WO2018111325A1

WO2018111325A1 - Methods and ingestible devices for the regio-specific release of il-6r inhibitors at the site of gastrointestinal tract disease

Info

Publication number: WO2018111325A1
Application number: PCT/US2017/025102
Authority: WO
Inventors: Mitchell Lawrence Jones; Sharat Singh; Christopher Loren WAHL; Harry Stylli
Original assignee: Progenity Inc.
Priority date: 2016-12-14
Filing date: 2017-03-30
Publication date: 2018-06-21

Abstract

This disclosure features methods and compositions for treating diseases of the gastrointestinal tract with an IL-6R inhibitor.

Description

METHODS AND INGESTIBLE DEVICES FOR THE REGIO- SPECIFIC RELEASE OF IL-6R INHIBITORS AT THE SITE OF GASTROINTESTINAL TRACT DISEASE

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Application Serial No. 62/434,367, filed on December 14, 2016. The disclosure of the prior application is considered part of the disclosure of this application, and is incorporated in its entirety into this application.

TECHNICAL FIELD

This disclosure features methods and compositions for treating diseases of the gastrointestinal tract with an IL-6R inhibitor. Background

Interleukin 6 receptor (IL-6R, also known as CD126 (Cluster of Differentiation 126)) is a type I cytokine receptor. IL-6R regulates cell growth and differentiation, and plays a role in immune responses. IL-6R is bound by its ligand IL-6. This complex then recruits gpl30, inducing dimerization and the initiation of signaling through signal transducer and activator of transcription-3 (STAT3). IL-6R is implicated in the pathogenesis of a variety of diseases, including multiple myeloma, autoimmune diseases, and prostate cancer. IL-6R is also implicated in gastrointestinal diseases such as, for example, inflammatory bowel disease (IBD), Crohn's disease, and colitis. In Crohn's disease, IL-6 is present at high levels in both serum and intestinal tissues, while increased levels of IL-6R and gpl30 expression have been also demonstrated in peripheral lymphocytes of patients with Crohn's disease together with an enhancement of serum IL-6R.

The gastrointestinal (GI) tract generally provides a therapeutic medium for an individual's body. At times, therapeutic drugs may need to be dispensed to specified locations within the small intestine or large intestine, which is more effective than oral administration of the therapeutic drugs to cure some medical conditions. For example, therapeutic drugs applied directly within the small intestine would not be contaminated, digested or otherwise compromised in the stomach, and thus allow a higher dose to be delivered at a specific location within the small intestine. However, dispensing therapeutic drugs directly within the small intestine inside a human body can be difficult, because a device or mechanism (e.g., special formulation) is needed to carry a therapeutically effective dose of drug to a desired location within the small intestine and then automatically deliver the therapeutic drug at the desired location. Such a device or mechanism also needs to be operated in a safe manner as the device or mechanism needs to enter the human body.

Provided herein in one embodiment is a novel treatment paradigm for inflammatory conditions of the gastrointestinal tract. The methods and compositions described herein allow for the regio-specific release of therapeutic drugs at or near the site of disease in the gastrointestinal tract. By releasing a therapeutic drug locally instead of systemically, the bioavailability of said drug can be increased at the site of injury and/or relative to a decrease in circulation; thereby, resulting in improved overall safety and/or efficacy and fewer side effects. Advantages may include one or more of increased drug engagement at the target, leading to new and more efficacious treatment regimens; and/or lower systemic drug levels, which means reduced toxicity and reduced immunogenicity in the case of biologies. For patients, clinicians and payors, this means an easier route of administration, fewer co- medicaments (e.g., immunomodulators), fewer side effects, and/or better outcomes. Summary

Provided herein in one embodiment is a method of treating a disease of the gastrointestinal tract in a subject, comprising:

delivering a IL-6R inhibitor at a location in the gastrointestinal tract of the subject, wherein the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the IL-6R inhibitor.

Provided herein in one embodiment is a method of treating a disease of the large intestine in a subject, comprising:

delivering a IL-6R inhibitor at a location in the proximal portion of the large intestine of the subject,

wherein the method comprises administering endoscopically to the subject a therapeutically effective amount of the IL-6R inhibitor.

releasing a IL-6R inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease,

wherein the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the IL-6R inhibitor. Provided herein in one embodiment is a method of treating a disease of the gastrointestinal tract in a subject, comprising:

wherein the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the IL-6R inhibitor, wherein the

pharmaceutical composition is an ingestible device, and the method comprises administering orally to the subject the pharmaceutical composition.

releasing a IL-6R inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease, wherein the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the IL-6R inhibitor, wherein the method provides a concentration of the IL-6R inhibitor in the plasma of the subject that is less than 3 μg/ml.

releasing a IL-6R inhibitor at a location in the proximal portion of the large intestine of the subject that is proximate to one or more sites of disease,

In another aspect of the present invention, there is provided an IL-6R inhibitor for use in a method of treating a disease of the gastrointestinal tract in a subject, wherein the method comprises orally administering to the subject an ingestible device loaded with the IL-6R inhibitor, wherein the IL-6R inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.

In another aspect, the present invention provides a composition comprising or consisting of an ingestible device loaded with a therapeutically effective amount of an IL-6R inhibitor, for use in a method of treatment, wherein the method comprises orally

administering the composition to the subject, wherein the IL-6R inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease. In another aspect, the present invention provides an ingestible device loaded with a therapeutically effective amount of a IL-6R inhibitor, wherein the device is controllable to release the IL-6R inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease. The device may be for use in a method of treatment of the human or animal body, for example, any method as described herein.

In still another aspect, the present invention provides an ingestible device for use in a method of treating a disease of the gastrointestinal tract in a subject, wherein the method comprises orally administering to the subject the ingestible device loaded with a

therapeutically effective amount of a IL-6R inhibitor, wherein the IL-6R inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.

An ingestible device as used in the present invention may comprise one or more mechanical and/or electrical mechanisms which actively control release of the IL-6R inhibitor. For example, in any of the above aspects and embodiments, the ingestible device as used in the present invention may comprise a release mechanism for release of the IL-6R inhibitor (e.g., from a reservoir comprising the IL-6R inhibitor) and an actuator controlling the release mechanism.

In one embodiment, the ingestible device comprises:

an ingestible housing comprising a reservoir having a therapeutically effective amount of the IL-6R inhibitor stored therein;

a release mechanism having a closed state which retains the IL-6R inhibitor in the reservoir and an open state which releases the IL-6R inhibitor from the reservoir to the exterior of the device; and

an actuator which changes the state of the release mechanism from the closed to the open state.

In one embodiment, the ingestible device comprises

a housing defined by a first end, a second end substantially opposite from the first end;

a reservoir located within the housing and containing the IL-6R inhibitor wherein a first end of the reservoir is attached to the first end of the housing;

a mechanism for releasing the IL-6R inhibitor from the reservoir;

and an exit valve configured to allow the IL-6R inhibitor to be released out of the housing from the reservoir.

Here, the exit valve can be considered as the release mechanism having a closed state which retains the IL-6R inhibitor in the reservoir and an open state which releases the IL-6R inhibitor from the reservoir to the exterior of the device, and the mechanism for releasing the IL-6R inhibitor from the reservoir can be considered as the actuator.

In some embodiments of methods of treatment as described herein, the one or more disease sites may have been pre-determined (e.g., determined in a step preceding the administration of the composition of the present invention). The disease site(s) may have been determined by imaging the gastrointestinal tract. For example, the disease site(s) may have been pre-determined by endoscopy (e.g., a step of colonoscopy, enteroscopy, or using a capsule endoscope). Determination that the device is proximate to the disease site may therefore comprise a determining that the device is in a location corresponding to this previously-determined disease site.

In some embodiments, the location of the device in the gut may be detected by tracking the device. For example, the device may comprise a localization mechanism which may be a communication system for transmitting localization data, e.g., by radiofrequency transmission. The device may additionally or alternatively comprise a communication system for receiving a signal remotely triggering the actuator and thus causing release of the IL-6R inhibitor. The signal may be sent when it is determined that the device is in the correct location in the gut.

Thus, the ingestible device may comprise: an ingestible housing comprising a reservoir having a therapeutically effective amount of the IL-6R inhibitor stored therein;

a release mechanism having a closed state which retains the IL-6R inhibitor in the reservoir and an open state which releases the IL-6R inhibitor from the reservoir to the exterior of the device;

a communication system for transmitting localization data to an external receiver and for receiving a signal from an external transmitter; and an actuator which changes the state of the release mechanism from the closed to the open state and which can be triggered by the signal.

In other embodiments, the ingestible device as used in the present invention may comprise an environmental sensor for detecting the location of the device in the gut and/or for detecting the presence of disease in the GI tract. For example, the environment sensor may be an image sensor for obtaining images in vivo.

Detecting the presence of disease may comprise, for example, detecting the presence of inflamed tissue, and/or lesions such as ulceration e.g., aphthoid ulcerations, "punched-out ulcers" and/or superficial ulcers of the mucosa, cobblestoning, stenosis, granulomas, crypt abscesses, fissures, e.g., extensive linear fissures, villous atrophy, fibrosis, and/or bleeding.

Detecting the presence of disease may also comprise molecular sensing, such as detecting the amount of an inflammatory cytokine or other marker of inflammation. Such a marker can be measured locally from a biopsy or systemically in the serum.

Where the ingestible device comprises an environmental sensor, actuation of the release mechanism may be triggered by a processor or controller communicably coupled to the environmental sensor. Thus, in some embodiments, the device may not require any external signal or control in order to release the drug.

In one embodiment, the ingestible device may comprise:

an actuator which controls the transition of the release mechanism from the closed to the open state;

a detector for detecting the location of the device in the gut and/or the presence of diseased tissue; and

a processor or controller which is coupled to the detector and to the actuator and which triggers the actuator to cause the release mechanism to transition from its closed state to its open state when it is determined that the device is in the presence of diseased tissue and/or in a location in the gut that has been predetermined to be proximal to diseased tissue.

In another embodiment, there is provided:

an ingestible housing comprising a reservoir having a therapeutically effective amount of the IL-6R inhibitor stored therein; a detector coupled to the ingestible housing, the detector configured to detect when the ingestible housing is proximate to a respective disease site of the one of the one or more sites of disease;

a valve system in fluid communication with the reservoir system; and a controller communicably coupled to the valve system and the detector, the controller configured to cause the valve system to open in response to the detector detecting that the ingestible housing is proximate to the respective disease site so as to release the therapeutically effective amount of the IL-6R inhibitor at the respective disease site.

As above, detection that the ingestible housing is proximate to the respective disease site may be based on environmental data indicating the location of the device in the GI tract (and reference to a pre-determined disease site) or on environmental data directly indicating the presence of diseased tissue.

Additionally or alternatively, the device may further comprise a communication system adapted to transmit the environment data to an external receiver (e.g., outside of the body). This data may be used, for example, for diagnostic purposes. The external receiver may comprise means for displaying the data.

In some embodiments, this data may be analyzed externally to the device and used to determine when the drug should be released: an external signal may then be sent to the device to trigger release of the drug. Thus, the communication system may further be adapted to receive a signal remotely triggering the actuator and thus causing release of the IL-6R inhibitor. The signal may be sent from an external transmitter in response to receipt/analysis and/or assessment of the environmental data, e.g., data indicating that the device has reached the desired location of the gut (where the location of the diseased tissue has been predetermined) and/or data indicating the presence of diseased tissue. "External" may be "outside of the body".

Thus, in another embodiment, the ingestible device may comprise:

an ingestible housing comprising a reservoir having a a therapeutically effective amount of the IL-6R inhibitor stored therein;

a release mechanism having a closed state which retains the IL-6R inhibitor in the reservoir and an open state which releases the IL-6R inhibitor from the reservoir to the exterior of the device; an environmental detector for detecting environmental data indicating the location of the device in the gut and/or the presence of diseased tissue;

a communication system for transmitting the environmental data to an external receiver and for receiving a signal from an external transmitter; and an actuator which controls the transition of the release mechanism from the closed to the open state in response to the signal.

