GB2575853A

GB2575853A - IL-1ß binding antibody

Info

Publication number: GB2575853A
Application number: GB1812182.2A
Authority: GB
Inventors: Robert Wotherspoon Hugh
Original assignee: Individual
Current assignee: Individual
Priority date: 2018-07-25
Filing date: 2018-07-25
Publication date: 2020-01-29

Abstract

This disclosure concerns an IL-1-beta binding antibody comprising at least the VH and VL CDR sequences of the anti-IL-1β antibody canakinumab (anti-interleukin-1-beta, Ilaris, ACZ885) or fragment thereof for use in reducing the risk of an acute pancreatitis event in a patient that has already suffered a prior acute pancreatitis episode. Preferably the antibody is administered subcutaneously at 50mg-300mg every three months to a patient with a raised CRP level and is administered no earlier than 28 days after the prior acute pancreatitis episode.

Description

IL-1B binding antibody

The present disclosure relates to IL-1 β binding antibody for use in preventing or reducing risk of having a recurrent pancreatitis event after a patient has already suffered a pancreatitis event, particularly to canakinumab for use in preventing or reducing risk of having a recurrent pancreatitis event after a patient has already suffered a pancreatitis event.

Pancreatitis is inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types of pancreatitis, acute pancreatitis and chronic pancreatitis. Signs and symptoms of pancreatitis include pain in the upper abdomen, nausea and vomiting. The pain often goes into the back and is usually severe. In acute pancreatitis a fever may occur and symptoms typically resolve in a few days. In chronic pancreatitis weight loss, fatty stool, and diarrhea may occur. Complications may include infection, bleeding, diabetes mellitus, or problems with other organs. The most common causes of acute pancreatitis are gallstones and heavy alcohol use. A patient who has recovered after a first bout of acute pancreatitis will typically be referred for medical investigation as to its cause. If the patient was a heavy alcohol user he will be encouraged to desist. If alcohol over use is eliminated as a cause, the dominant pathology in recurrent pancreatitis is related to a gallstone having been interfering with the delivery of pancreatic digestive enzymes into the gastrointestinal tract, for which the anatomy of the pancreas is adapted. In order better to describe this pathology some anatomy and physiology of the pancreas will be described.

The pancreatic enzymes are amylase (breaking down carbohydrate), protease (breaking down protein) and lipase (breaking down fats). Because these digestive enzymes are so powerful they are normally wrapped in a protective layer while they are in the pancreas. To reach the gastrointestinal tract these digestive enzymes travel through the pancreatic ducts and are eventually released into the duodenum. In about 90% of people most of the pancreatic enzymes pass through the Wirsung duct just upstream of the Greater papilla (which is the opening surrounded by the sphincter of Oddi connecting the Wirsung duct with the duodenum of the gastrointestinal tract). Once the pancreatic enzymes are completely out of the pancreas and into the duodenum their protective layer is removed from them and the enzymes become active. Bile from the gall bladder travels through the pancreas in the bile duct which joins with the Wirsung duct near where the Wirsung duct connects with the duodenum, so that bile and pancreatic enzymes travel in a common duct downstream of where the bile duct joins the Wirsung duct and just upstream of the opening of Greater papilla where the common bile/pancreatic duct joins the duodenum. The pathology of pancreatitis involves the pancreatic enzymes becoming active before they exit the pancreas thereby causing trauma to the pancreas. The pathology of gallstone involved pancreatitis involves gallstones contained within the bile blocking the common bile/pancreatic duct upstream of the opening of Greater papilla thereby causing ductal hypertension which causes the pancreatic enzymes to become active before they leave the pancreas, causing trauma to the pancreas.

When a patient with a first bout of acute pancreatiis presents to a physician, the physician will treat the symptoms of that acute pancreatitis first. Then that physician will over time eliminate alcohol over use and gallstones as a cause. Each of these causes will be considered eliminated once that patient has given up alcohol, has his/her gall bladder surgically removed, and yet he or she nevertheless continues periodically to suffer recurring bouts of acute pancreatitis. This situation pertains in about 10% of cases, and the underlying cause is difficult to diagnose. Administration of effective amounts of the IL1β binding antibody to those 10% of patients is useful in preventing or reducing the risk of the patient experiencing a further bout of acute pancreatitis after the patient has already recovered from a first bout of acute pancreatitis.

Interleukins are key mediators in the inflammatory response in inflammatory disease and have been demonstrated in animal models and in humans to be potent modulators of proinflammatory processes. Thus, antagonism of the IL-1 β mediated inflammation is a primary and attractive target for ameliorating the common bile/pancreatic duct vessel wall inflammation associated with non-alcohol associated, non-gallstone associated recurring acute pancreatitis.

WO2010/138939 generally relates to a method of treating cardiovascular disorders with an IL-Ιβ antibody.

