dogs--that I think the author is using to make some point, but I do not know what that point is.

The mystery itself is never more than a diversion, and fairly easily solved once the protagonist--a former drunk reporter re-assigned to city to the sticks with a boos he hates hello, boatload of cliches!

The real interest in the story is seeing the strains of modernity on Icelandic society. Think of it as The Wire in Iceland.

The book does, unfortunately, tie itself up with too much of a bow--it is too satisfied with its own analysis of the situation. Aug 02, Gretel rated it it was ok Shelves: Season of the Witch is an Icelandic crime mystery, set in the northern town of Akureyri.

According to Wikipedia, it has a population of 17, Putting that aside, I thought the novel was ok. Things become strange when a woman drowns and a high school student dies.

Einar sticks his nose into these stories and tries to get to the bottom of them. I also feel as though Einar has some missing backstory.

Being this the fourth in the series and the first translated into English, this is probably the case. If the other books do get translated into English I think I will read them, as I think Einar may have a pretty interesting past.

I feel as if the author drags the story out a little and it has a lot of padding. It takes a while to gain traction and get going.

The last page had me laughing. All in all, pretty average, but I would read other Einar books. Jun 06, Andrew Macrae rated it really liked it. Here the former crime reporter must—to his chagrin—turn his talents to penning stories about high school play productions and lost dogs Feb 01, Andy Bryant rated it it was ok.

The main disappointment for me though was the treatment of the setting - the thing that drew me to the book. The underlying social commentary around immigration and its effect on Icelandic society and politics seemed completely arbitrary and, ultimately, not even remotely relevant to the story - so the opportunity to make this distinctively a story about Iceland and its people was missed.

As other reviewers have said, it could have been set pretty much anywhere in Europe. The overall sense I got from the story was that none of the principal characters wanted to be out in the sticks, all of them wishing they could be in Reykjavik where the action is.

I got the impression that the author felt pretty much the same. Jul 24, Molly rated it did not like it Shelves: Unfortunately, this mystery felt a bit flat--because of the strange tone, the odd attempts at humor, nothing ever truly felt at risk.

At times, the author would give us a didactic non-sequitur, such as: And so it goes on. Once upon a time, I used to keep up with fashion.

How can you make a girl believe that a muffin-top of naked blubber sagging over her waistband is sexy? It may be kind of cute, and relaxed, and remind us that we all have a tummy.

How can that happen? I wonder as I smoke my cigarette. I think there were opportunities--sympathy or curiosity or even a Dan Brown-ish pulse.

Instead, I keep thinking of this character, soggy and dull, smoking a cigarette while asking strangers on the street random "Questions of the Day," calling this journalism in some confused way.

Oct 24, Rick rated it really liked it. Shortly after his arrival in the north, a woman on a corporate excursion dies unexpectedly, and after that a popular young student is murdered.

Einar spends the rest of the novel investigating the two deaths. The method according to aspect 41, wherein said ligand and said statin are administered simultaneously.

Das Verfahren nach einem der Aspekte 29 bis 43, wobei der Ligand durch subkutane Injektion verabreicht wird.

According to a forty-fourth aspect: The method according to any of aspects 29 to 43, wherein the ligand is administered by subcutaneous injection.

According to a forty-fifth aspect: According to a forty-sixth aspect: A method of PCSK9 Typisierens a protein sample of a human, the method comprising identifying in the sample the presence of human PCSK9 selected from the group consisting of the shapes f, c, r, p, m, e, h , aj and q comprises.

In one example, the method comprises obtaining a PCSK9 protein sample from the human, and then carrying out the identifying step.

According to a forty-seventh aspect: The method according to aspect 45 or 46, wherein one gets a serum, blood, faeces, hair, tissue, cell, urine, or saliva sample from a human, wherein the nucleic acid or protein sample is recovered and used in the step for identifying the sequence.

According to a forty eighth aspect: The method according to any of aspects 45 to 47, which comprises using a ligand according to any one of aspects 1 to 19 for carrying out the identification step.

Bei einem Beispiel umfasst die Reduzierung bzw. According to a fiftieth aspect: According to a fifty-first aspect: As a mature, split, autocatalyzed or active PCSK9.

In one example, this is the disease is a cardiovascular disease such as hyperlipidemia. In examples of the present invention, the ligand specifically binds to human PCSK9, z.

The determination of such binding may be by any known in the art, antibody binding assay, eg. For example, by surface plasmon resonance.

According to an embodiment, in both forms to mature forms. According to an embodiment, in both forms of pro-forms.

In examples of the present invention, the ligand neutralises human PCSK9, z. Regeneron Pharmaceuticals, Inc carried disclosed neutralization assay method.

In embodiments wherein the ligand for therapeutic applications is used, an antigen binding protein can have one or more biological activities of PCSK9 z.

In one embodiment, the ligand specifically binds to human PCSK9 eg. In one example, it is the ligand is an antibody.

In one example, the Kd is determined using SPR. Example in the range of 1 mM to 1. Example in the range of 1 mM to 1 pM. Such binding measurements can carried out by various known in the art, binding assays such.

According to one embodiment, the screening or testing of a ligand according to the invention takes place at or substantially at a pH value of 7 for.

Example, in in vitro tests and assays and at or substantially at RT. As shown, the sequence of which is hereby incorporated into the present application by reference.

In the examples of the present invention the ligand binds mature PCSK9, z. In the examples of the present invention, the ligand binds to the catalytic domain of PCSK9, z.

In the examples of the present invention, the ligand binds the prodomain of PCSK9, z. In examples of the present invention, wherein the ligand is a complete human antibody, or it comprises such.

Bei einem Beispiel umfasst der Ligand humane variable Regionen oder humanisierte variable Regionen. In one example, the ligand human variable regions or humanized variable regions comprises.

In one example, the ligand according to the invention specifically binds to an epitope of a human PCSK9 selected from the group consisting of the shapes f, c, r, p, m, e, h, j and q, wherein the epitope comprises at least one amino acid which is not found in the form of a.

In one example, is in the form of PCSK9 to the mature form. In one example, is in the form of PCSK9 to the pro-form. According to one embodiment, the ligand specifically binds to an epitope of the form f PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to an epitope of the Form c PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to an epitope of the form r PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to an epitope of the form p PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to an epitope of the form m PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to an epitope of the form e PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to an epitope of the form h PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to an epitope of the form aj PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to an epitope of the form q PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-selected domain of a human PCSK9 from the group consisting of the shapes f, c, r, p, m, e, h, j and q.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form f PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form c PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form r PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form p PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form m PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form e PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form h PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form aj PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form q PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment the ligand binds specifically selected to the catalytic domain of a human PCSK9 from the group consisting of the shapes f, c, r, p, m, e, h, j and q.

According to one embodiment, the ligand specifically binds to the catalytic domain of the form f PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the catalytic domain of Form c PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the catalytic domain of the form r PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the catalytic domain of the form p PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the catalytic domain of the form m PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the catalytic domain of the form e PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the catalytic domain of the form h PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the catalytic domain of the form aj PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the catalytic domain of the form q PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of a human PCSK9 selected from the group consisting of the shapes f, c, r, p, m, e, h, j and q.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form f PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form c PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form r PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form p PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form m PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form e PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form h PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form aj PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form q PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

Which is hereby incorporated by reference in their entirety in the present application. According to one embodiment, the ligand specifically binds to the substrate-binding groove of the form f PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the substrate-binding groove of the Form c PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the substrate-binding groove of the form r PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the substrate-binding groove of the form p PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the substrate-binding groove of the form m PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the substrate-binding groove of the form e PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the substrate-binding groove of the form h PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the substrate-binding groove of the form aj PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the substrate-binding groove of the form q PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

Amgen, Inc referenced, the entire disclosure of which is hereby incorporated into the present application by reference.

The present patent application discloses relevant ligands for use in the present invention as well as examples and methods for the preparation and testing of ligands that may be used with respect to the present invention.

Amgen, Inc disclosed antibodies, or the ligand includes such an antibody, or they are the ligand to a PCSK9-binding derivative thereof. Amgen, Inc , for example.

Amgen, Inc are used, and these sequences are hereby incorporated by reference in the same way in the present application, than if they would have been in detail and for possible inclusion in one or more claims or for use in the present invention listed here.

A one or more hypervariable regions of the heavy chain heavy chain complementary determining regions, CDRH selected from the group consisting of: Amgen, Inc , or an antibody that comprises the variable domains of AMG, 31H4, 16F12, 11F1, 8A3 or 21B12, or consists of, the disclosures including sequences are hereby incorporated by reference in the same way in the present application than if they would have been in detail and for possible inclusion in one or more claims or for use in the present invention listed here.

Vorzugsweise umfasst der auf PCSK9 zielende bzw. In one example, AMG, or other ligand according to the invention is glycosylated and has z.

In one example, the ligand according to the invention in CHO is produced. Regeneron Pharmaceuticals, Inc referenced, the entire disclosure of which is hereby incorporated into the present application by reference.