It will be understood from the above that when the device comprises one or more environmental detectors, e.g., comprises an image detector, the compositions may be used both for disease detection and for disease treatment.

Accordingly, in a further embodiment, there is provided an IL-6R inhibitor for use in a method of detecting and treating a disease of the gastrointestinal tract in a subject, wherein the method comprises orally administering to the subject an ingestible device loaded with the IL-6R inhibitor, wherein the ingestible device comprises an environmental sensor for determining the presence of diseased tissue in the GI tract, and wherein the IL-6R inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease, as detected by the environmental sensor. The device may be according to any of the embodiments described herein.

In another embodiment, there is provided a composition for use in a method of detecting and treating a disease of the gastrointestinal tract in a subject, wherein the composition comprises or consists of an ingestible device loaded with a therapeutically effective amount of an IL-6R inhibitor, wherein the ingestible device comprises an environmental sensor for determining the presence of diseased tissue in the GI tract, and wherein the IL-6R inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease, as detected by the

environmental sensor. Again, the device may be according to any of the embodiments described herein.

In some embodiments, where the ingestible device as used in the present invention comprises an environmental sensor for detecting the presence of disease in the GI tract and a communication system as described above, the method of treatment may comprise:

i) receiving at an external receiver from the ingestible device a signal transmitting the environmental data;

ii) assessing the environmental data to confirm the presence of the disease; and iii) when the presence of the disease is confirmed, sending from an external transmitter to the ingestible device a signal triggering release of the IL-6R inhibitor.

For example, the presence of disease may be confirmed based on the presence of inflamed tissue and/or lesions associated with any of the disease states referred to herein. For example, the presence of disease may be confirmed based on the presence of inflammation, ulceration e.g., aphthoid ulcerations, "punched-out ulcers" and/or superficial ulcers of the mucosa, cobblestoning, stenosis, granulomas, crypt abscesses, fissures, e.g., extensive linear fissures, villous atrophy, fibrosis, and/or bleeding.

In some embodiments, the present invention may relate to a system comprising: an ingestible device loaded with a therapeutically effective amount of an IL-6R inhibitor, a release mechanism for release of the IL-6R inhibitor (e.g., from a reservoir comprising the IL-6R inhibitor), an actuator controlling the release mechanism, an environmental sensor for determining the location of the device in the gut and/or for detecting the presence of diseased tissue and a communication system adapted to transmit the environment data and receive a signal triggering the actuator;

a receiver and display module for receiving and displaying outside of the body the environment data from the ingestible device;

a transmitter for sending to the ingestible device a signal triggering the actuator.

In any of the above embodiments, the ingestible device may further comprise an anchoring system for anchoring the device or a portion thereof in a location and an actuator for the anchoring system. This may be triggered in response to a determination that the device is at a location in the gastrointestinal tract of the subject proximate to one or more sites of disease. For instance, this may be detected by the environmental sensor. The triggering may be controlled by a processor in the device, that is, autonomously. A device where the triggering is controlled by a processor in the device is said to be an autonomous device. Alternatively, it may be controlled by a signal sent from outside of the body, as described above.

In any of the above aspects and embodiments, disease of the GI tract may be an inflammatory bowel disease.

In some embodiments, the disease of the GI tract is ulcerative colitis.

In some embodiments, the disease of the GI tract is Crohn's disease. In general, apparatuses, compositions, and methods disclosed herein are useful in the treatment of diseases of the gastrointestinal tract. Exemplary gastrointestinal tract diseases that can be treated include, without limitation, inflammatory bowel disease (IBD), Crohn's disease (e.g., active Crohn's disease, refractory Crohn's disease, or fistulizing Crohn's disease), ulcerative colitis, indeterminate colitis, microscopic colitis, infectious colitis, drug or chemical-induced colitis, diverticulitis, and ischemic colitis, gastritis, peptic ulcers, stress ulcers, bleeding ulcers, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, short-bowel (anastomosis) syndrome, a hypersecretory state associated with systemic mastocytosis or basophilic leukemia or hyperhistaminemia, Celiac disease (e.g., nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic

gastroenteritis, colitis associated with radiotherapy or chemotherapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-1, chronic granulomatous disease, food allergies, gastritis, infectious gastritis or enterocolitis (e.g., Helicobacter pylori- infected chronic active gastritis), other forms of gastrointestinal inflammation caused by an infectious agent, pseudomembranous colitis, hemorrhagic colitis, hemolytic-uremic syndrome colitis, diversion colitis, irritable bowel syndrome, irritable colon syndrome, and pouchitis. In some embodiments, apparatuses, compositions, and methods disclosed herein are used to treat one gastrointestinal disease. In some embodiments, apparatuses, compositions, and methods disclosed herein are used to treat more than one gastrointestinal disease. In some embodiments, apparatuses, compositions, and methods disclosed herein are used to treat multiple gastrointestinal diseases that occur in the same area of the gastrointestinal tract (e.g., each disease can occur in the small intestine, large intestine, colon, or any sub-region thereof). In some embodiments, apparatuses, compositions, and methods disclosed herein are used to treat multiple gastrointestinal diseases that occur in different areas of the

gastrointestinal tract. In some embodiments, administration (e.g., local administration to the gastrointestinal tract) of IL-6R inhibitor is useful in the treatment of gastrointestinal diseases including, but not limited to, inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, or any of the other gastrointestinal diseases described herein.

Aspects and embodiments as described herein are intended to be freely combinable.

For example, any details or embodiments described herein for methods of treatment apply equally to an IL-6R inhibitor, composition or ingestible device for use in said treatment. Any details or embodiments described for a device apply equally to methods of treatment using the device, or to an IL-6R inhibitor or composition for use in a method of treatment involving the device.

Brief Description of the Drawings

FIG. 1 provides exemplary structural diagrams illustrating aspects of an ingestible device 100 having a piston to push for drug delivery, according to some embodiments described herein. FIG. 2 provides another exemplary structural diagram illustrating aspects of an ingestible device 100 having a piston to push for drug delivery, according to some embodiments described herein.

Detailed description

Definitions:

By "ingestible", it is meant that the device can be swallowed whole.

"Gastrointestinal inflammatory disorders" are a group of chronic disorders that cause inflammation and/or ulceration in the mucous membrane. These disorders include, for example, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, indeterminate colitis and infectious colitis), mucositis (e.g., oral mucositis, gastrointestinal mucositis, nasal mucositis and proctitis), necrotizing enterocolitis and esophagitis.

"Inflammatory Bowel Disease" or "IBD" is a chronic inflammatory autoimmune condition of the gastrointestinal (GI) tract. The GI tract can be divided into four main different sections, the oesophagus, stomach, small intestine and large intestine or colon. The small intestine possesses three main subcompartments: the duodenum, jejunum and ileum. Similarly, the large intestine consists of six sections: the cecum, ascending colon, transverse colon, ascending colon, sigmoid colon, and the rectum. The small intestine is about 6 m long, its diameter is 2.5 to 3 cm and the transit time through it is typically 3 hours. The duodenum has a C-shape, and is 30 cm long. Due to its direct connection with the stomach, it is physically more stable than the jejunum and ileum, which are sections that can freely move. The jejunum is 2.4 m in length and the ileum is 3.6 m in length and their surface areas are 180 m² and 280 m² respectively. The large intestine is 1.5 m long, its diameter is between 6.3 and 6.5 cm, the transit time though this section is 20 hours and has a reduced surface area of approximately 150 m². The higher surface area of the small intestine enhances its capacity for systemic drug absorption.

The etiology of IBD is complex, and many aspects of the pathogenesis remain unclear. The treatment of moderate to severe IBD poses

significant challenges to treating physicians, because conventional therapy with

corticosteroids and immunomodulator therapy (e.g., azathioprine, 6 mercaptopurine, and methotrexate administered via traditional routes such as tablet form, oral suspension, or intravenously) is associated with side effects and intolerance and has not shown proven benefit in maintenance therapy (steroids). Monoclonal antibodies targeting tumor necrosis factor alpha (T F-a), such as infliximab (a chimeric antibody) and adalimumab (a fully human antibody), are currently used in the management of CD. Infliximab has also shown efficacy and has been approved for use in UC. However, approximately 10%-20% of patients with CD are primary nonresponders to anti T F therapy, and another ~20%-30% of CD patients lose response over time (Schnitzler et al., Gut 58:492-500 (2009)). Other adverse events (AEs) associated with anti TNFs include elevated rates of bacterial infection, including tuberculosis, and, more rarely, lymphoma and demyelination (Chang et al., Nat Clin Pract Gastroenterol Hepatology 3 :220 (2006); Hoentjen et al., World J. Gastroenterol. 15(17):2067 (2009)). No currently available therapy achieves sustained remission

in more than 20%-30% of IBD patients with chronic disease (Hanauer et al, Lancet 359: 1541-49 (2002); Sandborn et al, N Engl J Med 353 : 1912-25 (2005)). In addition, most patients do not achieve sustained steroid-free remission and mucosal healing, clinical outcomes that correlate with true disease modification.

Although the cause of IBD remains unknown, several factors such as genetic, infectious and immunologic susceptibility have been implicated. IBD is much more common in Caucasians, especially those of Jewish descent. The chronic inflammatory nature of the condition has prompted an intense search for a possible infectious cause. Although agents have been found which stimulate acute inflammation, none has been found to cause the chronic inflammation associated with IBD. The hypothesis that IBD is an autoimmune disease is supported by the previously mentioned extraintestinal manifestation of IBD as joint arthritis, and the known positive response to IBD by treatment with therapeutic agents such as adrenal glucocorticoids, cyclosporine and azathioprine, which are known to suppress immune response. In addition, the GI tract, more than any other organ of the body, is continuously exposed to potential antigenic substances such as proteins from food, bacterial byproducts (LPS), etc.

A chronic inflammatory autoimmune condition of the gastrointestinal (GI) tract presents clinically as either ulcerative colitis (UC) or Crohn's disease (CD). Both IBD conditions are associated with an increased risk for malignancy of the GI tract.

"Crohn's disease" ("CD") is a chronic transmural inflammatory disease

with the potential to affect any part of the entire GI tract, and UC is a mucosal

inflammation of the colon. Both conditions are characterized clinically by frequent bowel motions, malnutrition, and dehydration, with disruption in the activities of daily living.

CD is frequently complicated by the development of malabsorption, strictures, and fistulae and may require repeated surgery. UC, less frequently, may be complicated by severe bloody diarrhea and toxic megacolon, also requiring surgery. The most prominent feature Crohn's disease is the granular, reddish-purple edematous thickening of the bowel wall. With the development of inflammation, these granulomas often lose their circumscribed borders and integrate with the surrounding tissue. Diarrhea and obstruction of the bowel are the predominant clinical features. As with ulcerative colitis, the course of Crohn's disease may be continuous or relapsing, mild or severe, but unlike ulcerative colitis, Crohn's disease is not curable by resection of the involved segment of bowel. Most patients with Crohn's disease require surgery at some point, but subsequent relapse is common and continuous medical treatment is usual. Crohn's disease may involve any part of the alimentary tract from the mouth to the anus, although typically it appears in the ileocolic, small -intestinal or colonic- anorectal regions. Histopathologically, the disease manifests by discontinuous

granulomatomas, crypt abscesses, fissures and aphthous ulcers. The inflammatory infiltrate is mixed, consisting of lymphocytes (both T and B cells), plasma cells, macrophages, and neutrophils. There is a disproportionate increase in IgM- and IgG-secreting plasma cells, macrophages and neutrophils.