SUMMARY OF THE DISCLOSURE

Inflammation contributes to the process of pancreatitis and patients with elevated inflammatory biomarkers such as hsCRP have increased risk of pancreatitis. The present disclosure concerns direct inhibition of inflammation by administration of IL-1 β binding antibodies contributing to preventing or reducing the risk of experiencing a recurrent pancreatitis event after a patient has already suffered a pancreatitis event.

Accordingly, the present disclosure is directed to an IL-1 β binding antibody or functional fragment thereof for preventing or reducing risk of having a recurrent event of pancreatitis in a patient that has suffered a first acute event of pancreatitis.

Further features and advantages of the disclosure will become apparent from the following detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Balancing the IL-1 β system and its contributions to human disease. IL1 P=interleukin-I beta; IL-1R=interleukin-1 receptor; IL-1 Ra=interleukin-1 receptor antagonist; CAPS=cryopyrin-associated periodic syndrome; MWS=Muckle-Wells Syndrome; NOMID=neonatal-onset multi-system inflammatory disease.

FIG. 2: hsCRP lowering by canakinumab in gout patients supports quarterly dosing regimen (study H2251): the figure shows hsCRP lowering by a single canakinumab dose is durable for 3 months (85 days).

ACZ=ACZ885=canakinumab

Colch=colchicine

FIG. 3: Quarterly dosing regimen is supported by study CACZ885A2213 data on patients with T2DM. X axis indicates time in days (d)

FIG. 4: Phase II study data on hsCRP response supports selection of 15 and 50 mg monthly doses of canakinumab

Biological activity of canakinumab can be monitored using hsCRP as a surrogate Canakinumab dose selection based on primary analysis data from study 12202 (5 to 150 mg vs. placebo monthly, 16 weeks, N=524):

Safety (general safety and lipid effects) hsCRP lowering dose response characteristics 15 mg monthly dose of canakinumab was selected as a sub-maximal dose (30% hsCRP lowering and 95% upper CI<0) mg monthly dose of canakinumab as maximally efficacious dose (40% hsCRP lowering)

FIG. 5: The amino-terminal sequences of the heavy chain variable domain (VH) and the corresponding DNA sequences of canakinumab are given, in which the CDRs are shown in bold type and underlined, and leader sequence in italics.

FIG. 6: The amino-terminal sequences of the light chain variable domain (VL) and the corresponding DNA sequences of canakinumab are given, in which the CDRs are shown in bold type and underlined, and leader sequence in italics.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present invention provides, inter alia, an IL-1 β binding antibody or functional fragment thereof for preventing or reducing risk of having a recurrent event of acute pancreatitis in a patient that has suffered a first acute event of pancreatitis. Preferably the invention comprises a dosage of about 25 mg to about 300 mg of said IL-1 β binding antibody or functional fragment thereof for said use. More preferably a patient receiving said dosage of said antibody or functional fragment thereof has a CRP level of about 1 mg/L before receiving said dosage of said antibody or functional fragment thereof.

Canakinumab is a fully human monoclonal anti-human IL-1 β antibody of the lgG1/k isotype, being developed for the treatment of IL-1 β driven inflammatory diseases. It is designed to bind to human IL-1 β and thus blocks the interaction of this cytokine with its receptors. The antagonism of the IL-1 β mediated inflammation using canakinumab in lowering high sensitivity C-reactive protein (hsCRP) and other inflammatory marker levels has shown an acute phase response in patients with Cryopyrin-Associated Periodic Syndrome (CAPS) and rheumatoid arthritis. This evidence has been replicated in patients with type 2 diabetes mellitus (T2DM) using canakinumab and with other IL-1 β antibody therapies in development.

Type-2 diabetes mellitus (T2DM) is a disease that is characterized by a high inflammatory state. Pre-clinical data suggests IL-1 β is of key importance in the progressive functional impairment and destruction of β-cells in type 2 diabetes. Pancreatic β cells secrete IL-1 β in response to elevated glucose exposure promoting further impairment of cellular viability via an autocrine action. IL-1 β antagonism inhibits β cell death, promotes β cell proliferation, potentiates β cell glucose-induced insulin secretion and improves insulin sensitivity. Blocking IL-1 β activity with an IL-1 receptor antagonist as well as a neutralizing IL-1 β antibody in clinical trials reduced HbAlc (glycated haemoglobin). By measuring HbAlc clinicians are able to get an overall picture of what our average blood sugar levels have been over a period of weeks/months. Neutralization of IL-1 β activity in the pancreatic islets is thus emerging as an attractive target for the treatment and prevention of type 2 diabetes. For T2DM prevention canakinumab's primary direct action is expected to prevent the IL-1 β mediated destruction of pancreatic β-cells and thus prevent or delay progression of disease, which to date is a completely unmet need.

The inflammatory biomarker hsCRP is an independent risk factor for a number of autoinflammatory syndromes including future cardiovascular events.