The present patent application discloses relevant ligands for use in the present invention as well as examples and methods for the preparation and testing of ligands, and determining which can be used with respect to the present invention, the medical effectiveness.

Reference is made to the following PCT applications, the entire disclosures are hereby incorporated into the present application by reference.

These disclose relevant ligands for use in the present invention as well as examples and methods for the preparation and testing of ligands, and determining which can be used with respect to the present invention, the medical effectiveness.

All of these disclosures including the sequences of such proteins and the corresponding nucleotide sequences are incorporated as if they have been listed in detail herein, and for possible inclusion in one or more claims or for use in the present invention by reference in the same way in the present application, as would.

Die obige Literaturstelle wird hiermit durch Verweis in ihrer Gesamtheit Bestandteil der vorliegenden Anmeldung. The above reference is hereby incorporated by reference in their entirety into the present application.

In one example, the antibody is glycosylated and has, for. Vorzugsweise handelt es sich bei dem Liganden um Alirocumab bzw. According to one embodiment, the ligand for the variable domains of the antibody evolocumab, or it includes them, or is such an antibody or a PCSK9-binding derivative thereof or it comprises these.

Vorzugsweise handelt es sich bei dem Liganden um Evolocumab. Preferably, the ligand to evolocumab. Regeneron Pharmaceuticals, Inc disclosed include, for.

These documents may in each case by reference in their entirety into the present application. Die obigen Literaturstellen werden jeweils durch Verweis in ihrer Gesamtheit Bestandteil der vorliegenden Anmeldung.

The above references are in each case by reference in their entirety into the present application. Diagnostic procedures performed are used, the disclosure of which is incorporated into the present application by reference.

Diagnostische Anwendungen diagnostic applications. According to some embodiments, the ligand of the invention is a diagnostic tool.

As the skilled artisan will appreciate, such ligands need not be neutralizing ligands. According to some embodiments is in the diagnostic ligand is not a neutralizing ligands.

According to some embodiments of the diagnostic ligand binds to a different epitope from that to which a neutralizing ligand binds.

According to some embodiments, the two ligands do not compete with each other. To view the presence of a ligand different media can be used.

Man kann beispielsweise Fluorophore, andere molekulare Sonden oder Enzyme an den Liganden anbinden und das Vorhandensein des Liganden auf verschiedene Arten beobachten.

One can for example, bind fluorophores, other molecular probes, or enzymes to the ligand and observe the presence of the ligands in different ways.

The method for screening for such diseases, the application of the kit, or simply the use of the disclosed ligand and determining whether the ligand binds to PCSK9 in a sample include.

Dem Fachmann wird bewusst sein, dass hohe bzw. About the ligand binding degree thus can be determined how much PCSK9 is present in a sample.

Subjects or samples with an amount of PCSK9, which is above a predetermined amount eg. According to some embodiments, the invention provides a method which comprises administering to a subject a statin engaging the ligand to determine whether increased by the statin the amount of PCSK9.

For example one, two or disclosed more here rare form variants can bind and is characterized by at least one of: In some embodiments, an isolated nucleic acid molecule is provided which encodes the ligand.

In some embodiments, an expression vector is provided which comprises the nucleic acid molecule. According to some embodiments, a pharmaceutical composition is provided which may comprise the ligand and a pharmaceutically acceptable carrier.

According to some embodiments, a method for the treatment of a disease or affliction is provided with an inventive alleviated PCSK9 antagonist ligands improved, can be inhibited or prevented.

Das Verfahren kann die Verabreichung einer therapeutischen Menge der pharmazeutischen Zusammensetzung bzw.

The method may include administering a therapeutic amount of the pharmaceutical composition or of the ligand to a subject in need thereof. According to some embodiments, the subject is a human subject suffering from hypercholesterolemia or hyperlipidemia, in which a LDL apheresis was found that statin intolerant as heterozygous for familial hypercholesterolemia or was not identified in response to statins or in which the risk the occurrence of hypercholesterolemia, dyslipidemia, cholestatic liver disease, nephrotic syndrome, hypothyroidism, obesity, atherosclerosis and cardiovascular disease is.

In some embodiments, a subject is provided a method for providing a treatment or therapy. According to some embodiments, a method for obtaining a treatment or therapy is provided, the method may comprise the administration of a ligand in a frequency of once every 60 to 90 days.

According to one embodiment, the ligand according to the invention comprises an antibody or antigen-binding fragment of an antibody, which specifically binds to hPCSK9 and is characterized by at least one of: According to one embodiment, the invention comprises an antibody or antigen-binding fragment of an antibody, which specifically binds to hPCSK9 and is characterized by at least one of: According to one embodiment, the antibody or antigen-binding fragment is characterized by the fact that he or it enhanced binding affinity KD for hPCSK9 at a pH value of 5.

According to a particular embodiment, the antibody or fragment thereof is a least 20 fold, at least fold, or at least fold increased affinity for PCSK9 at an acidic pH as compared to a neutral pH, as measured by surface plasmon resonance.

According to one embodiment, the antibody or antigen-binding fragment is characterized in that it or it shows no increased binding affinity for PCSK9 at an acidic pH as compared to a neutral pH, as measured by surface plasmon resonance.

According to a particular embodiment, the antibody or fragment thereof exhibits a reduced binding affinity at an acidic pH. In one example, the invention is characterized by a pharmaceutical composition comprising a ligand according to the invention, wherein the ligand is a recombinant human antibody or a fragment thereof, or the hPCSK9 specifically binds includes or consists thereof, and a pharmaceutically acceptable carrier.

According to one embodiment, the invention is characterized by a composition which is a combination of the ligand according to the invention is z.

As an antibody or an antigen-binding portion of the antibody of the invention , wherein the therapeutic method comprising administering a therapeutically effective amount of a comprise an antibody of the invention or an antigen-binding fragment of an antibody according to the invention comprising the pharmaceutical composition.

Bei der behandelten Erkrankung handelt es sich um eine beliebige Krankheit oder ein beliebiges Leiden handeln, die bzw.

In the treated disease is any disease or any suffering act machine or improved by removing, inhibiting or reducing the PCSK9 activity, alleviated, inhibited or prevented.

In particular embodiments of the inventive method the ligand of the invention is z. The ligand according to the invention eg.

The term "isolated" in reference from a ligand, an antibody or a protein, for example, in one aspect, a configuration, an example or an embodiment means that a standing in speech ligand, standing in speech antibody, in speech standing protein, etc.

Typically, makes an "isolated" ligand, "isolated" antibody, an "isolated" protein, etc. Preferably, the isolated ligand isolated antibody, the isolated protein, etc.

An "isolated" antibody, for example, is one selected from a component of its production environment eg.

Vorzugsweise ist das isolierte Polypeptid frei von einer Assoziation mit allen anderen Komponenten aus seiner Produktionsumgebung, z. Preferably, the isolated polypeptide is free of association with all other components from its production environment, such.

As such that the antibody to an FDA certifiable or certified standard was isolated. Isolated antibodies include the antibody in situ within recombinant cells, since at least one component from the natural environment of the antibody will not be present.

Usually, an isolated polypeptide or an isolated antibody by at least one purification step is made. Die Erfindung umfasst den Liganden z. The invention includes the ligands eg.

Cytotoxic agents include any agents that damage cells. The antibodies of the present invention may be monospecific, bispecific or multispecific.

Multi-specific mAbs may be specific or contain antigen-binding domains that are specific for more than one target polypeptide for different epitopes on a target polypeptide.

The human anti-PCSK9- z. For example, be another peptide or protein, or be connected therewith expressed together. An antibody or fragment thereof may for example be functional z.

In an exemplary bispecific antibody format that can be used in the present invention, one wherein the first and second Ig CH3 domain using a first immunoglobulin Ig -CH 3 domain and a second Ig-CH3 domain, differ from each other in at least one amino acid, and wherein at least one amino acid difference, the binding of the bispecific antibody to protein a as compared to a bispecific antibody, which lacks the amino acid difference is reduced.

Variations of the bispecific antibody format described above are contemplated within the scope of the present invention.

The invention provides therapeutic methods of treating a human patient in need of a composition or ligand of the invention. While changes in lifestyle and treatment with conventional medicines are often successful in a reduction in cholesterol levels, not all patients able to achieve the recommended target cholesterol level about such approaches.

Various conditions such as familial hypercholesterolemia FH appear to be resistant, despite an aggressive use of conventional therapies in terms of a reduction of LDL-C levels.

Homozygous and heterozygous familial hypercholesterolemia HoFH, HeFH is an associate with premature atherosclerotic vascular disease suffering.

Patients who HoFH is diagnosed, but not speak mostly on a conventional drug therapy and have limited treatment options.

Specifically could treatment with statins, which reduce LDL-C by inhibiting cholesterol synthesis and upregulating the hepatic LDL receptor in patients who do not have LDL receptors or in which they are defective, have only a small effect.