To date, the primary outcome measure in Crohn's Disease clinical trials is the Crohn's Disease Activity Index (CDAI), which has served as the basis for approval of multiple drug treatments, including for example, vedolizumab and natalizumab. The CDAI was developed by regressing clinician global assessment of disease activity on eighteen potential items representing patient reported outcomes (PROs) (i.e. abdominal pain, pain awakening patient from sleep, appetite), physical signs (i.e. average daily temperature, abdominal mass), medication use (i.e. loperamide or opiate use for diarrhea) and a laboratory test (i.e.

hematocrit). Backward stepwise regression analysis identified eight independent predictors which are the number of liquid or soft stools, severity of abdominal pain, general well-being, occurrence of extra-intestinal symptoms, need for anti diarrheal drugs, presence of an abdominal mass, hematocrit, and body weight. The final score is a composite of these eight items, adjusted using regression coefficients and standardization to construct an overall CDAI score, ranging from 0 to 600 with higher score indicating greater disease activity. Widely used benchmarks are: CDAI <150 is defined as clinical remission, 150 to 219 is defined as mildly active disease, 220 to 450 is defined as moderately active disease, and above 450 is defined as very severe disease (Best WR, et al., Gastroenterology 77:843-6, 1979).

Vedolizumab and natalizumab have been approved on the basis of demonstrated clinical remission, i.e. CDAI < 150.

Although the CDAI has been in use for over 40 years, and has served as the basis for drug approval, it has several limitations as an outcome measure for clinical trials. For example, most of the overall score comes from the patient diary card items (pain,

number of liquid bowel movements, and general well-being), which are vaguely defined and not standardized terms (Sandler et al., J. Clin. Epidemiol 41 :451-8, 1988; Thia et al., Inflamm Bowel Dis 17: 105-11, 2011). In addition, measurement of pain is based on a four- point scale rather than an updated seven-point scale. The remaining 5 index items contribute very little to identifying an efficacy signal and may be a source of measurement noise.

Furthermore, concerns have been raised about poor criterion validity for the CDAI, a reported lack of correlation between the CDAI and endoscopic measures of inflammation (which may render the CDAI as a poor discriminator of active CD and irritable bowel syndrome) and high reported placebo rates (Korzenik et al., N Engl J Med. 352:2193-201, 2005; Sandborn WJ, et al., N Engl J Med 353 : 1912-25, 2005; Sandborn WJ, et al., Ann Intern 19; 146:829-38,

2007, Epub 2007 Apr 30; Kim et al., Gastroenterology 146: (5 supplement 1) S-368, 2014).

It is, thus, generally recognized that additional or alternative measures of CD symptoms are needed, such as new PRO tools or adaptations of the CDAI to derive a new PRO. The PR02 and PR03 tools are such adaptations of the CDAI and have been recently described in Khanna et al., Aliment Pharmacol. Ther. 41 : 77-86, 2015. The PR02

evaluates the frequency of loose/liquid stools and abdominal pain (Id). These items are derived and weighted accordingly from the CDAI and are the CDAI diary card items, along with general well-being, that contribute most to the observed clinical benefit measured by CDAI (Sandler et al., J. Clin. Epidemiol 41 :451-8, 1988; Thia et al., Inflamm Bowel Dis 17: 105-11, 2011; Kim et al., Gastroenterology 146: (5 supplement 1) S-368,

2014). The remission score of < 11 is the CDAI-weighted sum of the average stool frequency and pain scores in a 7-day period, which yielded optimum sensitivity and specificity for identification of CDAI remission (score of < 150) in a retrospective data

analysis of ustekinumab induction treatment for moderate to severe CD in a Phase II clinical study (Gasink C, et al., abstract, ACG Annual Meeting 2014). The PR02 was shown to be sensitive and responsive when used as a continuous outcome measure in a retrospective data analysis of MTX treatment in active CD (Khanna R, et al., Inflamm Bowel Dis 20: 1850-61, 2014) measured by CDAI. Additional outcome measures include the Mayo Clinic Score, the Crohn disease endoscopic index of severity (CDEIS), and the Ulcerative colitis endoscopic index of severity (UCEIS). Additional outcome measures include Clinical remission, Mucosal healing, Histological healing (transmural), MRI or ultrasound for measurement or evaluation of bowel wall thickness, abscesses, fistula and histology.

An additional means of assessing the extent and severity of Crohn's Disease is endoscopy. Endoscopic lesions typical of Crohn's disease have been described in numerous studies and include, e.g., aphthoid ulcerations, "punched-out ulcers," cobblestoning and stenosis. Endoscopic evaluation of such lesions was used to develop the first validated endoscopic score, the Crohn's Disease Endoscopic Index of Severity (CDEIS) (Mary et al., Gut 39:983-9, 1989). More recently, because the CDEIS is time-consuming, complicated and impractical for routine use, a Simplified Endoscopic Activity Score for Crohn's Disease (SES- CD) was developed and validated (Daperno et al., Gastrointest. Endosc. 60(4):505-12, 2004). The SES-CD consists of four endoscopic variables (size of ulcers,

proportion of surface covered by ulcers, proportion of surface with any other lesions (e.g., inflammation), and presence of narrowings [stenosis]) that are scored in five ileocolonic segments, with each variable, or assessment, rated from 0 to 3.

To date, there is no cure for CD. Accordingly, the current treatment goals for CD are to induce and maintain symptom improvement, induce mucosal healing, avoid surgery, and improve quality of life (Lichtenstein GR, et al., Am J Gastroenterol 104:465-83, 2009; Van Assche G, et al., J Crohns Colitis. 4:63-101, 2010). The current therapy of IBD usually involves the administration of antiinflammatory or immunosuppressive agents, such as sulfasalazine, corticosteroids, 6- mercaptopurine/azathioprine, or cyclosporine, all of which are not typically delivered by localized release of a drug at the site or location of disease. More recently, biologies like TNF-alpha inhibitors and IL-12/IL-23 blockers, are used to treat IBD. If anti-inflammatoiy/immunosuppressive/biologic therapies fail, colectomies are the last line of defense. The typical operation for CD not involving the rectum is resection (removal of a diseased segment of bowel) and anastomosis (reconnection) without an ostomy. Sections of the small or large intestine may be removed. About 30% of CD patients will need surgery within the first year after diagnosis. In the subsequent years, the rate is about 5% per year. Unfortunately, CD is characterized by a high rate of recurrence; about 5% of patients need a second surgery each year after initial surgery.

Refining a diagnosis of inflammatory bowel disease involves evaluating the progression status of the diseases using standard classification criteria. The classification systems used in IBD include the Truelove and Witts Index (Truelove S. C. and Witts, L.J. Br Med J. 1955;2: 1041-1048), which classifies colitis as mild, moderate, or severe, as well as Lennard- Jones. (Lennard- Jones JE. Scand J Gastroenterol Suppl 1989; 170:2-6) and the simple clinical colitis activity index (SCCAI). (Walmsley et. al. Gut. 1998;43 :29-32) These systems track such variables as daily bowel movements, rectal bleeding, temperature, heart rate, hemoglobin levels, erythrocyte sedimentation rate, weight, hematocrit score, and the level of serum albumin.

There is sufficient overlap in the diagnostic criteria for UC and CD that it is sometimes impossible to say which a given patient has; however, the type of lesion typically seen is different, as is the localization. UC mostly appears in the colon, proximal to the rectum, and the characteristic lesion is a superficial ulcer of the mucosa; CD can appear anywhere in the bowel, with occasional involvement of stomach, esophagus and duodenum, and the lesions are usually described as extensive linear fissures.

In approximately 10-15% of cases, a definitive diagnosis of ulcerative colitis or Crohn's disease cannot be made and such cases are often referred to as "indeterminate colitis." Two antibody detection tests are available that can help the diagnosis, each of which assays for antibodies in the blood. The antibodies are "perinuclear anti-neutrophil antibody" (pANCA) and "anti-Saccharomyces cervisiae antibody" (ASCA). Most patients with ulcerative colitis have the pANCA antibody but not the ASCA antibody, while most patients with Crohn's disease have the ASCA antibody but not the pANCA antibody. However, these two tests have shortcomings as some patients have neither antibody and some Crohn's disease patients may have only the pANCA antibody. A third test, which measures the presence and accumulation of circulating anti-microbial antibodies - particularly flagellin antibodies, has proven to be useful for detecting susceptibility to Crohn's Disease before disease development. See Choung, R. S., et al. "Serologic microbial associated markers can predict Crohn's disease behaviour years before disease diagnosis." Alimentary pharmacology & therapeutics 43.12 (2016): 1300-1310.

"Ulcerative colitis (UC)" afflicts the large intestine. The course of the disease may be continuous or relapsing, mild or severe. The earliest lesion is an inflammatory infiltration with abscess formation at the base of the crypts of Lieberkuhn. Coalescence of these distended and ruptured crypts tends to separate the overlying mucosa from its blood supply, leading to ulceration. Symptoms of the disease include cramping, lower abdominal pain, rectal bleeding, and frequent, loose discharges consisting mainly of blood, pus and mucus with scanty fecal particles. A total colectomy may be required for acute, severe or chronic, unremitting ulcerative colitis.

The clinical features of UC are highly variable, and the onset may be insidious or abrupt, and may include diarrhea, tenesmus and relapsing rectal bleeding. With fulminant involvement of the entire colon, toxic megacolon, a life-threatening emergency, may occur. Extraintestinal manifestations include arthritis, pyoderma gangrenoum, uveitis, and erythema nodosum.

The terms "antibody" and "immunoglobulin" are used interchangeably in the broadest sense and include monoclonal antibodies (for example, full length or intact monoclonal antibodies), polyclonal antibodies, multivalent antibodies, multispecific antibodies (e.g., bispecific, trispecific etc. antibodies so long as they exhibit the desired biological activity) and may also include certain antibody fragments (as described in greater detail herein). An antibody can be human, humanized and/or affinity matured.

"Antibody fragments" comprise only a portion of an intact antibody, where in certain embodiments, the portion retains at least one, and typically most or all, of the functions normally associated with that portion when present in an intact antibody. In one embodiment, an antibody fragment comprises an antigen binding site of the intact antibody and thus retains the ability to bind antigen. In another embodiment, an antibody fragment, for example one that comprises the Fc region, retains at least one of the biological functions normally associated with the Fc region when present in an intact antibody, such as FcRn binding, antibody half-life modulation, ADCC function and complement binding. In one embodiment, an antibody fragment is a monovalent antibody that has an in vivo half-life substantially similar to an intact antibody. For example, such an antibody fragment may comprise on antigen binding arm linked to an Fc sequence capable of conferring in vivo stability to the fragment.

The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigen. Furthermore, in contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.

The monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or

homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; and Morrison et al, Proc. Natl. Acad. Sci. USA 81 :6851-6855 (1984)).

"Treatment regimen" refers to a combination of dosage, frequency of administration, or duration of treatment, with or without addition of a second medication.

"Effective treatment regimen" refers to a treatment regimen that will offer beneficial response to a patient receiving the treatment.

"Patient response" or "patient responsiveness" can be assessed using any endpoint indicating a benefit to the patient, including, without limitation, (1) inhibition, to some extent, of disease progression, including slowing down and complete arrest; (2) reduction in the number of disease episodes and/or symptoms; (3) reduction in lesional size; (4) inhibition (i.e., reduction, slowing down or complete stopping) of disease cell infiltration into adjacent peripheral organs and/or tissues; (5) inhibition (i.e., reduction, slowing down or complete stopping) of disease spread; (6) decrease of auto-immune response, which may, but does not have to, result in the regression or ablation of the disease lesion; (7) relief, to some extent, of one or more symptoms associated with the disorder; (8) increase in the length of disease-free presentation following treatment; and/or (9) decreased mortality at a given point of time following treatment. The term "responsiveness" refers to a measurable response, including complete response (CR) and partial response (PR). As used herein, "complete response" or "CR" means the disappearance of all signs of inflammation or remission in response to treatment. This does not necessarily mean the disease has been cured.

"Partial response" or "PR" refers to a decrease of at least 50% in the severity of inflammation, in response to treatment.

A "beneficial response" of a patient to treatment with a therapeutic agent and similar wording refers to the clinical or therapeutic benefit imparted to a patient at risk for or suffering from a gastrointestinal inflammatory disorder from or as a result of the treatment with the agent. Such benefit includes cellular or biological responses, a complete response, a partial response, a stable disease (without progression or relapse), or a response with a later relapse of the patient from or as a result of the treatment with the agent.