Canakinumab and other IL-1 beta inhibiting agents, in particular other IL-1 β binding antibodies, will reduce the risk of future occurrence of acute pancreatic events in patients with recent past acute pancreatic events by preventing IL-1 β mediated pancreatic duct inflammation, particularly where scar tissue is present on the pancreatic duct wall resulting from wound healing from a previous acute pancreatitis event.

Canakinumab is disclosed in WO02/16436 which is hereby incorporated by reference in its entirety.

As mentioned, the present invention provides, inter alia, an IL-1 β binding antibody or functional fragment thereof for preventing or reducing risk of having a recurrent event of pancreatitis in a patient that has suffered a first acute event of pancreatitis. Preferably the invention comprises a dosage of about 25 mg to about 300 mg of said IL-1 β binding antibody or functional fragment thereof for said use. More preferably a patient receiving said dosage of said antibody or functional fragment thereof has a CRP level of about 1 mg/L before receiving said dosage of said antibody or functional fragment thereof.

Preferably, said CRP level is about 2 mg/L. More preferred CRP levels are about 1, about 1.1, about 1.2, about 1.3, about 1.4. about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, 1 about 2.6, about 2.7, about 2.8. about 2.9, about 3.0 mg/L.

In some preferred embodiments said CRP level is 1-3 mg/L, or 1.5-2.5 mg/L, or 1.7-2.3 mg/L or 1.8-2.2 mg/L or 1.9-2.1 mg/L.

In more preferred embodiments, said level of CRP level is hsCRP level.

In one preferred embodiment of the invention, said IL-1 β binding antibody or functional fragment thereof is administered 2-5 weeks from an initial acute pancreatitis event or a subsequent recurrent acute pancreatitis event (herein sometimes referred to as a or the 'qualifying PC event').

In other preferred embodiments of the invention, said IL-1 β binding antibody or functional fragment thereof is administered 3 weeks or 21 days, 4 weeks or 1 month or 28 days, 5 weeks or 35 days, or 6 weeks or 42 days from the qualifying PC event.

In one preferred embodiment of the invention, said IL-1 β binding antibody or functional fragment thereof is administered every 2 weeks, monthly, every 6 weeks, bimonthly (every 2 months), quarterly (every 3 months), every 5 months, or every 6 months from the first administration.

In any embodiment of the invention, said any embodiment further comprises administering the patient an additional dose of about 25 mg to about 300 mg of the IL-1 β binding antibody or functional fragment thereof at week 2, week 4 or week 6 from the first administration.

In one preferred embodiment, the invention provides an IL-1 β binding antibody or functional fragment thereof for preventing or reducing the risk of having a recurrent pancreatitis event in a patient that has suffered a qualifying PC event, comprising administering about 50 mg of an IL-1 β binding antibody or functional fragment thereof 2-5 weeks from the qualifying PC event, wherein said patient has a CRP level of = about 1 mg/L before administration of said antibody or functional fragment thereof, and further comprising administering the patient an additional dose of about 50 mg of the IL-1 β binding antibody or functional fragment thereof at week 2, week 4 or week 6 from the first administration and followed by a quarterly administration from the first administration.

In one preferred embodiment, the invention provides an IL-1 β binding antibody or functional fragment thereof for preventing or reducing risk of having a recurrent pancreatitis event in a patient that has suffered a qualifying PC event, comprising administering about 150 mg of an IL-1 β binding antibody or functional fragment thereof 2-5 weeks from the qualifying PC event, wherein said patient has a CRP level of k about 1 mg/L before administration of said antibody or functional fragment thereof, and further comprising administering the patient an additional dose of about 150 mg of the IL-1 β binding antibody or functional fragment thereof at week 2, week 4 or week 6 from the first administration and followed by a quarterly administration from the first administration.

In one preferred embodiment, the invention provides an IL-1 β binding antibody or functional fragment thereof for preventing or reducing risk of having a recurrent pancreatitis event in a patient that has suffered of a qualifying PC event, comprising administering about 300 mg of an IL-1 β binding antibody or functional fragment thereof 2-5 weeks from the qualifying PC event, wherein said patient has a CRP level of = about 1 mg/L before administration of said antibody or functional fragment thereof and followed by a quarterly administration from the first administration.

Any embodiment of the invention, or any preferred embodiment of the invention comprises administering about 25, 75, 100, 125, 175, 200, 225, 250, 275, 300 mg or any combination thereof of the IL-1 β binding antibody or functional fragment thereof. In other embodiments of the administration regimens described above, a dose of about 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105,110,115, 120, 125, 130, 135,140, 145,150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300 mg or any combination thereof of said IL-1 β binding antibody or functional fragment thereof can be administered.