There is a great unmet medical need for new treatments that address the inadequacies of current treatment options.

The invention provides therapeutic compositions that include the anti-PCSK9 ligands, antibodies or antigen binding fragments thereof of the present invention.

Administration of therapeutic compositions according to the invention is administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, better feed, better tolerance, and the like.

Eine Vielzahl geeigneter Formulierungen findet sich in der allen pharmazeutischen Chemikern bekannten Formulierungssammlung: A variety of suitable formulations can be found in all pharmaceutical chemists known formulation Collection: These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids cationic or anionic containing vesicles lipids such LIPOFECTINT TM DNA conjugates, anhydrous Resorptionspasten, oil-in-water and water-in- oil emulsions, emulsion Carbowax polyethylene glycols of different molecular weights , semi-solid gels, and semi-solid mixtures containing carbowax, a.

Siehe auch See also. The dose may vary depending on the age and size of a subject, wherein the administration is to be made vary the target disease, conditions, route of administration and the like.

Verwendet man den Liganden, z. Using the ligand for. As antibodies of the present invention for treatment of various conditions and diseases associated with PCSK9, including hypercholesterolemia, LDL, and apolipoprotein B associated diseases and disorders of lipid metabolism and dergleich, for an adult patient, it is advantageous for the ligand or to administer antibodies of the present invention intravenously, usually in a single dose of about 0.

Frequency and duration of treatment may be adjusted according to the severity of the disease. Thus, the composition of the invention the ligand for.

For example, by encapsulating in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis see, eg.

Mundschleimhaut, rektale und intestinale Schleimhaut usw. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings e.

Die Verabreichung kann systemisch oder lokal sein. The administration may be systemic or local. Die pharmazeutische Zusammensetzung kann auch in einem Vesikel, insbesondere einem Liposom, verabreicht werden siehe The pharmaceutical composition may also be administered in a vesicle, in particular a liposome see ; ; ; ; ; ; siehe allgemein ibid.

In bestimmten Situationen kann die pharmazeutische Zusammensetzung in einem System mit kontrollierter Freisetzung verabreicht werden.

In certain situations, the pharmaceutical composition may be administered in a controlled release system. According to yet another embodiment, one may place a controlled release system in the vicinity of the target of the composition, whereby a fraction of the systemic dose see, eg.

The injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, drip infusions, etc..

These injectable preparations can be prepared by publicly known methods. Die injizierbaren Zubereitungen lassen sich zum Beispiel herstellen, indem man z.

The injectable formulations can be prepared, for example, by z. As the antibody described above or its salt in a sterile aqueous medium or an oily medium conventionally used for injections, dissolved, suspended or emulsified.

Ethanol , einem Polyalkohol z. Propylenglykol, Polyethylenglykol , einem nicht ionischen Tensid [z. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic, containing glucose and other adjuvants solution, etc.

Polysorbate 80, HCO polyoxyethylene 50 mol adduct of hydrogenated castor oil may be used], and so on. As an oily medium z. As sesame oil, soybean oil used, etc.

The thus prepared injection is preferably filled in an appropriate ampoule. A pharmaceutical composition of the present invention may be administered subcutaneously or intravenously with a standard needle and syringe.

Moreover, it is often used a pin-shaped administering apparatus with respect to a subcutaneous administration in the administration of a pharmaceutical composition of the present invention.

Such a pen-shaped administering device is reusable or for single use. In a reusable pen-shaped administering apparatus in general, a replaceable cartridge is used, containing a pharmaceutical composition.

Nachdem die gesamte pharmazeutische Zusammensetzung in der Kartusche verabreicht wurde und die Kartusche leer ist, kann die leere Kartusche leicht entsorgt und durch eine neue, die pharmazeutische Zusammensetzung enthaltende Kartusche ersetzt werden.

After all of the pharmaceutical composition is administered in the cartridge and the cartridge is empty, the empty cartridge can be easily disposed of and replaced with a new one containing the pharmaceutical composition cartridge.

The pin-shaped administering device can then be reused. In a pin-shaped disposable administration set, there are no replaceable cartridge. Rather, the pin-shaped disposable administration device is pre-filled with the pharmaceutical composition that is located in a reservoir in the device, supplied.

Once the pharmaceutical composition has been emptied from the reservoir, the entire device is disposed of. Many reusable pen and autoinjector delivery devices find use in the subcutaneous administration of a pharmaceutical composition of the present invention.

Advantageously, the pharmaceutical compositions described above for oral or parenteral use as dosage forms in a unit dose, suitable to receive a dose of the active ingredients was prepared.

Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injectables ampoules , suppositories and so on. The invention provides therapeutic methods where the ligand according to the invention, z.

The anti-PCSK9 ligand invention, eg. For example, antibodies or antibody fragments, are particularly suitable for treatment of hypercholesterolemia and the like.

Niacin mit Lovastatin ; a statin with a bile resin, a fixed combination of niacin plus a statin e. Ligands according to the invention are suitable for example for assays of specific binding, for genotyping or phenotyping of people, for affinity purification of PCSK9 and for screening assays to identify other antagonists of PCSK9 activity.

Some of the ligands of the invention are useful for inhibiting the binding of PCSK9 to a related human receptor or such a protein, or to inhibit PCSK9-mediated activities.

The invention comprises anti-PCSK9- z. In some applications, a modification of undesirable glycosylation sites useful for removal may be, or z.

In other applications, the galactosylation can be modified in order to modify complement dependent cytotoxicity Complement-Dependent Cytotoxicity, CDC.

In one example, the invention is characterized by a pharmaceutical composition comprising a ligand according to the invention, wherein the ligand is a recombinant human antibody or a fragment thereof, or the the PCSK9 eg.

As a rare variant described herein specifically binds or consists thereof, and a pharmaceutically acceptable carrier. According to one embodiment, the invention is characterized by a composition in which it is a combination of an antibody ligands of the invention or an antigen-binding fragment of an antibody of the invention and a second therapeutic agent.

In the second therapeutic agent may be an anti-inflammatory agent, an anti-angiogenesis agent, an analgesic agent, a diuretic, a chemotherapeutic agent, an anticancer agent, a vasodilator, a vasoconstrictor, a statin, a beta-blocker, a nutrient, an adjuvant, a Antiobesitasmittel and act an antidiabetic.

A "pharmaceutically acceptable carrier, pharmaceutically acceptable excipient or pharmaceutically acceptable adjuvant" refers to a carrier, an excipient or an adjuvant, or vehicle of a subject together with an agent, such.

As an antibody or an antigen-binding portion of the antibody of the invention , wherein the therapeutic method comprising administering a therapeutically effective amount of includes a comprehensive ligand pharmaceutical composition.

Bei der behandelten Erkrankung handelt es sich um eine beliebige Krankheit oder ein beliebiges Leiden, die bzw. In the treated disease is any disease or suffering any machine or improved by removing, inhibiting or reducing the PCSK9 activity, alleviated, inhibited or prevented.

By the term "therapeutically effective amount" is meant an amount that produces the desired effect for which it is administered. Der Fachmann wird mit Techniken, die sich zur genauen Genotypisierung und Anwendung der Erfindung einsetzen lassen, vertraut sein.

The skilled person will be using techniques that can be used for accurate genotyping and use the invention, familiar. These include the following.

A method for hybridization based. Next-generation sequencing technologies such as pyrosequencing is also useful. Andere Hochdurchsatz-Methoden unterscheiden zwischen Allelen anhand differentieller Hybridisierung, Primer-Erweiterung, Ligation und Spaltung einer allelspezifischen Sonde Other high throughput methods distinguish between alleles based differential hybridization, primer extension, allele specific ligation, and cleavage of a probe ; ;.

One approach to a fully automatic SNP analysis on a large scale is the "homogeneous" assay, ie a Einphasenassay without separation steps, which allows a continuous monitoring during amplification.

The use of two allele-specific probes have different fluorophores allows the SNP determination in the same tube without post-PCR processing.

The genotype is determined from the ratio of intensities of the two fluorescent probes at the end of amplification. Thus, instead of using the entire set of real-time PCR data as in quantitative studies, only uses the endpoint data.

Die Ergebnisse des Assays lassen sich automatisch durch mit den Echtzeit-Thermozyklern gelieferte Genotypisierungs-Software z. The results of the assay can be automatically determined by that came with the real-time thermal cyclers genotyping software eg.

Through this classification process, the need for positive controls is eliminated and an accurate genotyping even in the absence of a genotype class, for example if one allele is rare possible.

The skilled person will be using techniques that can be used for accurate phenotyping and use the invention, familiar.

These include the use of amino acid sequencing of the isolated target protein and comparing the sequences of different variants eg. As the most common variant.

For identifying a specific variant one can use that specifically and selectively binds under stringent conditions in the region of a SNP also an antibody.