As used herein, "non-response" or "lack of response" or similar wording means an absence of a complete response, a partial response, or a beneficial response to treatment with a therapeutic agent.

"A patient maintains responsiveness to a treatment" when the patient' s responsiveness does not decrease with time during the course of a treatment.

A "symptom" of a disease or disorder (e.g., inflammatory bowel disease, e.g., ulcerative colitis or Crohn's disease) is any morbid phenomenon or departure from the normal in structure, function, or sensation, experienced by a subject and indicative of disease.

IL-6 Receptor Inhibitors

The term "IL-6 receptor inhibitor" refers to an agent which decreases IL-6 receptor expression and/or the ability of IL-6 to bind to an IL-6 receptor. In some embodiments, the IL-6 receptor inhibitor targets the IL-6 receptor β-subunit, glycoprotein 130 (sIL6gpl30). In other embodiments, the IL-6 receptor inhibitor targets the IL-6 receptor subunit (IL6R). In other embodiments, the IL-6 receptor inhibitor targets the complex consisting of both the IL- 6 receptor subunit (IL6R) and the IL-6 receptor β-subunit, glycoprotein 130 (sIL6gpl30). In some embodiments, the IL-6 receptor inhibitor targets IL-6.

In some embodiments, an IL-6 receptor inhibitor is an inhibitory nucleic acid, an antibody or an antigen-binding fragment thereof, a fusion protein, a IL-6 receptor antagonist, or a small molecule. In some embodiments, the inhibitory nucleic acid is a small interfering RNA, an antisense nucleic acid, an aptamer, or a microRNA. Exemplary IL-6 receptor inhibitors are described herein. Additional examples of IL-6 receptor inhibitors are known in the art.

Exemplary aspects of different inhibitory nucleic acids are described below. Any of the examples of inhibitory nucleic acids that can decrease expression of an IL6R, sIL6gpl30, or IL-6 mRNA. Inhibitory nucleic acids that can decrease the expression of IL6R, sIL6gpl30, or IL-6 mRNA in a mammalian cell include antisense nucleic acid molecules, i.e., nucleic acid molecules whose nucleotide sequence is complementary to all or part of an IL6R, sIL6gpl30, or IL-6 mRNA (e.g., complementary to all or a part of any one of SEQ ID NOs: 1-6).

Human IL6R mRNA Variant 1 (SEQ ID NO: 1)

1 ggcggtcccc tgttctcccc gctcaggtgc ggcgctgtgg caggaagcca ccccctcggt

61 cggccggtgc gcggggctgt tgcgccatcc gctccggctt tcgtaaccgc accctgggac

121 ggcccagaga cgctccagcg cgagttcctc aaatgttttc ctgcgttgcc aggaccgtcc

181 gccgctctga gtcatgtgcg agtgggaagt cgcactgaca ctgagccggg ccagagggag

241 aggagccgag cgcggcgcgg ggccgaggga ctcgcagtgt gtgtagagag ccgggctcct

301 gcggatgggg gctgcccccg gggcctgagc ccgcctgccc gcccaccgcc ccgccccgcc

361 cctgccaccc ctgccgcccg gttcccatta gcctgtccgc ctctgcggga ccatggagtg

421 gtagccgagg aggaagcatg ctggccgtcg gctgcgcgct gctggctgcc ctgctggccg

481 cgccgggagc ggcgctggcc ccaaggcgct gccctgcgca ggaggtggcg agaggcgtgc

541 tgaccagtct gccaggagac agcgtgactc tgacctgccc gggggtagag ccggaagaca

601 atgccactgt tcactgggtg ctcaggaagc cggctgcagg ctcccacccc agcagatggg

661 ctggcatggg aaggaggctg ctgctgaggt cggtgcagct ccacgactct ggaaactatt

721 catgctaccg ggccggccgc ccagctggga ctgtgcactt gctggtggat gttccccccg

781 aggagcccca gctctcctgc ttccggaaga gccccctcag caatgttgtt tgtgagtggg

841 gtcctcggag caccccatcc ctgacgacaa aggctgtgct cttggtgagg aagtttcaga

901 acagtccggc cgaagacttc caggagccgt gccagtattc ccaggagtcc cagaagttct

961 cctgccagtt agcagtcccg gagggagaca gctctttcta catagtgtcc atgtgcgtcg

1021 ccagtagtgt cgggagcaag ttcagcaaaa ctcaaacctt tcagggttgt ggaatcttgc

1081 agcctgatcc gcctgccaac atcacagtca ctgccgtggc cagaaacccc cgctggctca

1141 gtgtcacctg gcaagacccc cactcctgga actcatcttt ctacagacta cggtttgagc

1201 tcagatatcg ggctgaacgg tcaaagacat tcacaacatg gatggtcaag gacctccagc

1261 atcactgtgt catccacgac gcctggagcg gcctgaggca cgtggtgcag cttcgtgccc

1321 aggaggagtt cgggcaaggc gagtggagcg agtggagccc ggaggccatg ggcacgcctt

1381 ggacagaatc caggagtcct ccagctgaga acgaggtgtc cacccccatg caggcactta

1441 ctactaataa agacgatgat aatattctct tcagagattc tgcaaatgcg acaagcctcc

1501 cagtgcaaga ttcttcttca gtaccactgc ccacattcct ggttgctgga gggagcctgg

1561 ccttcggaac gctcctctgc attgccattg ttctgaggtt caagaagacg tggaagctgc

1621 gggctctgaa ggaaggcaag acaagcatgc atccgccgta ctctttgggg cagctggtcc

1681 cggagaggcc tcgacccacc ccagtgcttg ttcctctcat ctccccaccg gtgtccccca 1741 gcagcctggg gtctgacaat acctcgagcc acaaccgacc agatgccagg gacccacgga 1801 gcccttatga catcagcaat acagactact tcttccccag atagctggct gggtggcacc 1861 agcagcctgg accctgtgga tgataaaaca caaacgggct cagcaaaaga tgcttctcac 1921 tgccatgcca gcttatctca ggggtgtgcg gcctttggct tcacggaaga gccttgcgga 1981 aggttctacg ccaggggaaa atcagcctgc tccagctgtt cagctggttg aggtttcaaa

2041 cctccctttc caaatgccca gcttaaaggg gctagagtga acttgggcca ctgtgaagag 2101 aaccatatca agactctttg gacactcaca cggacactca aaagctgggc aggttggtgg 2161 gggcctcggt gtggagaagc ggctggcagc ccacccctca acacctctgc acaagctgca 2221 ccctcaggca ggtgggatgg atttccagcc aaagcctcct ccagccgcca tgctcctggc 2281 ccactgcatc gtttcatctt ccaactcaaa ctcttaaaac ccaagtgcct tagcaaattc

2341 tgtttttcta ggcctgggga cggcttttac ttaaaccgcc aaggctgggg gaagaagctc 2401 tctcctccct ttcttcccta cagttgaaaa acagctgagg gtgagtgggt gaataataca 2461 gtatctcagg gcctggtcgt tttcaacaga attataatta gttcctcatt agcattttgc 2521 taaatgtgaa tgatgatcct aggcatttgc tgaatacaga ggcaactgca ttggctttgg 2581 gttgcaggac ctcaggtgag aagcagagga aggagaggag aggggcacag ggtctctacc

2641 atcccctgta gagtgggagc tgagtggggg atcacagcct ctgaaaacca atgttctctc 2701 ttctccacct cccacaaagg agagctagca gcagggaggg cttctgccat ttctgagatc 2761 aaaacggttt tactgcagct ttgtttgttg tcagctgaac ctgggtaact agggaagata 2821 atattaagga agacaatgtg aaaagaaaaa tgagcctggc aagaatgtgt ttaaacttgg 2881 tttttaaaaa actgctgact gttttctctt gagagggtgg aatatccaat attcgctgtg

2941 tcagcataga agtaacttac ttaggtgtgg gggaagcacc ataactttgt ttagcccaaa 3001 accaagtcaa gtgaaaaagg aggaagagaa aaaatatttt cctgccaggc atggtggccc 3061 acgcacttcg ggaggtcgag gcaggaggat cacttgagtc cagaagtttg agatcagcct 3121 gggcaatgtg ataaaacccc atctctacaa aaagcataaa aattagccaa gtgtggtaga 3181 gtgtgcctga agtcccagat acttgggggg ctgaggtggg aggatctctt gagcctggga

3241 ggtcaaggct gcagtgagcc gagattgcac cactgcactc cagcctgggt gacagagcaa 3301 gtgagaccct gtctcaaaaa aagaaaaaga aaaagaaaaa atattttccc tattagagaa 3361 gagattgtgg tttcattctg tattttgttt ttgtcttaaa aagtggaaaa atagcctgcc

3421 tcttctctac tctagggaaa aaccagcgtg tgactactcc cccaggtggt tatggagagg 3481 gtgtccggtc cctgtcccag tgccgagaag gaagcctccc acgactgccc ggcagggtcc

3541 tagaaattcc ccaccctgaa agccctgagc tttctgctat caaagaggtt ttaaaaaaat 3601 cccatttaaa aaaaatccct tacctcggtg ccttcctctt tttatttagt tccttgagtt

3661 gattcagctc tgcaagaatt gaagcaggac taaatgtcta gttgtaacac catgattaac 3721 cacttcagct gacttttctg tccgagcttt gaaaattcag tggtgttagt ggttacccag 3781 ttagctctca agttatcagg gtattccaga gtggggatat gatttaaatc agccgtgtaa

3841 ccatggaccc aatatttacc agaccacaaa acttttctaa tactctaccc tcttagaaaa 3901 accaccacca tcaccagaca ggtgcgaaag gatgaaagtg accatgtttt gtttacggtt 3961 ttccaggttt aagctgttac tgtcttcagt aagccgtgat tttcattgct gggcttgtct 4021 gtagatttta gaccctattg ctgcttgagg caactcatct taggttggca aaaaggcagg 4081 atggccgggc gcggtggctc acgcctgtaa tcctagcact ttgggaggcc aaggtgggag

4141 gattgcttga gctcaggagt ttgagaccaa cctgggtaac atagtgagac accatctcta 4201 ttatgaacaa taacagttaa gaaaaaaaaa ggcaggcagg cggttatggt ggttccctcc 4261 catcccacca cataaagttt ctgagacttg agaacagcaa aatgctgtta aagggaaata 4321 ttaagaatga gaatctgcag taagggtgat tctgtgccca cagttcttca attctttata 4381 ccgttttacc cacatgtggt gttaccaaag ccgggcagaa ccatgctagc ggaagatgtg 4441 aaatccagat agctcattat tgccaagagc taggcagctt tgatctccaa attgttattg 4501 ctttcatttt tattgtaatg gaattgcttt gttttgtttt tttgtttttg tattgaagag

4561 ggttgttttc cctttatttt tcataagcta atgtaaatga agaaaaaatg tcttctctgg

4621 gctgtaggcc tggctcagcg tacacaggta tacatcctaa gctctctatg ttctctaatc

4681 tgtggtgact gaacatgtgt ctcaatgcac ggggcatttc tacctgtgtt tctgcagcac 4741 ccccactgcc ttgagtcccc agcagtgctg ttatttgcct aacacctgta gccatctgcc 4801 acgcagccag acgtgaaacg ctgagacaga gaccatttag gttaaatacg acagcttatc 4861 ctgctgggtg gggaaagtaa aaaatatgct ggttcaaggc ctaaagtaaa atgatcaata 4921 atgtttgtag cattaatgaa atattttcaa gaaatgtgtc caggggtagc actggctatg

4981 ttgacgaggc ctttggtaac tcagagagct cttggccctg atggggactt gcccttacgc 5041 tttctttatc aggctctgag ttcacacgga gcctctggca cttccctgct gtcttgggag 5101 aaaggaaact ggttgccgcg gcaggttgtg gaatctgttg ctggaaccag gctggaagcc 5161 cacctggtag tgaacagggc ccagtggggc aggctgggca tgttgtggtc tatgggtttg 5221 tttcctggag aatgttcagg aatgtcttcc cagctgcttt ggtgctgagc tctattatct