In any embodiment of the invention, or any preferred embodiment of the invention, said IL1β binding antibody or functional fragment thereof is an IL-1 β binding antibody. In any embodiment of the invention, or any preferred embodiment of the invention, said IL-1 β binding antibody or functional fragment thereof is capable of inhibiting the binding of IL-1 β to its receptor and has a KD for binding to IL-1 β of about 50 pM or less.

In any embodiment of the invention, or any preferred embodiment of the invention said IL1β binding antibody is selected from the group consisting of:

a) an IL-Ιβ binding antibody directed to an antigenic epitope of human IL-1 β which includes the loop comprising the Glu64 residue of the mature IL-1 β, wherein said IL-Ιβ binding antibody is capable of inhibiting the binding of IL-Ιβ to its receptor, and further wherein said IL-Ιβ binding antibody has a KD for binding to IL-Ιβ of about 50 pM or less;

b) an IL-Ιβ binding antibody that competes with the binding of an IL-Ιβ binding antibody comprising a VH domain comprising SEQ ID NO:1 and a VL domain comprising SEQ ID NO:2;

c) an IL-Ιβ binding antibody comprising the three CDRs of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5;

d) an anti-IL-Ιβ binding antibody comprising the three CDRs of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8;

e) an anti-IL-Ιβ binding antibody comprising the three CDRs of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and the three CDRs of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8;

f) an anti-IL-Ιβ binding antibody comprising a VH domain comprising SEQ ID NO:1;

g) an anti-IL-Ιβ binding antibody comprising a VL domain comprising SEQ ID NO:2;

h) an anti-IL-Ιβ binding antibody comprising a VH domain comprising SEQ ID NO:1 and a VL domain comprising SEQ ID NO:2.

In any embodiment of the invention, or any preferred embodiment of the invention, said ILΙβ binding antibody or fragment thereof comprises the 3 CDRs of SEQ ID NO:1 are set forth in SEQ ID NO:3, 4, and 5 and wherein the 3 CDRs of SEQ ID NO:2 are set forth in SEQ ID NO:6, 7, and 8.

In any embodiment of the invention, or any preferred embodiment of the invention, the IL1 β binding antibody comprises:

a) a VH having a first CDR having 0,1 or 2 amino acid substitutions in comparison to the CDR set forth in SEQ ID NO:3, a second CDR having 0, 1 or 2 amino acid substitutions in comparison to the CDR set forth in SEQ ID NO:4, a third CDR having 0, 1 or 2 amino acid substitutions in comparison to the CDR set forth in SEQ ID NO:5; and

b) a VL having a first CDR having 0, 1 or 2 amino acid substitutions in comparison to the CDR set forth in SEQ ID NO:6, a second CDR having 0, 1 or 2 amino acid substitutions in comparison to the CDR set forth in SEQ ID NO:7, and a third CDR having 0,1 or 2 amino acid substitutions in comparison to the CDR set forth in SEQ ID NO:8, wherein said antibody has a KD for IL-1 beta of 50 pM or less and wherein said antibody inhibits the binding of IL-Ιβ to its receptor.

Substituted amino acids are ideally conservative substitutions, and once substituted a skilled artisan could use an assay such as those described in WO02/16436.

In any embodiment of the invention, or any preferred embodiment of the invention, said ILΙβ binding antibody is canakinumab. In other embodiments of the invention, said IL-Ιβ binding antibody or functional fragment thereof is selected from the group consisting of XQMA052 or gevokizumab, LY-2189102 orAMG-108.

In some embodiments described above, the antibody or fragment binds to human IL-Ιβ with a dissociation constant of about 50 pM or less. In some embodiments, the antibody or fragment binds to human IL-Ιβ with a dissociation constant of about 500 pM or less. In some embodiments, the IL-Ιβ binding antibody or functional fragment thereof binds to human IL-Ιβ with a dissociation constant of about 250 pM or less. In some embodiments, the IL-1 β binding antibody or functional fragment thereof binds to human IL-1 β with a dissociation constant of about 100 pM or less. In some embodiments described above, the IL-1 β binding antibody or functional fragment thereof binds to human IL-1 β with a dissociation constant of about 5 pM or less. In some embodiments, the IL-1 β binding antibody or functional fragment thereof binds to human IL-1 β with a dissociation constant of about 1 pM or less. In some embodiments, the IL-1 β binding antibody or functional fragment thereof binds to human IL-1 β with dissociation constant of about 0.3 pM or less.

In some embodiments described above, the IL-13 binding antibody or functional fragment thereof is a neutralizing antibody.

The canakinumab heavy chain variable region (VH) is set forth as SEQ ID NO:1 of the sequence listing. CDR1 of the VH of canakinumab is set forth as SEQ ID NO:3 of the sequence listing. CDR2 of the VH of canakinumab is set forth as SEQ ID NO:4 of the sequence listing. CDR3 of the VH of canakinumab is set forth as SEQ ID NO:5 of the sequence listing.