In another method, the genotype is determined, and a corresponding amino acid sequence phenotype determines z. For example, by computer translation.

Unless otherwise stated or apparent from the context, the following terms and phrases include the meanings set forth below.

The definitions are provided to assist in the description of certain embodiments, and shall not limit the claimed invention, since the scope of the invention is only limited by the claims.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention counts.

Sollte es eine scheinbare Diskrepanz zwischen der Weise, in der ein Begriff im Stand der Technik verwendet wird, und den hier gegebenen Definitionen geben, so soll der in der Beschreibung bereitgestellten Definition der Vorrang gegeben werden.

Should an apparent discrepancy between where a term is used in the prior art the way, and give the definitions given here, the definition provided in the description of the priority to be given.

For simplicity, here given here in the description, the terms used collected the examples and the appended claims. The terms "reduce", "reduced" or "reduction" are all used herein to mean a reduction of a statistically significant amount.

As used herein includes "reduction" is not a complete reduction compared to a comparison mirror. A reduction is preferably carried out down to a level recognized by the that it is for an individual without a given disease in the normal range.

For purposes of the lowering or reduction of cholesterol levels, for example, a reduction of about points as a "decrease" or "reduction" are considered.

In certain aspects of all embodiments of the invention, the term "inhibition" is used. In connection with a marker or a symptom is "increasing" a statistically significant increase of such a mirror.

Thus, as the term is used herein, "substantially" refers to the qualitative condition that a complete or nearly complete extent or such a degree of interest Charakteristikums or a property is shown.

With the term "substantially" is therefore here the possible lack of completeness that is inherent in many biological and chemical phenomena are expressed.

Um Zweifel zu vermeiden: Just as the term is used herein, "subject" a human or animal. They are usually the animal is a vertebrate such as a primate, a rodent, a pet or a wild game.

To primates including chimpanzees, cynomolgus monkeys, spider monkeys and macaques, eg. Among the rodents are mice, rats, woodchucks, ferrets, rabbits and hamsters.

According to some embodiments, the subject is a mammal, for example. As a primate, eg. As a human being. The terms "individual," "patient" and "subject" are used interchangeably herein.

According to some embodiments may be the subject is a non-human vertebrate, eg. As a primate, a rodent, a mouse, a rat, a pig, a sheep, a zebra fish, a frog, etc.

The subject is preferably a mammal. The mammal may be a human, a non-human primate, a mouse, a rat, a dog, a cat, a horse or a cow, but these examples are not limiting.

Mammals, which are other than humans, can be used advantageously as subjects, the animal models of a disease or a disorder such. A subject can be male or female.

Ein Subjekt kann eines sein, bei dem zuvor diagnostiziert bzw. A subject may be one that was in the diagnosed or previously stated that it suffers from an ailment or has this, in need of treatment, or one or more complications associated with such conditions associated, and where appropriate to have already undergone treatment for the disorder or one or more related with the suffering complications.

Alternativ dazu kann es sich bei dem Subjekt auch um eines handeln, bei dem das Leiden oder die eine oder die mehreren mit dem Leiden in Zusammenhang stehenden Komplikationen bisher noch nicht diagnostiziert wurden.

Alternatively, it may also be the subject is one in which the condition or one or more related with the suffering complications have not yet been diagnosed.

For example, it may be the subject is one that is one or more risk factors for the condition or having one or more related with the suffering complications, or a subject which has no risk factors.

In a treatment of a particular condition "subject in need" or "those in need" can be a subject that this suffering such.

As increased cholesterol levels, has, in which such suffering was diagnosed or where there is a risk of occurrence of suffering.

Thus, as used herein, the terms "protein" and "polypeptide" are used interchangeably to designate a series of amino acid residues linked together by peptide bonds between the alpha-amino and carboxy groups of adjacent residues.

The terms "protein" and "polypeptide" refer to a polymer of amino acids with unnatural amino acids. When reference is made to "modified polypeptides", this refers to polypeptides phosphorylated z.

The terms "protein" and "polypeptide" are used interchangeably herein when it referred to a gene and fragments.

Exemplary polypeptides or proteins thus include gene products, naturally occurring proteins with the specified sequence a.

You can also use Peptidhomologe, Peptidorthologe, Peptideparaloge, peptide fragments, and other equivalents, variants, fragments and analogues of the peptides, as the person of ordinary skill in these terms is familiar.

Thus, as used herein, the term "nucleic acid" or "nucleic acid sequence" refers to any molecule, preferably a polymeric molecule comprising units of ribonucleic acid comprises deoxyribonucleic acid.

The nucleic acid may be either single or double stranded. In a single-stranded nucleic it can be a nucleic acid strand of a denatured double-stranded DNA.

Alternatively, it may be a single-stranded nucleic acid which is not derived from a double-stranded DNA. According to one aspect may be the nucleic acid is DNA.

According to another aspect may be the nucleic acid is RNA. In some aspects, one can also use analogues of nucleic acids.

Thus, as used herein, the term "nucleic acid probe" refers to an isolated oligonucleotide molecule with a nucleic acid sequence that can hybridize with a target nucleic acid sequence, eg.

According to some embodiments, a nucleic acid probe may further comprise a detectable label. According to some embodiments, a nucleic acid probe may be bound to a solid surface.

According to some embodiments, a nucleic acid having a length from about 5 nt to about nt. Thus, as used herein, the term "siRNA" refers to a nucleic acid, which forms an RNA molecule comprising two separate RNA strands which are substantially complementary to each other.

Typically, the siRNA has a length of at least about nucleotides z. According to some embodiments, an siRNA may have blunt ends. The length of the overhang is independent between the two strands, ie the length of the overhang on one strand does not depend on the length of the overhang on the second strand.

As the target RNA present, or is expressed therein. The sequence of PCSK9 different species is known for. Nucleotide and polypeptide sequences for a number of PCSK9 isoforms provided herein are for.

PCSK9 exists both as a pro-form and as a mature form. The inactive form of this cleavage can herein as "inactive", "pro-form" or "not processed" form of PCSK9 are called.

The C-terminal fragment generated by the autocatalysis event can herein as "mature", "split", "processed" or "active" are called PCSK9. Examples of pro-form and mature PCSK9 isoforms are provided herein.

As used herein, a "by PCSK9-mediated" disease or to be suffering from a disease or a condition which is caused by a change of PCSK9 or characterized, for example.

Include hypercholesterolemia a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication, type II diabetes, hypertension and cardiovascular disease or cardiovascular-disease.

In one example, it concerns with the disease or the condition is an inflammatory or autoimmune disease or to be suffering. A subject in which there is a risk of presence or occurrence of a mediated PCSK9 disease or condition may be a subject who displays one or more signs or symptoms of such a disease or condition, or in which one or more risk factors for such a disease or to be suffering exist for.

As obesity, high cholesterol levels, one or more genetic polymorphisms of which is known to predispose to the disease or condition, for example.

As used herein, "ligand" refers to a molecule that can bind to a second molecule, or a receptor, z. According to some embodiments, it may be in a ligand z.

The term "variant" refers, as used herein, refers to a peptide or a nucleic acid, or that which of the polypeptide or the nucleic acid z.

Amino acid substitutions include changes in which one amino acid is replaced by another naturally occurring amino acid residue. Such substitutions may be referred to as "conservative", in which a contained in a polypeptide amino acid residue is replaced by another naturally occurring amino acid of similar character with respect to polarity, side chain functionality or size in this case.

Such conservative substitutions are well known in the art of the present invention comprised substitutions may also be "non-conservative" be, wherein a is in a peptide existing amino acid residue replaced by an amino acid having different properties, such as a naturally occurring amino acid from a different group wherein z.

In some embodiments, amino acid substitutions are conservative. Also included within the term variant, when used in reference to a polynucleotide or polypeptide for.

Example, refers to a polynucleotide or polypeptide, whose primary, secondary or tertiary structure may deviate from a Vergleichspolynukleotid or polypeptide compared to a wild-type polynucleotide or polypeptide.

Variants of PCSK9 are provided elsewhere herein. Variants of PCSK9 can herein as a, f, c, r, p, m, eh, include aj and q forms described.

Sequenzen dieser Varianten werden hier bereitgestellt, siehe z. Sequences of these variants are provided here. In some aspects, can be "synthetic variants", "recombinant variants" or "chemically modified" polynucleotide variants or polypeptide using techniques well known in the prior art methods to isolate or produce.

Some aspects include insertion variants, deletion variants or substituted variants with substitutions of amino acids, including insertions and substitutions of amino acids and other molecules, which do not normally occur in the peptide sequence, which is the basis for the variant, for example, but not by way of limitation, the insertion of ornithine, which does not normally occur in human proteins.

In the Beschriebung of a polypeptide, the term "conservative substitution" refers to a change in the amino acid composition of the polypeptide, the activity of the polypeptide does not change significantly through the.

A conservative substitution refers for example to the replacement of an amino acid residue for another amino acid residue with similar chemical properties.