5281 cacagcacgt ccagaaggct aacccaggtg gggaggatgc tgacaccagc tccaggtgga 5341 gttggtggtc ttaatttgga gatgcagggg caacctgtga ccctttgagg caagagccct 5401 gcacccagct gtcccgtgca gccgtgggca ggggctgcac acggaggggc aggcgggcca 5461 gttcagggtc cgtgccaggc cctcctcagt gccctgtgaa ggcctcctgt cctccgtgcg 5521 gctgggcacc agcaccaggg agtttctatg gcaaccttag tgattattaa ggaacactgt

5581 cagttttatg aacatatgct caaatgaaat tctactttag gaggaaagga ttggaacagc 5641 atgtcacaag gctgttaatt aacagagaga ccttattgga tggagatcac atctgttaaa 5701 tagaatacct caactctacg ttgttttctt ggagataaat aatagtttca agtttttgtt

5761 tgtttgtttt acctaattac ctgaaagcaa ataccaaagg ctgatgtctg tatatggggc 5821 aaagggtcag tatatttttc agtgtttttt tttctaccag ctattttgca tttaaagtga

5881 acattgtgtt tggaataaat actcttaaaa aataaaaaaa aaaaaaaa

Human IL6R mRNA Variant 2 (SEQ ID NO: 2)

1 ggcggtcccc tgttctcccc gctcaggtgc ggcgctgtgg caggaagcca ccccctcggt 61 cggccggtgc gcggggctgt tgcgccatcc gctccggctt tcgtaaccgc accctgggac

121 ggcccagaga cgctccagcg cgagttcctc aaatgttttc ctgcgttgcc aggaccgtcc 181 gccgctctga gtcatgtgcg agtgggaagt cgcactgaca ctgagccggg ccagagggag 241 aggagccgag cgcggcgcgg ggccgaggga ctcgcagtgt gtgtagagag ccgggctcct 301 gcggatgggg gctgcccccg gggcctgagc ccgcctgccc gcccaccgcc ccgccccgcc 361 cctgccaccc ctgccgcccg gttcccatta gcctgtccgc ctctgcggga ccatggagtg

421 gtagccgagg aggaagcatg ctggccgtcg gctgcgcgct gctggctgcc ctgctggccg 481 cgccgggagc ggcgctggcc ccaaggcgct gccctgcgca ggaggtggcg agaggcgtgc 541 tgaccagtct gccaggagac agcgtgactc tgacctgccc gggggtagag ccggaagaca 601 atgccactgt tcactgggtg ctcaggaagc cggctgcagg ctcccacccc agcagatggg 661 ctggcatggg aaggaggctg ctgctgaggt cggtgcagct ccacgactct ggaaactatt

721 catgctaccg ggccggccgc ccagctggga ctgtgcactt gctggtggat gttccccccg 781 aggagcccca gctctcctgc ttccggaaga gccccctcag caatgttgtt tgtgagtggg 841 gtcctcggag caccccatcc ctgacgacaa aggctgtgct cttggtgagg aagtttcaga 901 acagtccggc cgaagacttc caggagccgt gccagtattc ccaggagtcc cagaagttct 961 cctgccagtt agcagtcccg gagggagaca gctctttcta catagtgtcc atgtgcgtcg 1021 ccagtagtgt cgggagcaag ttcagcaaaa ctcaaacctt tcagggttgt ggaatcttgc 1081 agcctgatcc gcctgccaac atcacagtca ctgccgtggc cagaaacccc cgctggctca 1141 gtgtcacctg gcaagacccc cactcctgga actcatcttt ctacagacta cggtttgagc 1201 tcagatatcg ggctgaacgg tcaaagacat tcacaacatg gatggtcaag gacctccagc

1261 atcactgtgt catccacgac gcctggagcg gcctgaggca cgtggtgcag cttcgtgccc 1321 aggaggagtt cgggcaaggc gagtggagcg agtggagccc ggaggccatg ggcacgcctt 1381 ggacagaatc caggagtcct ccagctgaga acgaggtgtc cacccccatg caggcactta 1441 ctactaataa agacgatgat aatattctct tcagagattc tgcaaatgcg acaagcctcc 1501 caggttcaag aagacgtgga agctgcgggc tctgaaggaa ggcaagacaa gcatgcatcc

1561 gccgtactct ttggggcagc tggtcccgga gaggcctcga cccaccccag tgcttgttcc 1621 tctcatctcc ccaccggtgt cccccagcag cctggggtct gacaatacct cgagccacaa 1681 ccgaccagat gccagggacc cacggagccc ttatgacatc agcaatacag actacttctt 1741 ccccagatag ctggctgggt ggcaccagca gcctggaccc tgtggatgat aaaacacaaa 1801 cgggctcagc aaaagatgct tctcactgcc atgccagctt atctcagggg tgtgcggcct

1861 ttggcttcac ggaagagcct tgcggaaggt tctacgccag gggaaaatca gcctgctcca 1921 gctgttcagc tggttgaggt ttcaaacctc cctttccaaa tgcccagctt aaaggggcta 1981 gagtgaactt gggccactgt gaagagaacc atatcaagac tctttggaca ctcacacgga 2041 cactcaaaag ctgggcaggt tggtgggggc ctcggtgtgg agaagcggct ggcagcccac 2101 ccctcaacac ctctgcacaa gctgcaccct caggcaggtg ggatggattt ccagccaaag

2161 cctcctccag ccgccatgct cctggcccac tgcatcgttt catcttccaa ctcaaactct 2221 taaaacccaa gtgccttagc aaattctgtt tttctaggcc tggggacggc ttttacttaa 2281 accgccaagg ctgggggaag aagctctctc ctccctttct tccctacagt tgaaaaacag 2341 ctgagggtga gtgggtgaat aatacagtat ctcagggcct ggtcgttttc aacagaatta 2401 taattagttc ctcattagca ttttgctaaa tgtgaatgat gatcctaggc atttgctgaa

2461 tacagaggca actgcattgg ctttgggttg caggacctca ggtgagaagc agaggaagga 2521 gaggagaggg gcacagggtc tctaccatcc cctgtagagt gggagctgag tgggggatca 2581 cagcctctga aaaccaatgt tctctcttct ccacctccca caaaggagag ctagcagcag 2641 ggagggcttc tgccatttct gagatcaaaa cggttttact gcagctttgt ttgttgtcag 2701 ctgaacctgg gtaactaggg aagataatat taaggaagac aatgtgaaaa gaaaaatgag

2761 cctggcaaga atgtgtttaa acttggtttt taaaaaactg ctgactgttt tctcttgaga

2821 gggtggaata tccaatattc gctgtgtcag catagaagta acttacttag gtgtggggga 2881 agcaccataa ctttgtttag cccaaaacca agtcaagtga aaaaggagga agagaaaaaa 2941 tattttcctg ccaggcatgg tggcccacgc acttcgggag gtcgaggcag gaggatcact 3001 tgagtccaga agtttgagat cagcctgggc aatgtgataa aaccccatct ctacaaaaag

3061 cataaaaatt agccaagtgt ggtagagtgt gcctgaagtc ccagatactt ggggggctga 3121 ggtgggagga tctcttgagc ctgggaggtc aaggctgcag tgagccgaga ttgcaccact 3181 gcactccagc ctgggtgaca gagcaagtga gaccctgtct caaaaaaaga aaaagaaaaa 3241 gaaaaaatat tttccctatt agagaagaga ttgtggtttc attctgtatt ttgtttttgt

3301 cttaaaaagt ggaaaaatag cctgcctctt ctctactcta gggaaaaacc agcgtgtgac

3361 tactccccca ggtggttatg gagagggtgt ccggtccctg tcccagtgcc gagaaggaag 3421 cctcccacga ctgcccggca gggtcctaga aattccccac cctgaaagcc ctgagctttc 3481 tgctatcaaa gaggttttaa aaaaatccca tttaaaaaaa atcccttacc tcggtgcctt 3541 cctcttttta tttagttcct tgagttgatt cagctctgca agaattgaag caggactaaa 360 tgtctagttg taacaccatg attaaccact tcagctgact tttctgtccg agctttgaaa 366 attcagtggt gttagtggtt acccagttag ctctcaagtt atcagggtat tccagagtgg 372 ggatatgatt taaatcagcc gtgtaaccat ggacccaata tttaccagac cacaaaactt 378 ttctaatact ctaccctctt agaaaaacca ccaccatcac cagacaggtg cgaaaggatg 384 aaagtgacca tgttttgttt acggttttcc aggtttaagc tgttactgtc ttcagtaagc 390 cgtgattttc attgctgggc ttgtctgtag attttagacc ctattgctgc ttgaggcaac 396 tcatcttagg ttggcaaaaa ggcaggatgg ccgggcgcgg tggctcacgc ctgtaatcct 402 agcactttgg gaggccaagg tgggaggatt gcttgagctc aggagtttga gaccaacctg 408 ggtaacatag tgagacacca tctctattat gaacaataac agttaagaaa aaaaaaggca 414 ggcaggcggt tatggtggtt ccctcccatc ccaccacata aagtttctga gacttgagaa 420 cagcaaaatg ctgttaaagg gaaatattaa gaatgagaat ctgcagtaag ggtgattctg 426 tgcccacagt tcttcaattc tttataccgt tttacccaca tgtggtgtta ccaaagccgg 432 gcagaaccat gctagcggaa gatgtgaaat ccagatagct cattattgcc aagagctagg 438 cagctttgat ctccaaattg ttattgcttt catttttatt gtaatggaat tgctttgttt

444 tgtttttttg tttttgtatt gaagagggtt gttttccctt tatttttcat aagctaatgt

450 aaatgaagaa aaaatgtctt ctctgggctg taggcctggc tcagcgtaca caggtataca 456 tcctaagctc tctatgttct ctaatctgtg gtgactgaac atgtgtctca atgcacgggg 462 catttctacc tgtgtttctg cagcaccccc actgccttga gtccccagca gtgctgttat 468 ttgcctaaca cctgtagcca tctgccacgc agccagacgt gaaacgctga gacagagacc 474 atttaggtta aatacgacag cttatcctgc tgggtgggga aagtaaaaaa tatgctggtt 480 caaggcctaa agtaaaatga tcaataatgt ttgtagcatt aatgaaatat tttcaagaaa 486 tgtgtccagg ggtagcactg gctatgttga cgaggccttt ggtaactcag agagctcttg 492 gccctgatgg ggacttgccc ttacgctttc tttatcaggc tctgagttca cacggagcct 498 ctggcacttc cctgctgtct tgggagaaag gaaactggtt gccgcggcag gttgtggaat 504 ctgttgctgg aaccaggctg gaagcccacc tggtagtgaa cagggcccag tggggcaggc 510 tgggcatgtt gtggtctatg ggtttgtttc ctggagaatg ttcaggaatg tcttcccagc 516 tgctttggtg ctgagctcta ttatctcaca gcacgtccag aaggctaacc caggtgggga 522 ggatgctgac accagctcca ggtggagttg gtggtcttaa tttggagatg caggggcaac 528 ctgtgaccct ttgaggcaag agccctgcac ccagctgtcc cgtgcagccg tgggcagggg 534 ctgcacacgg aggggcaggc gggccagttc agggtccgtg ccaggccctc ctcagtgccc 540 tgtgaaggcc tcctgtcctc cgtgcggctg ggcaccagca ccagggagtt tctatggcaa 546 ccttagtgat tattaaggaa cactgtcagt tttatgaaca tatgctcaaa tgaaattcta 552 ctttaggagg aaaggattgg aacagcatgt cacaaggctg ttaattaaca gagagacctt 558 attggatgga gatcacatct gttaaataga atacctcaac tctacgttgt tttcttggag 564 ataaataata gtttcaagtt tttgtttgtt tgttttacct aattacctga aagcaaatac

570 caaaggctga tgtctgtata tggggcaaag ggtcagtata tttttcagtg tttttttttc 576 taccagctat tttgcattta aagtgaacat tgtgtttgga ataaatactc ttaaaaaata 582 aaaaaaaaaa aaaa