The canakinumab light chain variable region (VL) is set forth as SEQ ID NO:2 of the sequence listing. CDR1 of the VL of canakinumab is set forth as SEQ ID NO:6 of the sequence listing. CDR2 of the VL of canakinumab is set forth as SEQ ID NO:7 of the sequence listing. CDR3 of the VL of canakinumab is set forth as SEQ ID NO:8 of the sequence listing.

In some embodiments described above, the anti-IL-1 β binding antibody or binding fragment thereof competes with the binding of an antibody having the heavy chain variable region of SEQ ID NO:1 and the light chain variable region of SEQ ID NO:2.

FIG. 5 illustrates the sequence of VH and of the three CDRs

Some embodiments comprise administering an anti-IL-1 β binding antibody having the three CDRs of SEQ ID NO:1. In further embodiments, the three CDRs of SEQ ID NO:1 are set forth as SEQ ID Nos:3-5. Some embodiments comprise administering an anti-IL-1 β binding antibody having the three CDRs of SEQ ID NO:2. In further embodiments, the three CDRs of SEQ ID NO:2 are set forth as SEQ ID NOs:6-8.

FIG. 6 illustrates the sequence of VL and of the three CDRs.

Some embodiments comprise administering an anti-IL-1 β binding antibody having the three CDRs of SEQ ID NO:1 and the three CDRs of SEQ ID NO:2. In further embodiments, the three CDRs of SEQ ID NO:1 are set forth as SEQ ID NOs:3-5 and the three CDRs of SEQ ID NO:2 are set forth as SEQ ID NOs:6-8.

In some embodiments described above, said IL-1 β binding antibody or functional fragment thereof is administered subcutaneously or intravenously.

When administered subcutaneously, canakinumab can be administered in a reconstituted formulation comprising canakinumab at concentration 10-150 mg/ml, 270 mM sucrose, 30 mM histidine and 0.06% polysorbate 80, wherein the pH of the formulation is 6.3-6.7, preferably 6.5.

When administered subcutaneously, canakinumab can be administered in a liquid formulation comprising canakinumab at concentration: 10-150 mg/ml, 270 mM mannitol, 20 mM histidine and 0.04% polysorbate 80 (or polysorbate 20), wherein the pH of the formulation is 6.3-6.7, preferably 6.5.

When administered subcutaneously, canakinumab or any of said IL-1 β binding antibody or functional fragment thereof can be administered to the patient in a liquid form or lyophilized form for reconstitution contained in a prefilled syringe.

In other embodiments, biomarkers other than hsCRP include but are not limited to: IL-1Ra, IL-6, IL-18, leptin, adiponectin (total and high MW), TNFa, PAI-1 and fibrinogen.

In a particularly preferred embodiment, said IL-1 β binding antibody is canakinumab.

In other embodiments, said IL-1 β binding antibody is XOMA052 or gevokizumab, LY2189102 orAMG-108.

Other embodiments of the invention include the use of an IL-1 β binding antibody or a functional fragment thereof as herein described in any embodiment of the invention, or any preferred embodiment of the invention in a method of treatment for preventing or reducing risk of having a recurrent event of pancreatitis in a patient that has suffered a first acute event of pancreatitis.

Other embodiments of any aspect described above include a pharmaceutical composition comprising an IL-1 β binding antibody or functional fragment thereof for preventing or reducing risk of having a recurrent event of pancreatitis in a patient that has suffered a first acute event of pancreatitis. Preferably the invention comprises a dosage of about 25 mg to about 300 mg of said pharmaceutical composition for said use. More preferably a patient receiving said dosage of said pharmaceutical composition for said use has a CRP level of = about 1 mg/L before receiving said dosage of said pharmaceutical composition for said use.

Biomedicine & Pharmacotherapy (2012) 66 83-88 Shen 'Recombinant human interleukin-1 receptor antagonist (rhlL-1Ra) attenuates caerulein-induced chronic pancreatitis in mice' NLM22281291 describes that an IL-1 β binding antibody or functional fragment thereof might have a protective role in chronic pancreatitis in mice. Shen et al first induced chronic pancreatitis in mice similar to the disease of chronic pancrearitis in humans and then treated a first group of the mice having induced chronic pancreatitis with normal saline and a second group of the mice having induced chronic pancreatitis with an IL-1 β binding antibody or functional fragment thereof. They observed that treatment with an IL-1 β binding antibody or functional fragment thereof resulted in attenuation of pancreatic damage and a reduction in pancreatic fibrosis. Chronic pancreatitis is a progressive inflammatory disease featuring progressive irreversible irregular scarring of the exocrine parenchyma characterised by acinar destruction and fibrosis subsequent to inflammation in the pancreas. Preventing cellular damage over the course of a progressive inflammatory disease such as chronic pancreatitis is different from preventing the onset of acute pancreatitis which does not include a pathology of chronic inflammatory response to pre existing scarring but the demonstrated protective effect of an IL-1 β binding antibody or functional fragment thereof in the former at least makes plausible its effective use in the latter.