Conservative amino acid substitutions include the replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, or a threonine with a serine.

A "conservative substitution" of a particular amino acid sequence thus refers to the substitution of amino acids that are not critical to the polypeptide, or the substitution of amino acids with other amino acids with similar characteristics such.

Conservative substitution tables providing functionally similar amino acids are well known in the art. Siehe auch See also , die hiermit durch Verweis in ihrer Gesamtheit Bestandteil der vorliegenden Anmeldung wird.

That herewith by reference in their entirety into the present application. According to some embodiments, can also be individual substitutions, deletions or additions, in which a single amino acid or a small percentage of amino acids changed, added or deleted as "conservative substitutions "See if the activity of the peptide is not reduced by the change.

Insertions or deletions are typically in the range of about 1 to 5 amino acids. The choice of Conservative amino acids may be based on the position of the replaced amino acid in the peptide, for example, when the amino acid is on the outside on the peptide and exposed to solvents is or is located in the interior and solvents is not accessible.

In alternative embodiments, can be the amino acid which replaces an existing amino acid, based on the position of the existing amino acid, ie their exposure to solvents, to select ie, when the amino acid is exposed to solvents, or is present on the outer surface of the peptide or polypeptide, unlike amino acids that are inside and are not accessible solvents.

In alternative embodiments, one may select conservative amino acid substitutions include those which are suitable for amino acids within a protein or peptide, for example, can be carried out suitable conservative substitutions of amino acids that are located in the interior of a protein or peptide ie, the amino acids are not exposed to the solvent , for example, but not by way of limitation, one can perform the following conservative substitutions: In some embodiments, This also non-conservative amino acid substitutions within the definition of variations.

Antibodies can be humanized by routine methods. Typically, antigens of antibody ligands are bound and are capable of eliciting an antibody response in vivo.

In one antigen may be a polypeptide, a protein, nucleic acid or other molecule or a portion thereof.

The term "antigenic determinant" refers to an epitope on the antigen, more specifically by an antigen-binding molecule of the antigen binding site of the molecule recognized.

Thus, as the term is used herein, "antibody fragment" refers to a polypeptide which includes at least one immunoglobulin variable domain or immunoglobulin variable domain sequence and binds specifically to a given antigen.

An antibody fragment may comprise an antibody or polypeptide comprising an antigen binding domain of an antibody.

According to some embodiments, an antibody fragment may comprise a monoclonal antibody or a polypeptide comprising an antigen binding domain of a monoclonal antibody.

For example, an antibody, a variable region of a heavy Heavy, H chain abbreviated herein as VH and a variable region of a light L chain abbreviated herein as VL include.

According to another example, an antibody includes two variable regions of a heavy H chain and two variable regions of a light L chain.

The term "antibody fragment" includes antigen-binding fragments of antibodies eg. Antibodies can be derived from any source, including mouse, rabbit, pig, rat and primate human and non-human primate , and primatized antibodies.

Antibodies also include Midi Bodies, humanized antibodies, chimeric antibodies and the like. As used herein, refers to "variable domain of an antibody" in the portions of the light and heavy chains of antibody molecules, the amino acid sequences of hypervariable regions complementarity determining regions, CDRs; ie CDR1, CDR2 and CDR3 , and framework regions framework regions, FRs form.

VH refers to the variable domain of the heavy chain. VL refers to the variable domain of the light chain. Or define according to the IMGT nomenclature.

An antibody "gene segment" z. For example, a VH gene segment, D gene segment or JH gene segment, refers to an oligonucleotide having a nucleic acid sequence encoding this portion of an antibody, a VH gene segment z.

The VH and VL regions can continue in hypervariability regions as "complementarity determining regions" "CDR" , respectively, between which more conserved regions are known as "framework regions" "FR" are referred to, divided become.

The terms "antigen-binding fragment" or "antigen binding domain" which are used interchangeably herein, refers to one or more fragments of an unabridged antibody are which retain the ability to specifically bind to the target of interest.

Beispielsweise umfasst das Polypeptid eine CDR3 z. For example, the polypeptide comprises a CDR3 z. The polypeptide includes, for example CDRs 1 and 2 eg.

In one example, the antibody binding site by a single variable domain eg. As a VH or VL domain is provided. Bei einem diagnostischen Test beispielsweise kann durch die spezifische Bindung eines Liganden zwischen zwei wie hier beschriebenen PCSK9-Proteinvarianten unterschieden werden.

In a diagnostic test, for example, PCSK9-protein variants can be distinguished by specific binding of a ligand between two as described herein.

According to some embodiments, specific binding to an affinity of the first entity to the second entity, the at least fold, at least fold, at least fold, at least fold, at least fold or greater than the affinity for the third non-may -target structure is to relate.

As part of oligonucleotide strands that interact with each other via hybridization, a specific binding can be a "specific hybridization".

In this regard, functional activity means a polypeptide which is capable of, one or more of the functional activities associated with a recombinant antibody as described herein or antibody reagent thereof to show.

Such functional activities include the ability to bind a target molecule, for example. The term "immunizing" refers to the step or steps of administering one or more antigens to an animal so that antibodies formed in the animal.

In general, immunization involves the injection of the antigen or antigens into the animal. Bei einer Immunisierung kann das Antigen bzw.

In an immunization, the antigen or antigens may be administered once or several times.

Example in the range of 1 mM to 1 pM. Such binding measurements can carried out by various known in the art, binding assays such.

According to one embodiment, the screening or testing of a ligand according to the invention takes place at or substantially at a pH value of 7 for.

Example, in in vitro tests and assays and at or substantially at RT. As shown, the sequence of which is hereby incorporated into the present application by reference.

In the examples of the present invention the ligand binds mature PCSK9, z. In the examples of the present invention, the ligand binds to the catalytic domain of PCSK9, z.

In the examples of the present invention, the ligand binds the prodomain of PCSK9, z. In examples of the present invention, wherein the ligand is a complete human antibody, or it comprises such.

Bei einem Beispiel umfasst der Ligand humane variable Regionen oder humanisierte variable Regionen. In one example, the ligand human variable regions or humanized variable regions comprises.

In one example, the ligand according to the invention specifically binds to an epitope of a human PCSK9 selected from the group consisting of the shapes f, c, r, p, m, e, h, j and q, wherein the epitope comprises at least one amino acid which is not found in the form of a.

In one example, is in the form of PCSK9 to the mature form. In one example, is in the form of PCSK9 to the pro-form. According to one embodiment, the ligand specifically binds to an epitope of the form f PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to an epitope of the Form c PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to an epitope of the form r PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to an epitope of the form p PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to an epitope of the form m PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to an epitope of the form e PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to an epitope of the form h PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to an epitope of the form aj PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to an epitope of the form q PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-selected domain of a human PCSK9 from the group consisting of the shapes f, c, r, p, m, e, h, j and q.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form f PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form c PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form r PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form p PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form m PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form e PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form h PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form aj PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the Pro-domain of the form q PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment the ligand binds specifically selected to the catalytic domain of a human PCSK9 from the group consisting of the shapes f, c, r, p, m, e, h, j and q.

According to one embodiment, the ligand specifically binds to the catalytic domain of the form f PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the catalytic domain of Form c PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the catalytic domain of the form r PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the catalytic domain of the form p PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the catalytic domain of the form m PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the catalytic domain of the form e PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the catalytic domain of the form h PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the catalytic domain of the form aj PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the catalytic domain of the form q PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of a human PCSK9 selected from the group consisting of the shapes f, c, r, p, m, e, h, j and q.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form f PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form c PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form r PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form p PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form m PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form e PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form h PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form aj PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the C-terminal domain of the form q PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

Which is hereby incorporated by reference in their entirety in the present application. According to one embodiment, the ligand specifically binds to the substrate-binding groove of the form f PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the substrate-binding groove of the Form c PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the substrate-binding groove of the form r PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the substrate-binding groove of the form p PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the substrate-binding groove of the form m PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the substrate-binding groove of the form e PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the substrate-binding groove of the form h PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the substrate-binding groove of the form aj PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

According to one embodiment, the ligand specifically binds to the substrate-binding groove of the form q PCSK9, wherein the epitope comprises an amino acid at least, is not found in the form of a.

Amgen, Inc referenced, the entire disclosure of which is hereby incorporated into the present application by reference. The present patent application discloses relevant ligands for use in the present invention as well as examples and methods for the preparation and testing of ligands that may be used with respect to the present invention.

Amgen, Inc disclosed antibodies, or the ligand includes such an antibody, or they are the ligand to a PCSK9-binding derivative thereof.

Amgen, Inc , for example. Amgen, Inc are used, and these sequences are hereby incorporated by reference in the same way in the present application, than if they would have been in detail and for possible inclusion in one or more claims or for use in the present invention listed here.