Human IL6R mRNA Variant 3 (SEQ ID NO: 3)

1 ggcggtcccc tgttctcccc gctcaggtgc ggcgctgtgg caggaagcca ccccctcggt 61 cggccggtgc gcggggctgt tgcgccatcc gctccggctt tcgtaaccgc accctgggac 121 ggcccagaga cgctccagcg cgagttcctc aaatgttttc ctgcgttgcc aggaccgtcc 181 gccgctctga gtcatgtgcg agtgggaagt cgcactgaca ctgagccggg ccagagggag 241 aggagccgag cgcggcgcgg ggccgaggga ctcgcagtgt gtgtagagag ccgggctcct 301 gcggatgggg gctgcccccg gggcctgagc ccgcctgccc gcccaccgcc ccgccccgcc 361 cctgccaccc ctgccgcccg gttcccatta gcctgtccgc ctctgcggga ccatggagtg

421 gtagccgagg aggaagcatg ctggccgtcg gctgcgcgct gctggctgcc ctgctggccg 481 cgccgggagc ggcgctggcc ccaaggcgct gccctgcgca ggaggtggcg agaggcgtgc

541 tgaccagtct gccaggagac agcgtgactc tgacctgccc gggggtagag ccggaagaca 601 atgccactgt tcactgggtg ctcaggaagc cggctgcagg ctcccacccc agcagatggg 661 ctggcatggg aaggaggctg ctgctgaggt cggtgcagct ccacgactct ggaaactatt 721 catgctaccg ggccggccgc ccagctggga ctgtgcactt gctggtggat gttccccccg 781 aggagcccca gctctcctgc ttccggaaga gccccctcag caatgttgtt tgtgagtggg

841 gtcctcggag caccccatcc ctgacgacaa aggctgtgct cttggtgagg aagtttcaga

901 acagtccggc cgaagacttc caggagccgt gccagtattc ccaggagtcc cagaagttct 961 cctgccagtt agcagtcccg gagggagaca gctctttcta catagtgtcc atgtgcgtcg

1021 ccagtagtgt cgggagcaag ttcagcaaaa ctcaaacctt tcagggttgt ggaatcttgc

1081 agcctgatcc gcctgccaac atcacagtca ctgccgtggc cagaaacccc cgctggctca

1141 gtgtcacctg gcaagacccc cactcctgga actcatcttt ctacagacta cggtttgagc

1201 tcagatatcg ggctgaacgg tcaaagacat tcacaacatg gatggtcaag gacctccagc 1261 atcactgtgt catccacgac gcctggagcg gcctgaggca cgtggtgcag cttcgtgccc 1321 aggaggagtt cgggcaaggc gagtggagcg agtggagccc ggaggccatg ggcacgcctt 1381 ggacagacag gctttctcct cgttgcccag gatggagtac agcagtgcaa tcacagctca

1441 cggcaacttc tgcctcctgg gttcaagcaa tcctcccgcc tcagcctcct aagtagctgg

1501 gaccacaggc gtgtgccaca atgctaattt tttaaaaatg ttttgtagag acagggtttc

1561 accatgctgc ccaggctggt ctcgaactcc tggcctcaag tgatccacca gcctcagact 1621 cccaaagtgc tgggattact ggtgtgagcc actgcacctg actaaacttt aaattttttt

1681 ttttagacgg aatctcgctc tgttgcccag gctggagtgc agtggcatga tattggctca

1741 ctgcaagctc tgcctcttgg gttcacgcta ttctcctgcc tcagcctcct gagtagctgg

1801 gactacaggt gcacaccacc acgcccggct aatttttttt tttttttagt agagacgggg

1861 tttcactgtg ttggccaggc tggtcttgaa ctcctgacct cgtgatccac ccgcctcgcc

1921 ctcccaaaat gctgggatta caggtgtgag ccaccgcgcc tggcctaaac ttttaaaatt

1981 ttaatcaaat taatacatgc acatggcaaa gaagtaataa acagcttata acactgaaaa

2041 aaaaaaaaaa aaaaaaaa

Human IL-6 receptor β-subunit, glycoprotein 130 (sIL6gpl30) (SEQ ID NO: 4)

1 gagcagccaa aaggcccgcg gagtcgcgct gggccgcccc ggcgcagctg aaccgggggc 61 cgcgcctgcc aggccgacgg gtctggccca gcctggcgcc aaggggttcg tgcgctgtgg

121 agacgcggag ggtcgaggcg gcgcggcctg agtgaaaccc aatggaaaaa gcatgacatt 181 tagaagtaga agacttagct tcaaatccct actccttcac ttactaattt tgtgatttgg

241 aaatatccgc gcaagatgtt gacgttgcag acttgggtag tgcaagcctt gtttattttc

301 ctcaccactg aatctacagg tgaacttcta gatccatgtg gttatatcag tcctgaatct

361 ccagttgtac aacttcattc taatttcact gcagtttgtg tgctaaagga aaaatgtatg

421 gattattttc atgtaaatgc taattacatt gtctggaaaa caaaccattt tactattcct

481 aaggagcaat atactatcat aaacagaaca gcatccagtg tcacctttac agatatagct

541 tcattaaata ttcagctcac ttgcaacatt cttacattcg gacagcttga acagaatgtt

601 tatggaatca caataatttc aggcttgcct ccagaaaaac ctaaaaattt gagttgcatt 661 gtgaacgagg ggaagaaaat gaggtgtgag tgggatggtg gaagggaaac acacttggag 721 acaaacttca ctttaaaatc tgaatgggca acacacaagt ttgctgattg caaagcaaaa 781 cgtgacaccc ccacctcatg cactgttgat tattctactg tgtattttgt caacattgaa 841 gtctgggtag aagcagagaa tgcccttggg aaggttacat cagatcatat caattttgat 901 cctgtatata aagtgaagcc caatccgcca cataatttat cagtgatcaa ctcagaggaa

961 ctgtctagta tcttaaaatt gacatggacc aacccaagta ttaagagtgt tataatacta 1021 aaatataaca ttcaatatag gaccaaagat gcctcaactt ggagccagat tcctcctgaa 1081 gacacagcat ccacccgatc ttcattcact gtccaagacc ttaaaccttt tacagaatat 1141 gtgtttagga ttcgctgtat gaaggaagat ggtaagggat actggagtga ctggagtgaa 1201 gaagcaagtg ggatcaccta tgaagataga ccatctaaag caccaagttt ctggtataaa

1261 atagatccat cccatactca aggctacaga actgtacaac tcgtgtggaa gacattgcct 1321 ccttttgaag ccaatggaaa aatcttggat tatgaagtga ctctcacaag atggaaatca 1381 catttacaaa attacacagt taatgccaca aaactgacag taaatctcac aaatgatcgc 1441 tatctagcaa ccctaacagt aagaaatctt gttggcaaat cagatgcagc tgttttaact 1501 atccctgcct gtgactttca agctactcac cctgtaatgg atcttaaagc attccccaaa

1561 gataacatgc tttgggtgga atggactact ccaagggaat ctgtaaagaa atatatactt 1621 gagtggtgtg tgttatcaga taaagcaccc tgtatcacag actggcaaca agaagatggt 1681 accgtgcatc gcacctattt aagagggaac ttagcagaga gcaaatgcta tttgataaca 1741 gttactccag tatatgctga tggaccagga agccctgaat ccataaaggc ataccttaaa 1801 caagctccac cttccaaagg acctactgtt cggacaaaaa aagtagggaa aaacgaagct

1861 gtcttagagt gggaccaact tcctgttgat gttcagaatg gatttatcag aaattatact 1921 atattttata gaaccatcat tggaaatgaa actgctgtga atgtggattc ttcccacaca 1981 gaatatacat tgtcctcttt gactagtgac acattgtaca tggtacgaat ggcagcatac 2041 acagatgaag gtgggaagga tggtccagaa ttcactttta ctaccccaaa gtttgctcaa 2101 ggagaaattg aagccatagt cgtgcctgtt tgcttagcat tcctattgac aactcttctg

2161 ggagtgctgt tctgctttaa taagcgagac ctaattaaaa aacacatctg gcctaatgtt 2221 ccagatcctt caaagagtca tattgcccag tggtcacctc acactcctcc aaggcacaat 2281 tttaattcaa aagatcaaat gtattcagat ggcaatttca ctgatgtaag tgttgtggaa 2341 atagaagcaa atgacaaaaa gccttttcca gaagatctga aatcattgga cctgttcaaa 2401 aaggaaaaaa ttaatactga aggacacagc agtggtattg gggggtcttc atgcatgtca

2461 tcttctaggc caagcatttc tagcagtgat gaaaatgaat cttcacaaaa cacttcgagc 2521 actgtccagt attctaccgt ggtacacagt ggctacagac accaagttcc gtcagtccaa 2581 gtcttctcaa gatccgagtc tacccagccc ttgttagatt cagaggagcg gccagaagat 2641 ctacaattag tagatcatgt agatggcggt gatggtattt tgcccaggca acagtacttc 2701 aaacagaact gcagtcagca tgaatccagt ccagatattt cacattttga aaggtcaaag

2761 caagtttcat cagtcaatga ggaagatttt gttagactta aacagcagat ttcagatcat 2821 atttcacaat cctgtggatc tgggcaaatg aaaatgtttc aggaagtttc tgcagcagat 2881 gcttttggtc caggtactga gggacaagta gaaagatttg aaacagttgg catggaggct 2941 gcgactgatg aaggcatgcc taaaagttac ttaccacaga ctgtacggca aggcggctac 3001 atgcctcagt gaaggactag tagttcctgc tacaacttca gcagtaccta taaagtaaag

3061 ctaaaatgat tttatctgtg aattc

Human IL-6 mRNA Transcript 1 (SEQ ID NO: 5) 1 gtctcaatat tagagtctca acccccaata aatataggac tggagatgtc tgaggctcat 61 tctgccctcg agcccaccgg gaacgaaaga gaagctctat ctcccctcca ggagcccagc 121 tatgaactcc ttctccacaa gcgccttcgg tccagttgcc ttctccctgg ggctgctcct 181 ggtgttgcct gctgccttcc ctgccccagt acccccagga gaagattcca aagatgtagc 241 cgccccacac agacagccac tcacctcttc agaacgaatt gacaaacaaa ttcggtacat

301 cctcgacggc atctcagccc tgagaaagga gacatgtaac aagagtaaca tgtgtgaaag 361 cagcaaagag gcactggcag aaaacaacct gaaccttcca aagatggctg aaaaagatgg 421 atgcttccaa tctggattca atgaggagac ttgcctggtg aaaatcatca ctggtctttt 481 ggagtttgag gtatacctag agtacctcca gaacagattt gagagtagtg aggaacaagc 541 cagagctgtg cagatgagta caaaagtcct gatccagttc ctgcagaaaa aggcaaagaa

601 tctagatgca ataaccaccc ctgacccaac cacaaatgcc agcctgctga cgaagctgca 661 ggcacagaac cagtggctgc aggacatgac aactcatctc attctgcgca gctttaagga 721 gttcctgcag tccagcctga gggctcttcg gcaaatgtag catgggcacc tcagattgtt 781 gttgttaatg ggcattcctt cttctggtca gaaacctgtc cactgggcac agaacttatg 841 ttgttctcta tggagaacta aaagtatgag cgttaggaca ctattttaat tatttttaat

901 ttattaatat ttaaatatgt gaagctgagt taatttatgt aagtcatatt tatattttta

961 agaagtacca cttgaaacat tttatgtatt agttttgaaa taataatgga aagtggctat 1021 gcagtttgaa tatcctttgt ttcagagcca gatcatttct tggaaagtgt aggcttacct 1081 caaataaatg gctaacttat acatattttt aaagaaatat ttatattgta tttatataat 1141 gtataaatgg tttttatacc aataaatggc attttaaaaa attcagcaaa aaaaaaa

Human IL-6 mRNA Transcript 2 (SEQ ID NO: 6)