General:

All patents, published patent applications, publications, references and other material referred to herein are incorporated by reference herein in their entirety.

As used herein, the term “comprising” encompasses “including” as well as “consisting,” e.g. a composition “comprising X may consist exclusively of X or may include something additional, e.g., X+Y.

As used herein, the term “administering” in relation to a compound, e.g., an IL-1 β binding antibody, is used to refer to delivery of that compound by any route of delivery.

As used herein, the term “assaying” is used to refer to the act of detecting, identifying, screening, or determining, which act may be performed by any conventional means. For example, a sample may be assayed for the presence of a particular marker by using an ELISA assay, a Northern blot, imaging, etc. to detect whether that marker is present in the sample.

As used herein, The term “about” in relation to a numerical value x means, for example, +/ -10%.

As used herein, The word “substantially” does not exclude “completely, e.g., a composition which is “substantially free” from Y may be completely free from Y. Where necessary, the word “substantially” may be omitted from the definition of the disclosure.

As used herein, “C-reactive protein” and “GRP” refers to serum C-reactive protein, which is used as an indicator of the acute phase response to inflammation. The level of CRP in plasma may be given in any concentration, e.g., mg/dl, mg/L, nmol/L. Levels of CRP may be measured by a variety of well known methods, e.g., radial immunodiffusion, electroimmunoassay, immunoturbidimetry, ELISA, turbidimetric methods, fluorescence polarization immunoassay, and laser nephelometry.

Testing for CRP may employ a standard CRP test or a high sensitivity CRP (hsCRP) test (i.e., a high sensitivity test that is capable of measuring low levels of CRP in a sample using laser nephelometry). Kits for detecting levels of CRP may be purchased from various companies, e.g., Calbiotech, Inc, Cayman Chemical, Roche Diagnostics Corporation, Abazyme, DADE Behring, Abnova Corporation, Aniara Corporation, Bio-Quant Inc., Siemens Healthcare Diagnostics, etc.

As used herein, the term “hsCRP” refers to the level of CRP in the blood as measured by high sensitivity CRP testing.

Each local laboratory will employ a cutoff value for abnormal (high) CRP based on that laboratory's rule for calculating normal maximum CRP. A physician generally orders a CRP test from a local laboratory, and the local laboratory reports normal or abnormal (low or high) CRP using the rule that particular laboratory employs to calculate normal CRP.

By “IL-1 β binding antibody” is meant any antibody capable of binding to the IL-1 β antigen either alone or associated with other molecules. The binding reaction may be shown by standard methods (qualitative assays) including, for example, a bioassay for determining the inhibition of IL-1 β binding to its receptor or any kind of binding assays, with reference to a negative control test in which an antibody of unrelated specificity but of the same isotype, e.g. an anti-CD25 antibody, is used. Advantageously, the binding of the IL-1 β binding antibodies used in the invention to IL-1 β may be shown in a competitive binding assay.

As used herein the term “antibody” includes whole antibodies and any antigen binding fragment or single chains thereof (i.e., “functional fragment”). A naturally occurring “antibody is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.

As used herein, the term “functional fragment” of an antibody, refers to portions or fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., IL1β). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term “functional fragment” of an antibody include a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CH1 domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment (Ward et al., 1989), which consists of a VH domain; and an isolated complementarity determining region (CDR). Exemplary antigen binding sites include the CDRs of canakinumab as set forth in SEQ ID NOs: 3-5 and SEQ ID NOs: 6-8. Although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see, e.g., Bird et al., 1988; and Huston et al., 1988). Such single chain antibodies are also intended to be encompassed within the term “functional fragments” of an antibody. These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.

As used herein, the terms “monoclonal antibody” or “monoclonal antibody composition” refer to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.

As used herein, the term “human antibody”, is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region also is derived from such human sequences, e.g., human germline sequences, or mutated versions of human germline sequences or antibody containing consensus framework sequences derived from human framework sequences analysis as described in Knappik, et al. A “human antibody” need not be produced by a human, human tissue or human cell. The human antibodies of the disclosure may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or sitespecific mutagenesis in vitro or by somatic mutation in vivo). However, the term “human antibody”, as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

As used herein, the term “KD”, is intended to refer to the dissociation constant, which is obtained from the ratio of Kd to Ka (i.e. Kd/Ka) and is expressed as a molar concentration (M). KD values for antibodies can be determined using methods well established in the art. A method for determining the KD of an antibody is by using surface plasmon resonance, or using a biosensor system such as a Biacore® system.

As used herein, the term “patient” includes any human or nonhuman animal. The term “nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.