A one or more hypervariable regions of the heavy chain heavy chain complementary determining regions, CDRH selected from the group consisting of: Amgen, Inc , or an antibody that comprises the variable domains of AMG, 31H4, 16F12, 11F1, 8A3 or 21B12, or consists of, the disclosures including sequences are hereby incorporated by reference in the same way in the present application than if they would have been in detail and for possible inclusion in one or more claims or for use in the present invention listed here.

Vorzugsweise umfasst der auf PCSK9 zielende bzw. In one example, AMG, or other ligand according to the invention is glycosylated and has z.

In one example, the ligand according to the invention in CHO is produced. Regeneron Pharmaceuticals, Inc referenced, the entire disclosure of which is hereby incorporated into the present application by reference.

The present patent application discloses relevant ligands for use in the present invention as well as examples and methods for the preparation and testing of ligands, and determining which can be used with respect to the present invention, the medical effectiveness.

Reference is made to the following PCT applications, the entire disclosures are hereby incorporated into the present application by reference.

These disclose relevant ligands for use in the present invention as well as examples and methods for the preparation and testing of ligands, and determining which can be used with respect to the present invention, the medical effectiveness.

All of these disclosures including the sequences of such proteins and the corresponding nucleotide sequences are incorporated as if they have been listed in detail herein, and for possible inclusion in one or more claims or for use in the present invention by reference in the same way in the present application, as would.

Die obige Literaturstelle wird hiermit durch Verweis in ihrer Gesamtheit Bestandteil der vorliegenden Anmeldung. The above reference is hereby incorporated by reference in their entirety into the present application.

In one example, the antibody is glycosylated and has, for. Vorzugsweise handelt es sich bei dem Liganden um Alirocumab bzw. According to one embodiment, the ligand for the variable domains of the antibody evolocumab, or it includes them, or is such an antibody or a PCSK9-binding derivative thereof or it comprises these.

Vorzugsweise handelt es sich bei dem Liganden um Evolocumab. Preferably, the ligand to evolocumab. Regeneron Pharmaceuticals, Inc disclosed include, for.

These documents may in each case by reference in their entirety into the present application. Die obigen Literaturstellen werden jeweils durch Verweis in ihrer Gesamtheit Bestandteil der vorliegenden Anmeldung.

The above references are in each case by reference in their entirety into the present application. Diagnostic procedures performed are used, the disclosure of which is incorporated into the present application by reference.

Diagnostische Anwendungen diagnostic applications. According to some embodiments, the ligand of the invention is a diagnostic tool.

As the skilled artisan will appreciate, such ligands need not be neutralizing ligands. According to some embodiments is in the diagnostic ligand is not a neutralizing ligands.

According to some embodiments of the diagnostic ligand binds to a different epitope from that to which a neutralizing ligand binds. According to some embodiments, the two ligands do not compete with each other.

To view the presence of a ligand different media can be used. Man kann beispielsweise Fluorophore, andere molekulare Sonden oder Enzyme an den Liganden anbinden und das Vorhandensein des Liganden auf verschiedene Arten beobachten.

One can for example, bind fluorophores, other molecular probes, or enzymes to the ligand and observe the presence of the ligands in different ways.

The method for screening for such diseases, the application of the kit, or simply the use of the disclosed ligand and determining whether the ligand binds to PCSK9 in a sample include.

Dem Fachmann wird bewusst sein, dass hohe bzw. About the ligand binding degree thus can be determined how much PCSK9 is present in a sample. Subjects or samples with an amount of PCSK9, which is above a predetermined amount eg.

According to some embodiments, the invention provides a method which comprises administering to a subject a statin engaging the ligand to determine whether increased by the statin the amount of PCSK9.

For example one, two or disclosed more here rare form variants can bind and is characterized by at least one of: In some embodiments, an isolated nucleic acid molecule is provided which encodes the ligand.

In some embodiments, an expression vector is provided which comprises the nucleic acid molecule. According to some embodiments, a pharmaceutical composition is provided which may comprise the ligand and a pharmaceutically acceptable carrier.

According to some embodiments, a method for the treatment of a disease or affliction is provided with an inventive alleviated PCSK9 antagonist ligands improved, can be inhibited or prevented.

Das Verfahren kann die Verabreichung einer therapeutischen Menge der pharmazeutischen Zusammensetzung bzw.

The method may include administering a therapeutic amount of the pharmaceutical composition or of the ligand to a subject in need thereof.

According to some embodiments, the subject is a human subject suffering from hypercholesterolemia or hyperlipidemia, in which a LDL apheresis was found that statin intolerant as heterozygous for familial hypercholesterolemia or was not identified in response to statins or in which the risk the occurrence of hypercholesterolemia, dyslipidemia, cholestatic liver disease, nephrotic syndrome, hypothyroidism, obesity, atherosclerosis and cardiovascular disease is.

In some embodiments, a subject is provided a method for providing a treatment or therapy. According to some embodiments, a method for obtaining a treatment or therapy is provided, the method may comprise the administration of a ligand in a frequency of once every 60 to 90 days.

According to one embodiment, the ligand according to the invention comprises an antibody or antigen-binding fragment of an antibody, which specifically binds to hPCSK9 and is characterized by at least one of: According to one embodiment, the invention comprises an antibody or antigen-binding fragment of an antibody, which specifically binds to hPCSK9 and is characterized by at least one of: According to one embodiment, the antibody or antigen-binding fragment is characterized by the fact that he or it enhanced binding affinity KD for hPCSK9 at a pH value of 5.

According to a particular embodiment, the antibody or fragment thereof is a least 20 fold, at least fold, or at least fold increased affinity for PCSK9 at an acidic pH as compared to a neutral pH, as measured by surface plasmon resonance.

According to one embodiment, the antibody or antigen-binding fragment is characterized in that it or it shows no increased binding affinity for PCSK9 at an acidic pH as compared to a neutral pH, as measured by surface plasmon resonance.

According to a particular embodiment, the antibody or fragment thereof exhibits a reduced binding affinity at an acidic pH. In one example, the invention is characterized by a pharmaceutical composition comprising a ligand according to the invention, wherein the ligand is a recombinant human antibody or a fragment thereof, or the hPCSK9 specifically binds includes or consists thereof, and a pharmaceutically acceptable carrier.

According to one embodiment, the invention is characterized by a composition which is a combination of the ligand according to the invention is z.

As an antibody or an antigen-binding portion of the antibody of the invention , wherein the therapeutic method comprising administering a therapeutically effective amount of a comprise an antibody of the invention or an antigen-binding fragment of an antibody according to the invention comprising the pharmaceutical composition.

Bei der behandelten Erkrankung handelt es sich um eine beliebige Krankheit oder ein beliebiges Leiden handeln, die bzw.

In the treated disease is any disease or any suffering act machine or improved by removing, inhibiting or reducing the PCSK9 activity, alleviated, inhibited or prevented.

In particular embodiments of the inventive method the ligand of the invention is z. The ligand according to the invention eg.

The term "isolated" in reference from a ligand, an antibody or a protein, for example, in one aspect, a configuration, an example or an embodiment means that a standing in speech ligand, standing in speech antibody, in speech standing protein, etc.

Typically, makes an "isolated" ligand, "isolated" antibody, an "isolated" protein, etc. Preferably, the isolated ligand isolated antibody, the isolated protein, etc.

An "isolated" antibody, for example, is one selected from a component of its production environment eg. Vorzugsweise ist das isolierte Polypeptid frei von einer Assoziation mit allen anderen Komponenten aus seiner Produktionsumgebung, z.

Preferably, the isolated polypeptide is free of association with all other components from its production environment, such. As such that the antibody to an FDA certifiable or certified standard was isolated.

Isolated antibodies include the antibody in situ within recombinant cells, since at least one component from the natural environment of the antibody will not be present.

Usually, an isolated polypeptide or an isolated antibody by at least one purification step is made. Die Erfindung umfasst den Liganden z.

The invention includes the ligands eg. Cytotoxic agents include any agents that damage cells. The antibodies of the present invention may be monospecific, bispecific or multispecific.

Multi-specific mAbs may be specific or contain antigen-binding domains that are specific for more than one target polypeptide for different epitopes on a target polypeptide.

The human anti-PCSK9- z. For example, be another peptide or protein, or be connected therewith expressed together. An antibody or fragment thereof may for example be functional z.

In an exemplary bispecific antibody format that can be used in the present invention, one wherein the first and second Ig CH3 domain using a first immunoglobulin Ig -CH 3 domain and a second Ig-CH3 domain, differ from each other in at least one amino acid, and wherein at least one amino acid difference, the binding of the bispecific antibody to protein a as compared to a bispecific antibody, which lacks the amino acid difference is reduced.

Variations of the bispecific antibody format described above are contemplated within the scope of the present invention.

The invention provides therapeutic methods of treating a human patient in need of a composition or ligand of the invention. While changes in lifestyle and treatment with conventional medicines are often successful in a reduction in cholesterol levels, not all patients able to achieve the recommended target cholesterol level about such approaches.