1 gtctcaatat tagagtctca acccccaata aatataggac tggagatgtc tgaggctcat 61 tctgccctcg agcccaccgg gaacgaaaga gaagctctat ctcccctcca ggagcccagc 121 tatgaactcc ttctccacaa acatgtaaca agagtaacat gtgtgaaagc agcaaagagg

181 cactggcaga aaacaacctg aaccttccaa agatggctga aaaagatgga tgcttccaat 241 ctggattcaa tgaggagact tgcctggtga aaatcatcac tggtcttttg gagtttgagg 301 tatacctaga gtacctccag aacagatttg agagtagtga ggaacaagcc agagctgtgc 361 agatgagtac aaaagtcctg atccagttcc tgcagaaaaa ggcaaagaat ctagatgcaa 421 taaccacccc tgacccaacc acaaatgcca gcctgctgac gaagctgcag gcacagaacc

481 agtggctgca ggacatgaca actcatctca ttctgcgcag ctttaaggag ttcctgcagt 541 ccagcctgag ggctcttcgg caaatgtagc atgggcacct cagattgttg ttgttaatgg 601 gcattccttc ttctggtcag aaacctgtcc actgggcaca gaacttatgt tgttctctat 661 ggagaactaa aagtatgagc gttaggacac tattttaatt atttttaatt tattaatatt 721 taaatatgtg aagctgagtt aatttatgta agtcatattt atatttttaa gaagtaccac

781 ttgaaacatt ttatgtatta gttttgaaat aataatggaa agtggctatg cagtttgaat 841 atcctttgtt tcagagccag atcatttctt ggaaagtgta ggcttacctc aaataaatgg 901 ctaacttata catattttta aagaaatatt tatattgtat ttatataatg tataaatggt

961 ttttatacca ataaatggca ttttaaaaaa ttcagcaaaa aaaaaa Inhibitory Nucleic Acids

An antisense nucleic acid molecule can be complementary to all or part of a non- coding region of the coding strand of a nucleotide sequence encoding an IL6R, sIL6gpl30, or IL-6 protein. Non-coding regions (5' and 3' untranslated regions) are the 5' and 3' sequences that flank the coding region in a gene and are not translated into amino acids.

Based upon the sequences disclosed herein, one of skill in the art can easily choose and synthesize any of a number of appropriate antisense nucleic acids to target a nucleic acid encoding an IL6R, sIL6gpl30, or IL-6 protein described herein. Antisense nucleic acids targeting a nucleic acid encoding an IL6R, sIL6gpl30, or IL-6 protein can be designed using the software available at the Integrated DNA Technologies website.

An antisense nucleic acid can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides or more in length. An antisense oligonucleotide can be constructed using chemical synthesis and enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used.

Examples of modified nucleotides which can be used to generate an antisense nucleic acid include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl- 2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1 -methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2- methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7- methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D- mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6- isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2- thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5- oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3- N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest). The antisense nucleic acid molecules described herein can be prepared in vitro and administered to a mammal, e.g., a human. Alternatively, they can be generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding an IL6R, sIL6gpl30, or IL-6 protein to thereby inhibit expression, e.g., by inhibiting transcription and/or translation. The hybridization can be by conventional nucleotide complementarities to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. The antisense nucleic acid molecules can be delivered to a mammalian cell using a vector (e.g., a lentivirus, a retrovirus, or an adenovirus vector).

An antisense nucleic acid can be an a-anomeric nucleic acid molecule. An a- anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual, β-units, the strands run parallel to each other (Gaultier et al., Nucleic Acids Res. 15:6625-6641, 1987). The antisense nucleic acid can also comprise a 2'-0-methylribonucleotide (Inoue et al., Nucleic Acids Res. 15:6131-6148, 1987) or a chimeric RNA-DNA analog (Inoue et al., FEBS Lett. 215:327-330, 1987).

Exemplary antisense nucleic acids that are IL-6 receptor inhibitors are described in Keller et al., J. Immunol. 154(8):4091-4098, 1995; and Jiang et al., Anticancer Res. 31(9): 2899-2906, 2011.

Another example of an inhibitory nucleic acid is a ribozyme that has specificity for a nucleic acid encoding an IL6R, sIL6gpl30, or IL-6 protein (e.g., specificity for an IL6R, sIL6gpl30, or IL-6 mRNA, e.g., specificity for any one of SEQ ID NOs: 1-6). Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single- stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach, Nature 334:585-591, 1988)) can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of the protein encoded by the mRNA. A ribozyme having specificity for an IL6R, sIL6gpl30, or IL-6 mRNA can be designed based upon the nucleotide sequence of any of the IL6R, sIL6gpl30, or IL-6 mRNA sequences disclosed herein. For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in an IL6R, sIL6gpl30, or IL-6 mRNA (see, e.g., U.S. Patent. Nos. 4,987,071 and 5, 116,742). Alternatively, a SMAD7 mRNA can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., Science 261 : 1411-1418, 1993. An inhibitory nucleic acid can also be a nucleic acid molecule that forms triple helical structures. For example, expression of an IL6R, sIL6gpl30, or IL-6 polypeptide can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the gene encoding the IL6R, sIL6gpl30, or IL-6 polypeptide (e.g., the promoter and/or enhancer, e.g., a sequence that is at least 1 kb, 2 kb, 3 kb, 4 kb, or 5 kb upstream of the transcription initiation start state) to form triple helical structures that prevent transcription of the gene in target cells. See generally Helene, Anticancer Drug Des. 6(6):569-84, 1991; Helene, Ann. N Y. Acad. Sci. 660:27-36, 1992; and Maher, Bioassays 14(12):807-15, 1992.

In various embodiments, inhibitory nucleic acids can be modified at the base moiety, sugar moiety, or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see, e.g., Hyrup et al., Bioorganic Medicinal Chem. 4(l):5-23, 1996). Peptide nucleic acids (PNAs) are nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a

pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs allows for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols (see, e.g., Perry-O'Keefe et al., Proc. Natl. Acad. Sci.

U.S.A. 93 : 14670-675, 1996). PNAs can be used as antisense or antigene agents for sequence- specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication.

PNAs can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA- DNA chimeras can be generated which may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA recognition enzymes, e.g., RNAse H and DNA polymerases, to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation.

The synthesis of PNA-DNA chimeras can be performed as described in Finn et al., Nucleic Acids Res. 24:3357-63, 1996. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry and modified nucleoside analogs. Compounds such as 5'-(4-methoxytrityl)amino-5'-deoxy-thymidine phosphoramidite can be used as a link between the PNA and the 5' end of DNA (Mag et al., Nucleic Acids Res. 17:5973-88, 1989). PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment (Finn et al., Nucleic Acids Res. 24:3357-63, 1996). Alternatively, chimeric molecules can be synthesized with a 5' DNA segment and a 3' PNA segment (Peterser et al., Bioorganic Med. Chem. Lett. 5: 1119-11124, 1975).

In some embodiments, the inhibitory nucleic acids can include other appended groups such as peptides, or agents facilitating transport across the cell membrane (see, Letsinger et al., Proc. Natl. Acad. Sci. U.S.A. 86:6553-6556, 1989; Lemaitre et al., Proc. Natl. Acad. Sci. U.S.A. 84:648-652, 1989; and WO 88/09810). In addition, the inhibitory nucleic acids can be modified with hybridization-triggered cleavage agents (see, e.g., Krol et al., Bio/Techniques 6:958-976, 1988) or intercalating agents (see, e.g., Zon, Pharm. Res. 5:539-549, 1988). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, hybridization triggered cross-linking agent, transport agent, hybridization-triggered cleavage agent, etc.

Another means by which expression of an IL6R, sIL6gpl30, or IL-6 mRNA can be decreased in a mammalian cell is by RNA interference (RNAi). RNAi is a process in which mRNA is degraded in host cells. To inhibit an mRNA, double-stranded RNA (dsRNA) corresponding to a portion of the gene to be silenced (e.g., a gene encoding an IL6R, sIL6gpl30, or IL-6 polypeptide) is introduced into a mammalian cell. The dsRNA is digested into 21-23 nucleoti de-long duplexes called short interfering RNAs (or siRNAs), which bind to a nuclease complex to form what is known as the RNA-induced silencing complex (or RISC). The RISC targets the homologous transcript by base pairing interactions between one of the siRNA strands and the endogenous mRNA. It then cleaves the mRNA about 12 nucleotides from the 3' terminus of the siRNA (see Sharp et al., Genes Dev. 15:485- 490, 2001, and Hammond et a\., Nature Rev. Gen. 2: 110-119, 2001).

RNA-mediated gene silencing can be induced in a mammalian cell in many ways, e.g., by enforcing endogenous expression of RNA hairpins (see, Paddison et al., Proc. Natl. Acad. Sci. U.S.A. 99: 1443-1448, 2002) or, as noted above, by transfection of small (21-23 nt) dsRNA (reviewed in Caplen, Trends Biotech. 20:49-51, 2002). Methods for modulating gene expression with RNAi are described, e.g., in U.S. Patent No. 6,506,559 and US

2003/0056235, which are hereby incorporated by reference. Standard molecular biology techniques can be used to generate siRNAs. Short interfering RNAs can be chemically synthesized, recombinantly produced, e.g., by expressing RNA from a template DNA, such as a plasmid, or obtained from commercial vendors, such as Dharmacon. The RNA used to mediate RNAi can include synthetic or modified nucleotides, such as phosphorothioate nucleotides. Methods of transfecting cells with siRNA or with plasmids engineered to make siRNA are routine in the art.

The siRNA molecules used to decrease expression of an IL6R, sIL6gpl30, or IL-6 mRNA can vary in a number of ways. For example, they can include a 3' hydroxyl group and strands of 21, 22, or 23 consecutive nucleotides. They can be blunt ended or include an overhanging end at either the 3' end, the 5' end, or both ends. For example, at least one strand of the RNA molecule can have a 3' overhang from about 1 to about 6 nucleotides (e.g., 1-5, 1- 3, 2-4, or 3-5 nucleotides (whether pyrimidine or purine nucleotides) in length. Where both strands include an overhang, the length of the overhangs may be the same or different for each strand.

To further enhance the stability of the RNA duplexes, the 3' overhangs can be stabilized against degradation (by, e.g., including purine nucleotides, such as adenosine or guanosine nucleotides or replacing pyrimidine nucleotides by modified analogues (e.g., substitution of uridine 2-nucleotide 3' overhangs by 2'-deoxythymidine is tolerated and does not affect the efficiency of RNAi). Any siRNA can be used in the methods of decreasing an IL6R, sIL6gpl30, or IL-6 mRNA, provided it has sufficient homology to the target of interest (e.g., a sequence present in any one of SEQ ID NOs: 1-6, e.g., a target sequence

encompassing the translation start site or the first exon of the mRNA). There is no upper limit on the length of the siRNA that can be used (e.g., the siRNA can range from about 21 base pairs of the gene to the full length of the gene or more (e.g., about 20 to about 30 base pairs, about 50 to about 60 base pairs, about 60 to about 70 base pairs, about 70 to about 80 base pairs, about 80 to about 90 base pairs, or about 90 to about 100 base pairs).

Non-limiting examples of short interfering RNA (siRNA) that are IL-6 receptor inhibitors are described in Yi et al., Int. J. Oncol. 41(1):310-316, 2012; and Shinriki et al., Clin. Can. Res. 15(17):5426-5434, 2009). Non-limiting examples of microRNAs that are IL- 6 receptor inhibitors are described in miR34a (Li et al., Int. J. Clin. Exp. Pathol. 8(2): 1364- 1373, 2015) and miR-451 (Liu et al., Cancer Epidemiol. 38(l):85-92, 2014).

Non-limiting examples of aptamers that are IL-6 receptor inhibitors are described in Meyer et al., RNA Biol. 1 l(l):57-65, 2014; Meyer et al., RNA Biol. 9(l):67-80, 2012; and Mittelberger et al., RNA Biol. 12(9): 1043-1053, 2015. Additional examples of inhibitory nucleic acids that are IL-6 receptor inhibitors are described in, e.g., WO 96/040157.