As used herein, an antibody that “inhibits” one or more of these IL-1 β functional properties (e.g., biochemical, immunochemical, cellular, physiological or other biological activities, or the like) as determined according to methodologies known to the art and described herein, will be understood to relate to a statistically significant decrease in the particular activity relative to that seen in the absence of the antibody (or when a control antibody of irrelevant specificity is present). An antibody that inhibits IL-1 β activity affects a statistically significant decrease, e.g., by at least 10% of the measured parameter, by at least 50%, 80% or 90%, and in certain embodiments an antibody of the disclosure may inhibit greater than 95%, 98% or 99% of IL-1 β functional activity.

As used herein the term “polypeptide”, if not otherwise specified herein, includes any peptide or protein comprising amino acids joined to each other by peptide bonds, having an amino acid sequence starting at the N-terminal extremity and ending at the C-terminal extremity.

EXAMPLE 1

Rationale of Dose/Regimen, Duration of Treatment/Safety

Canakinumab 50 mg and 150 mg Quarterly

The 50 mg and 150 mg canakinumab dosing schedule has been selected on the basis of anticipated efficacy, safety, and biomarker modeling data. In phase II development, all canakinumab doses up to 300 mg subcutaneous (s.c.) every other week have been found safe, well tolerated, and free of adverse lipid effects. Canakinumab efficacy in lowering hsCRP, IL-6 and fibrinogen was assessed based on studies CACZ885A2213 and CACZ88512202. The maximum efficacy of hsCRP lowering in study CACZ88512202 was at approximately 50-75 mg of canakinumab monthly, with persistent lowering across a wide range of higher doses. Therefore, 50 mg monthly as fully efficacious dose and 15 mg monthly as submaximal dose were selected for further development (see FIG. 3). The optimal dosing interval was examined using data from CACZ885A2213 (diabetes) and from gout studies with canakinumab (see FIG. 3). These studies indicated that canakinumab effect on lowering hsCRP was durable for up to approximately 3 months (see FIG. 2). Further, modeling and simulation methods showed that 150 mg quarterly dosing had similar free IL-1 β suppression compared to 50 mg monthly dosing and 50 mg quarterly dosing had similar free IL-1 β suppression compared to 15 mg monthly dosing. This conclusion was reached by comparing the doses and regimens based on both the time for maintenance of suppression and the fraction of patients below a specified suppression threshold of ‘tissue free’ IL-1 β. Therefore, canakinumab 50 mg and 150 mg quarterly administration are safe and efficacious dosages.

Canakinumab 300 mg Quarterly

Given evidence of safety across a wide dosing range, a 300 mg quarterly dosing schedule for canakinumab has also been developed. This allows evaluation of a higher canakinumab dose if required. A higher dose may deliver greater efficacy than the other selected dose, 150 mg quarterly. This 300 mg quarterly dosing regimen also includes an induction period over 2 weeks, dosing at randomization (month 0) and at week 2 (month 0.5), in order to assure that auto-induction of IL-1 β pathway is adequately inhibited at study initiation. The complete suppression of IL-1 β related gene expression achieved with this early high dose administration, coupled with the continuous canakinumab treatment effect which has been proven to last the entire quarterly dosing period, is expected to minimize the potential for IL-1 β rebound. This may be relevant for pathogenesis of acute pancreatitis because it is theorized that IL-1 auto-induction provides a positive feedback mechanism for pancreatitis.

In phase II studies in patients with gout, diabetes, and acute inflammatory conditions, safety of canakinumab across a wide range of doses has not emerged as a major clinical issue. Due to long term suppression of inflammatory biomarkers, quarterly dosing of canakinumab is feasible and likely to be clinically effective. In addition, data in the setting of acute inflammation suggests that higher initial doses of canakinumab that can be achieved through induction are safe and provide an opportunity to ameliorate concern regarding potential auto-induction of IL-1 β and to achieve greater early suppression of IL1β related gene expression. IL-1 β auto-induction has been shown in human mononuclear blood, human vascular endothelial, and vascular smooth muscle cells in vitro and in rabbits in vivo where IL-1 has been shown to induce its own gene expression and circulating IL-1 β level (Dinarello et al. 1987, Warner et al. 1987a, and Warner et al. 1987b). These studies suggested that IL-1 induced IL-1 gene expression may provide a positive feedback mechanism in the pathogenesis of pancreatitis and promote pancreatitis. This consequently suggests that suppression of this feedback mechanism may provide benefits in pancreatitis. Specifically, data supporting an induction dose of canakinumab includes the following: In CACZ885A2102, a CAPS mechanism of action study of patients with Muckle Wells Syndrome (N=4), canakinumab treatment with 10 mg/kg i.v. (equivalent to 600 mg i.v.) single dose induced clinical (improved skin lesions and conjuctival injection) and biomarker (hsCRP and SAA) responses in 24 hrs which was durable up to 180 days.