Various conditions such as familial hypercholesterolemia FH appear to be resistant, despite an aggressive use of conventional therapies in terms of a reduction of LDL-C levels.

Homozygous and heterozygous familial hypercholesterolemia HoFH, HeFH is an associate with premature atherosclerotic vascular disease suffering.

Patients who HoFH is diagnosed, but not speak mostly on a conventional drug therapy and have limited treatment options.

Specifically could treatment with statins, which reduce LDL-C by inhibiting cholesterol synthesis and upregulating the hepatic LDL receptor in patients who do not have LDL receptors or in which they are defective, have only a small effect.

There is a great unmet medical need for new treatments that address the inadequacies of current treatment options. The invention provides therapeutic compositions that include the anti-PCSK9 ligands, antibodies or antigen binding fragments thereof of the present invention.

Administration of therapeutic compositions according to the invention is administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, better feed, better tolerance, and the like.

Eine Vielzahl geeigneter Formulierungen findet sich in der allen pharmazeutischen Chemikern bekannten Formulierungssammlung: A variety of suitable formulations can be found in all pharmaceutical chemists known formulation Collection: These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids cationic or anionic containing vesicles lipids such LIPOFECTINT TM DNA conjugates, anhydrous Resorptionspasten, oil-in-water and water-in- oil emulsions, emulsion Carbowax polyethylene glycols of different molecular weights , semi-solid gels, and semi-solid mixtures containing carbowax, a.

Siehe auch See also. The dose may vary depending on the age and size of a subject, wherein the administration is to be made vary the target disease, conditions, route of administration and the like.

Verwendet man den Liganden, z. Using the ligand for. As antibodies of the present invention for treatment of various conditions and diseases associated with PCSK9, including hypercholesterolemia, LDL, and apolipoprotein B associated diseases and disorders of lipid metabolism and dergleich, for an adult patient, it is advantageous for the ligand or to administer antibodies of the present invention intravenously, usually in a single dose of about 0.

Frequency and duration of treatment may be adjusted according to the severity of the disease. Thus, the composition of the invention the ligand for.

For example, by encapsulating in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis see, eg.

Mundschleimhaut, rektale und intestinale Schleimhaut usw. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings e.

Die Verabreichung kann systemisch oder lokal sein. The administration may be systemic or local. Die pharmazeutische Zusammensetzung kann auch in einem Vesikel, insbesondere einem Liposom, verabreicht werden siehe The pharmaceutical composition may also be administered in a vesicle, in particular a liposome see ; ; ; ; ; ; siehe allgemein ibid.

In bestimmten Situationen kann die pharmazeutische Zusammensetzung in einem System mit kontrollierter Freisetzung verabreicht werden.

In certain situations, the pharmaceutical composition may be administered in a controlled release system. According to yet another embodiment, one may place a controlled release system in the vicinity of the target of the composition, whereby a fraction of the systemic dose see, eg.

The injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, drip infusions, etc..

These injectable preparations can be prepared by publicly known methods. Die injizierbaren Zubereitungen lassen sich zum Beispiel herstellen, indem man z.

The injectable formulations can be prepared, for example, by z. As the antibody described above or its salt in a sterile aqueous medium or an oily medium conventionally used for injections, dissolved, suspended or emulsified.

Ethanol , einem Polyalkohol z. Propylenglykol, Polyethylenglykol , einem nicht ionischen Tensid [z. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic, containing glucose and other adjuvants solution, etc.

Polysorbate 80, HCO polyoxyethylene 50 mol adduct of hydrogenated castor oil may be used], and so on. As an oily medium z. As sesame oil, soybean oil used, etc.

The thus prepared injection is preferably filled in an appropriate ampoule. A pharmaceutical composition of the present invention may be administered subcutaneously or intravenously with a standard needle and syringe.

Moreover, it is often used a pin-shaped administering apparatus with respect to a subcutaneous administration in the administration of a pharmaceutical composition of the present invention.

Such a pen-shaped administering device is reusable or for single use. In a reusable pen-shaped administering apparatus in general, a replaceable cartridge is used, containing a pharmaceutical composition.

Nachdem die gesamte pharmazeutische Zusammensetzung in der Kartusche verabreicht wurde und die Kartusche leer ist, kann die leere Kartusche leicht entsorgt und durch eine neue, die pharmazeutische Zusammensetzung enthaltende Kartusche ersetzt werden.

After all of the pharmaceutical composition is administered in the cartridge and the cartridge is empty, the empty cartridge can be easily disposed of and replaced with a new one containing the pharmaceutical composition cartridge.

The pin-shaped administering device can then be reused. In a pin-shaped disposable administration set, there are no replaceable cartridge.

Rather, the pin-shaped disposable administration device is pre-filled with the pharmaceutical composition that is located in a reservoir in the device, supplied.

Once the pharmaceutical composition has been emptied from the reservoir, the entire device is disposed of. Many reusable pen and autoinjector delivery devices find use in the subcutaneous administration of a pharmaceutical composition of the present invention.

Advantageously, the pharmaceutical compositions described above for oral or parenteral use as dosage forms in a unit dose, suitable to receive a dose of the active ingredients was prepared.

Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injectables ampoules , suppositories and so on. The invention provides therapeutic methods where the ligand according to the invention, z.

The anti-PCSK9 ligand invention, eg. For example, antibodies or antibody fragments, are particularly suitable for treatment of hypercholesterolemia and the like.

Niacin mit Lovastatin ; a statin with a bile resin, a fixed combination of niacin plus a statin e. Ligands according to the invention are suitable for example for assays of specific binding, for genotyping or phenotyping of people, for affinity purification of PCSK9 and for screening assays to identify other antagonists of PCSK9 activity.

Some of the ligands of the invention are useful for inhibiting the binding of PCSK9 to a related human receptor or such a protein, or to inhibit PCSK9-mediated activities.

The invention comprises anti-PCSK9- z. In some applications, a modification of undesirable glycosylation sites useful for removal may be, or z.

In other applications, the galactosylation can be modified in order to modify complement dependent cytotoxicity Complement-Dependent Cytotoxicity, CDC.

In one example, the invention is characterized by a pharmaceutical composition comprising a ligand according to the invention, wherein the ligand is a recombinant human antibody or a fragment thereof, or the the PCSK9 eg.

As a rare variant described herein specifically binds or consists thereof, and a pharmaceutically acceptable carrier.

According to one embodiment, the invention is characterized by a composition in which it is a combination of an antibody ligands of the invention or an antigen-binding fragment of an antibody of the invention and a second therapeutic agent.

In the second therapeutic agent may be an anti-inflammatory agent, an anti-angiogenesis agent, an analgesic agent, a diuretic, a chemotherapeutic agent, an anticancer agent, a vasodilator, a vasoconstrictor, a statin, a beta-blocker, a nutrient, an adjuvant, a Antiobesitasmittel and act an antidiabetic.

A "pharmaceutically acceptable carrier, pharmaceutically acceptable excipient or pharmaceutically acceptable adjuvant" refers to a carrier, an excipient or an adjuvant, or vehicle of a subject together with an agent, such.

As an antibody or an antigen-binding portion of the antibody of the invention , wherein the therapeutic method comprising administering a therapeutically effective amount of includes a comprehensive ligand pharmaceutical composition.

Bei der behandelten Erkrankung handelt es sich um eine beliebige Krankheit oder ein beliebiges Leiden, die bzw. In the treated disease is any disease or suffering any machine or improved by removing, inhibiting or reducing the PCSK9 activity, alleviated, inhibited or prevented.

By the term "therapeutically effective amount" is meant an amount that produces the desired effect for which it is administered.

Der Fachmann wird mit Techniken, die sich zur genauen Genotypisierung und Anwendung der Erfindung einsetzen lassen, vertraut sein.

The skilled person will be using techniques that can be used for accurate genotyping and use the invention, familiar.

These include the following. A method for hybridization based. Next-generation sequencing technologies such as pyrosequencing is also useful.

Andere Hochdurchsatz-Methoden unterscheiden zwischen Allelen anhand differentieller Hybridisierung, Primer-Erweiterung, Ligation und Spaltung einer allelspezifischen Sonde Other high throughput methods distinguish between alleles based differential hybridization, primer extension, allele specific ligation, and cleavage of a probe ; ;.

One approach to a fully automatic SNP analysis on a large scale is the "homogeneous" assay, ie a Einphasenassay without separation steps, which allows a continuous monitoring during amplification.

The use of two allele-specific probes have different fluorophores allows the SNP determination in the same tube without post-PCR processing.

The genotype is determined from the ratio of intensities of the two fluorescent probes at the end of amplification. Thus, instead of using the entire set of real-time PCR data as in quantitative studies, only uses the endpoint data.

Die Ergebnisse des Assays lassen sich automatisch durch mit den Echtzeit-Thermozyklern gelieferte Genotypisierungs-Software z. The results of the assay can be automatically determined by that came with the real-time thermal cyclers genotyping software eg.