In contrast, canakinumab doses of 1 mg/kg i.v. without induction were only durable up to 90 days. Support for more sustained and higher dose canakinumab therapy was also seen in the rheumatoid arthritis proof of concept study CACZ885A2101, where higher doses of canakinumab were required (^3.0 mg/kg i.v.) to achieve a significant clinical response as scored by the ACR system. Furthermore, in the CACZ885A2102 study, analysis of gene expression known to be related to IL-1 β expression, inflammasome activity, and autoinduction of IL-1 β, showed more complete response to higher dose (10 mg/kg i.v.) than lower dose (1 mg/kg i.v.) canakinumab. In addition, IL-1 β and inflammasome related gene expression modification began to decrease with the lower dose (1 mg/kg i.v.) compared to the higher dose (10 mg/kg i.v.) between 10 and 12 weeks. Similar results were obtained in a canakinumab rheumatoid arthritis study where IL-1 β related genes were suppressed more with 300 mg s.c. q2 weeks dosing than 150 mg q4 weeks dosing.

The documented safety record of canakinumab up to doses of 300 mg s.c. every 2 weeks with and without induction dose of 600 mg i.v., in a study in rheumatoid arthritis patients up to 6 months, 300 mg q1 month, in a study in gout patients up to 6 months, and 150 mg q1 month, in a study in T2DM patients up to 4 months supports the use of this higher dose regimen.

Claims

CLAIMS:

1. An IL-1 β binding antibody or functional fragment thereof for use in reducing the risk of having an event of acute pancreatitis in a patient who has had a prior event of acute pancreatitis.

2. The IL-1 β binding antibody or functional fragment thereof of claim 1 for the use of claim 1, wherein said IL-1 β binding antibody or functional fragment thereof is administered subcutaneously in amounts of from 50 mg to 300 mg every three months.

3. The IL-1 β binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim wherein said IL-1 β binding antibody or functional fragment thereof is administered to a patient having a hsCRP level of ^2 mg/L before said administration of said antibody or functional fragment thereof.

4. The IL-1 β binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim wherein said IL-1 β binding antibody or functional fragment thereof is first administered 0-5 weeks, preferably 2-5 weeks after said prior event of acute pancreatitis.

5. The IL-1 β binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim, wherein said IL-1 β binding antibody or functional fragment thereof is administered in an amount of 50 mg.

6. The IL-1 β binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim, wherein said IL-1 β binding antibody or functional fragment thereof is administered in an amount of 150 mg.

7. The IL-1 β binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim, wherein said IL-1 β binding antibody or functional fragment thereof is administered in an amount of 300 mg.

8. The IL-1 β binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim, wherein said IL-1 β binding antibody or functional fragment thereof is capable of inhibiting the binding of IL-1 β to its receptor and has a KD for binding to IL-1 β of 50 pM or less.

9. The IL-1 β binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim, wherein said IL-1 β binding antibody or functional fragment thereof is administered at week 0 and week 2, and then every three months thereafter beginning at week 12 after said prior event of acute pancreatitis.

10. The IL-1 β binding antibody or functional fragment thereof of any one of preceding claim 1-8 for the use of any one of preceding claims 1-8, wherein a first dose of said IL-1 β binding antibody or functional fragment thereof is administered no earlier than 28 days after prior event of acute pancreatitis.

11. The IL-1 β binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim, wherein the pathology of said pancreatitis in said patient who has had a prior event of acute pancreatitis is not alcohol related and not gall stone related.

12. The IL-1 β binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim, wherein said IL-1 β binding antibody or functional fragment thereof is canakinumab.

13. The IL-1 β binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim, wherein administration of said IL-1 β binding antibody or functional fragment thereof is commenced after the symptoms of said acute pancreatitis have disappeared.

14. The IL-1 β binding antibody or functional fragment thereof of any preceding claim for the use of any preceding claim, wherein said IL-1 β binding antibody or functional fragment thereof comprises:

a) the three complementarity determining regions (CDRs) set forth as SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and the three CDRs set forth as SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8; or

b) a VH domain comprising SEQ ID NO:1 and a VL domain comprising SEQ ID NO:2.

15. The IL-1 β binding antibody or functional fragment thereof of claim 14 for the use of claim 14 wherein the said three complementarity determining regions (CDRs) set forth as SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 are located in the heavy chain variable domain of said antibody and wherein the said three CDRs set forth as SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8; are located in the light chain variable domain of said antibody.

16. The IL-1 β binding antibody or functional fragment thereof of claim 15 for the use of claim 15 wherein the said three complementarity determining regions (CDRs) set forth in the heavy chain variable domain of said antibody are as shown by underlining in Fig 5 hereof and wherein the said three complementarity determining regions (CDRs) set forth in the light chain variable domain of said antibody are as shown by underlining in Fig 6 hereof.