Through this classification process, the need for positive controls is eliminated and an accurate genotyping even in the absence of a genotype class, for example if one allele is rare possible.

The skilled person will be using techniques that can be used for accurate phenotyping and use the invention, familiar.

These include the use of amino acid sequencing of the isolated target protein and comparing the sequences of different variants eg.

As the most common variant. For identifying a specific variant one can use that specifically and selectively binds under stringent conditions in the region of a SNP also an antibody.

In another method, the genotype is determined, and a corresponding amino acid sequence phenotype determines z. For example, by computer translation.

Unless otherwise stated or apparent from the context, the following terms and phrases include the meanings set forth below.

The definitions are provided to assist in the description of certain embodiments, and shall not limit the claimed invention, since the scope of the invention is only limited by the claims.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention counts.

Sollte es eine scheinbare Diskrepanz zwischen der Weise, in der ein Begriff im Stand der Technik verwendet wird, und den hier gegebenen Definitionen geben, so soll der in der Beschreibung bereitgestellten Definition der Vorrang gegeben werden.

Should an apparent discrepancy between where a term is used in the prior art the way, and give the definitions given here, the definition provided in the description of the priority to be given.

For simplicity, here given here in the description, the terms used collected the examples and the appended claims. The terms "reduce", "reduced" or "reduction" are all used herein to mean a reduction of a statistically significant amount.

As used herein includes "reduction" is not a complete reduction compared to a comparison mirror. A reduction is preferably carried out down to a level recognized by the that it is for an individual without a given disease in the normal range.

For purposes of the lowering or reduction of cholesterol levels, for example, a reduction of about points as a "decrease" or "reduction" are considered.

In certain aspects of all embodiments of the invention, the term "inhibition" is used. In connection with a marker or a symptom is "increasing" a statistically significant increase of such a mirror.

Thus, as the term is used herein, "substantially" refers to the qualitative condition that a complete or nearly complete extent or such a degree of interest Charakteristikums or a property is shown.

With the term "substantially" is therefore here the possible lack of completeness that is inherent in many biological and chemical phenomena are expressed.

Um Zweifel zu vermeiden: Just as the term is used herein, "subject" a human or animal. They are usually the animal is a vertebrate such as a primate, a rodent, a pet or a wild game.

To primates including chimpanzees, cynomolgus monkeys, spider monkeys and macaques, eg. Among the rodents are mice, rats, woodchucks, ferrets, rabbits and hamsters.

According to some embodiments, the subject is a mammal, for example. As a primate, eg. As a human being. The terms "individual," "patient" and "subject" are used interchangeably herein.

According to some embodiments may be the subject is a non-human vertebrate, eg. As a primate, a rodent, a mouse, a rat, a pig, a sheep, a zebra fish, a frog, etc.

The subject is preferably a mammal. The mammal may be a human, a non-human primate, a mouse, a rat, a dog, a cat, a horse or a cow, but these examples are not limiting.

Mammals, which are other than humans, can be used advantageously as subjects, the animal models of a disease or a disorder such.

A subject can be male or female. See examples translated by sweet 18 examples with alignment. See examples containing high 87 examples with alignment.

See examples containing well 83 examples with alignment. See examples containing bad 56 examples with alignment. See examples containing sound 55 examples with alignment.

See examples containing best 53 examples with alignment. See examples containing kind 46 examples with alignment. See examples containing right 39 examples with alignment.

Ich war immer ein guter Lehrer. I was a good hand at teaching young crews. Du bist sicher ein guter Pfeifer. Rafael ist sicherlich ein guter Typ.

So ein guter Junge verdient mehr. Such a good boy deserves to have more. All I know is that the Faustian play, based on a popular Icelandic folktale, is about a student who sells his soul to the devil.

This cannot be called a gripping mystery, but I found it charming and entertaining. The fact that I visited Akureyri recently probably coloured my enjoyment of the book.

I will keep checking to see if more of the series is translated; I would definitely read them. Its chatty style felt more like a cosy mystery than the Scandi-noir I was expecting from the cover art.

The central mystery is an interesting idea, but it i See more of my book reviews on my blog, Literary Flits Season Of The Witch was a surprising read for me.

The central mystery is an interesting idea, but it is intertwined with other personal storylines that I felt were included more for padding than necessity.

It is entertaining and gives an idea of life in small-town Iceland - very different to that of the city! I just would personally have preferred less cosiness!

Feb 24, AngryGreyCat rated it liked it. Einar is a journalist and he falls into murder investigations through his work for the paper. The voice of Einar is written somewhat strangely.

It took me a while to realize he was a man, there was just something about it that made me assume Einar was female.

The other characters are ok and even provide some comic relief. By the end, I was drawn into the story, but it is not one of my favourite series.

Aug 11, Lynn Weber rated it liked it Shelves: I particularly liked the protagonist of this mystery, a middle-aged journalist who is quirky and funny and outgoing, not the gruff, noir-tinged figure of most police procedurals.

Jan 11, Suspense Magazine added it. Icelandic newspaper reporter Einar has failed at pretty much everything that matters: Now he has been assigned to the northern city of Akureyri, far from bustling Rekyjavik as a last chance to keep his job with the Evening News.

Here the former crime reporter must—to his chagrin—turn his talents to penning stories about high school play productions and lost dogs…or at least until the first body pops up.

So begins this Nordic knot of a story where the Icelandic newspaper reporter Einar has failed at pretty much everything that matters: So begins this Nordic knot of a story where the strands and strains of daily modern Icelandic life weave together to create a perplexing pattern of envy, greed, and lust.

Einar follows these strands, one by one and through every twist and turn as he unravels the mystery confronting him. Meanwhile, at the other end of the economic scale, powerful and politically connected industrialists make clear their interests in keeping, to all outward appearances, everything neat and tidy.

In the end, a line from the play performed sums up the crucial crux of this tangled tale: Ich bin aber froh darum. Es hat ein bisschen gedauert, bis ich reingekommen bin, aber nachher hat mir das Buch ziemlich gut gefallen.

Es ist aber m. Nov 25, Booknblues rated it really liked it Shelves: Season of the Witch By Arni Thorarinsson 3 stars pp.

The protagonist, Einar is a journalist who covers crime. Starting with the fourth of a series, one misses some of the back story of the protagonist and must fill in the where possible.

It appears the Einar used to bend his elbow a bit but is now trying to dry up. He is an intrepid investigator and that is what makes him interesting.

The story is intricate and interesting. I did have some problems with the resolution and the use of justice. I suppose each reader will have to answer if this satisfies their moral code.

I do think that this was interesting enough and promising to read more of the series, when they become available in English. Jul 18, Marije rated it it was ok.

I think I expected more dramatic Icelandic nature, to lose myself in the dark, desolate beauty and grimness of the northern wild. But it was hard to get more than names and places from this book.

It was as if I was reading a book-adaptation of a movie. Telling instead of showing is not always a bad thing, but in this case it is.

Dec 07, Carol Jean rated it liked it. Chatty Icelandic murder mystery with a newspaper reporter protagonist. Amusing and entertaining, but not terribly involving, somehow.

Juoni hatara, liikaa sivuja. Jun 07, Lora rated it liked it. The mystery kept me guessing, the characters were interesting and there were some interesting observations and bits about Icelandic culture.

I would definitely read future translations by this author, even though this one had some minor flaws.

One chapter felt a bit disjointed, and in a couple places the author mentioned a new chara The mystery kept me guessing, the characters were interesting and there were some interesting observations and bits about Icelandic culture.

One chapter felt a bit disjointed, and in a couple places the author mentioned a new character in such a way as I thought it was an existing character I had forgotten about.

The time period was not mentioned but presumed to be the same as the publication date of This is important because so much has changed technology since its publication, and that has some bearing on our understanding of the plot.

Nothing outstanding but I did rather enjoy reading this - the central voice was very clear. May 22, Jane Segal rated it really liked it Shelves: This book takes place in a remote northern city; the amateur sleuth is a journalist who must unravel the quaint city facade to solve several local murders.

Great background and character development. Jan 30, Heather rated it liked it Shelves: It was worthwhile for me due to my Iceland obsession, but I would recommend anyone go out of the way to read this one unless the obsession is mutual.

Jun 08, Buchdoktor rated it really liked it Shelves: Das Handwerkliche Bei amazon-crossing erscheint "Seasons of the witch" als Paperback, das in Format und Seitenlayout den deutschen Klappenbroschuren entspricht.

Mar 10, Linda Branham Greenwell rated it really liked it Shelves: A recovering alcoholic newspaper reporter, Einar is sent to a small town in the northern Iceland for a second chance and a new start.

His main assignment is to write human interest stories, but soon Einar finds himself delving into into some mysterious events that are happening in the small town.

I found the first approximately 90 pages to not be very interesting - more background on the characters - but then it picks up and became a very good story.

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