In certain embodiments, a therapeutically effective amount of an inhibitory nucleic acid targeting a nucleic acid encoding an IL6R, sIL6gpl30, or IL-6 protein can be

administered to a subject (e.g., a human subject) in need thereof.

In some embodiments, the inhibitory nucleic acid can be about 10 nucleotides to about 40 nucleotides (e.g., about 10 to about 30 nucleotides, about 10 to about 25 nucleotides, about 10 to about 20 nucleotides, about 10 to about 15 nucleotides, 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, 30 nucleotides, 31 nucleotides, 32 nucleotides, 33 nucleotides, 34 nucleotides, 35 nucleotides, 36 nucleotides, 37 nucleotides, 38 nucleotides, 39 nucleotides, or 40 nucleotides) in length. One skilled in the art will appreciate that inhibitory nucleic acids may comprise at least one modified nucleic acid at either the 5' or 3 'end of DNA or RNA.

As is known in the art, the term "thermal melting point (Tm)" refers to the

temperature, under defined ionic strength, pH, and inhibitory nucleic acid concentration, at which 50% of the inhibitory nucleic acids complementary to the target sequence hybridize to the target sequence at equilibrium. In some embodiments, an inhibitory nucleic acid can bind specifically to a target nucleic acid under stingent conditions, e.g., those in which the salt concentration is at least about 0.01 to 1.0 M Na ion concentration (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30 °C. for short oligonucleotides (e.g., 10 to 50 nucleotide). Stringent conditions can also be achieved with the addition of destabilizing agents such as formamide.

In some embodiments of any of the inhibitory nucleic acids described herein, the inhibitory nucleic acid binds to a target nucleic acid (e.g., a nucleic acid encoding any one of IL6R, sIL6gpl30, or IL-6) with a Tm of greater than 20 °C, greater than 22 °C, greater than 24 °C, greater than 26 °C, greater than 28 °C, greater than 30 °C, greater than 32 °C, greater than 34 °C, greater than 36 °C, greater than 38 °C, greater than 40 °C, greater than 42 °C, greater than 44 °C, greater than 46 °C, greater than 48 °C, greater than 50 °C, greater than 52 °C, greater than 54 °C, greater than 56 °C, greater than 58 °C, greater than 60 °C, greater than 62 °C, greater than 64 °C, greater than 66 °C, greater than 68 °C, greater than 70 °C, greater than 72 °C, greater than 74 °C, greater than 76 °C, greater than 78 °C, or greater than 80 °C, e.g., as measured in phosphate buffered saline using a UV spectrophotometer.

In some embodiments of any of the inhibitor nucleic acids described herein, the inhibitory nucleic acid binds to a target nucleic acid (e.g., a nucleic acid encoding any one of IL6R, sIL6gpl30, or IL-6) with a T_m of about 20 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, about 36 °C, about 34 °C, about 32 °C, about 30 °C, about 28 °C, about 26 °C, about 24 °C, or about 22 °C

(inclusive); about 22 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, about 36 °C, about 34 °C, about 32 °C, about 30 °C, about 28 °C, about 26 °C, or about 24 °C (inclusive); about 24 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, about 36 °C, about 34 °C, about 32 °C, about 30 °C, about 28 °C, or about 26 °C (inclusive); about 26 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, about 36 °C, about 34 °C, about 32 °C, about 30 °C, or about 28 °C

(inclusive); about 28 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, about 36 °C, about 34 °C, about 32 °C, or about 30 °C (inclusive); about 30 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, about 36 °C, about 34 °C, or about 32 °C (inclusive); about 32 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, about 36 °C, or about 34 °C (inclusive); about 34 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, or about 36 °C (inclusive); about 36 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, or about 38 °C (inclusive); about 38 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, or about 40 °C (inclusive); about 40 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, or about 42 °C (inclusive); about 42 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, or about 44 °C (inclusive); about 44 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, or about 46 °C (inclusive); about 46 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, or about 48 °C (inclusive); about 48 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, or about 50 °C (inclusive); about 50 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, or about 52 °C

(inclusive); about 52 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, or about 54 °C (inclusive); about 54 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, or about 56 °C (inclusive); about 56 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, or about 58 °C (inclusive); about 58 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, or about 60 °C (inclusive); about 60 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, or about 62 °C (inclusive); about 62 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, or about 64 °C (inclusive); about 64 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, or about 66 °C (inclusive); about 66 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, or about 68 °C (inclusive); about 68 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, or about 70 °C (inclusive); about 70 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, or about 72 °C (inclusive); about 72 °C to about 80 °C, about 78 °C, about 76 °C, or about 74 °C (inclusive); about 74 °C to about 80 °C, about 78 °C, or about 76 °C (inclusive); about 76 °C to about 80 °C or about 78 °C (inclusive); or about 78 °C to about 80 °C (inclusive),

In some embodiments, the inhibitory nucleic acid can be formulated in a nanoparticle

(e.g., a nanoparticle including one or more synthetic polymers, e.g., Patil et al.,

Pharmaceutical Nanotechnol. 367: 195-203, 2009; Yang et al., ACS Appl. Mater. Interfaces, doi: 10.1021/acsami.6bl6556, 2017; Perepelyuk et al., Mol. Ther. Nucleic Acids 6:259-268, 2017). In some embodiments, the nanoparticle can be a mucoadhesive particle (e.g., nanoparticles having a positively-charged exterior surface) (Andersen et al., Methods Mol.

Biol. 555:77-86, 2009). In some embodiments, the nanoparticle can have a neutrally-charged exterior surface.

In some embodiments, the inhibitory nucleic acid can be formulated, e.g., as a liposome (Buyens et al., J. Control Release 158(3): 362-370, 2012; Scarabel et al., Expert Opin. DrugDeliv. 17: 1-14, 2017), a micelle (e.g., a mixed micelle) (Tangsangasaksri et al., BioMacromolecules 17:246-255, 2016; Wu et al., Nanotechnology, doi: 10.1088/1361- 6528/aa6519, 2017), a microemulsion (WO 11/004395), a nanoemulsion, or a solid lipid nanoparticle (Sahay et al., Nature Biotechnol. 31 :653-658, 2013; and Lin et al., Nanomedicine 9(1): 105-120, 2014). Additional exemplary structural features of inhibitory nucleic acids and formulations of inhibitory nucleic acids are described in US 2016/0090598.

In some embodiments, a pharmaceutical composition can include a sterile saline solution and one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein). In some examples, a pharmaceutical composition consists of a sterile saline solution and one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein). In certain embodiments, the sterile saline is a pharmaceutical grade saline. In certain embodiments, a pharmaceutical composition can include one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein) and sterile water. In certain embodiments, a pharmaceutical composition consists of one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein) and sterile water. In certain embodiments, a pharmaceutical composition includes one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein) and phosphate-buffered saline (PBS). In certain embodiments, a pharmaceutical composition consists of one or more inhibitory nucleic acids (e.g., any of the inhibitory nucleic acids described herein) and sterile phosphate-buffered saline (PBS). In some examples, the sterile saline is a pharmaceutical grade PBS.

In certain embodiments, one or more inhibitory nucleic acids (e.g., any of the inhibitory nucleic acids described herein) may be admixed with pharmaceutically acceptable active and/or inert substances for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions depend on a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.

Pharmaceutical compositions including one or more inhibitory nucleic acids encompass any pharmaceutically acceptable salts, esters, or salts of such esters. Non-limiting examples of pharmaceutical compositions include pharmaceutically acceptable salts of inhibitory nucleic acids. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.

Also provided herein are prodrugs that can include additional nucleosides at one or both ends of an inhibitory nucleic acid which are cleaved by endogenous nucleases within the body, to form the active inhibitory nucleic acid. Lipid moieties can be used to formulate an inhibitory nucleic acid. In certain such methods, the inhibitory nucleic acid is introduced into preformed liposomes or lipoplexes made of mixtures of cationic lipids and neutral lipids. In certain methods, inhibitory nucleic acid complexes with mono- or poly-cationic lipids are formed without the presence of a neutral lipid. In certain embodiments, a lipid moiety is selected to increase distribution of an inhibitory nucleic acid to a particular cell or tissue in a mammal. In some examples, a lipid moiety is selected to increase distribution of an inhibitory nucleic acid to fat tissue in a mammal. In certain embodiments, a lipid moiety is selected to increase distribution of an inhibitory nucleic acid to muscle tissue.

In certain embodiments, pharmaceutical compositions provided herein comprise one or more inhibitory nucleic acid and one or more excipients. In certain such embodiments, excipients are selected from water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin,

hydroxymethylcellulose and polyvinylpyrrolidone.

In some examples, a pharmaceutical composition provided herein includes liposomes and emulsions. Liposomes and emulsions can be used to formulate hydrophobic compounds. In some examples, certain organic solvents such as dimethylsulfoxide are used.

In some examples, a pharmaceutical composition provided herein includes one or more tissue-specific delivery molecules designed to deliver one or more inhibitory nucleic acids to specific tissues or cell types in a mammal. For example, a pharmaceutical composition can include liposomes coated with a tissue-specific antibody.

In some embodiments, a pharmaceutical composition provided herein can include a co-solvent system. Examples of such co-solvent systems include benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™ and 65% w/v polyethylene glycol 300. As can be appreciated, other surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

In some examples, a pharmaceutical composition can be formulated for oral administration. In some examples, pharmaceutical compositions are formulated for buccal administration. In some examples, a pharmaceutical composition is formulated for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In some of these

embodiments, a pharmaceutical composition includes a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In some examples, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In some examples, injectable suspensions are prepared using appropriate liquid carriers, suspending agents, and the like. Some pharmaceutical compositions for injection are formulated in unit dosage form, e.g., in ampoules or in multi-dose containers. Some pharmaceutical compositions for injection are suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.

Solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.

Antibodies

In some embodiments, the IL-6 receptor inhibitor is an antibody or an antigen-binding fragment thereof (e.g., a Fab or a scFv). In some embodiments, an antibody or antigen- binding fragment described herein binds specifically to IL-6. In some embodiments, an antibody or antigen-binding fragment described herein binds specifically to IL-6 receptor (e.g., one or both of IL6R and sIL6gpl30).

In some embodiments, the antibody can be a humanized antibody, a chimeric antibody, a multivalent antibody, or a fragment thereof. In some embodiments, an antibody can be a scFv-Fc, a VHH domain, a VNAR domain, a (scFv)₂, a minibody, or a BiTE. In some embodiments, an antibody can be a DVD-Ig, and a dual-affinity re-targeting antibody

(DART), a triomab, kih IgG with a common LC, a crossmab, an ortho-Fab IgQ a 2-in-l-IgQ IgG-ScFv, scFv₂-Fc, a bi-nanobody, tanden antibody, a DART-Fc, a scFv-HAS-scFv, D L- Fab3, DAF (two-in-one or four-in-one), DutaMab, DT-IgQ knobs-in-holes common LC, knobs-in-holes assembly, charge pair antibody, Fab-arm exchange antibody, SEEDbody, Triomab, LUZ-Y, Fcab, k -body, orthogonal Fab, DVD-IgG, IgG(H)-scFv, scFv-(H)IgQ IgG(L)-scFv, scFv-(L)-IgQ IgG (L,H)-Fc, IgG(H)-V, V(H)-IgQ IgG(L)-V, V(L)-IgQ KIH IgG-scFab, 2scFv-IgQ IgG-2scFv, scFv4-Ig, Zybody, DVI-IgQ nanobody, nanobody-HSA, a diabody, a TandAb, scDiabody, scDiabody-CH3, Diabody-CH3, Triple Body, miniantibody, minibody, TriBi minibody, scFv-CH3 KIH, Fab-scFv, scFv-CH-CL-scFv, F(ab')2-scFV2, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, diabody-Fc, tandem scFv-Fc, intrabody, dock and lock bispecific antibody, ImmTAC, HSAbody, scDiabody-HAS, tandem scFv, IgG-IgQ Cov-X-Body, and scFvl-PEG-scFv2.

Non-limiting examples of an antigen-binding fragment of an antibody include an Fv fragment, a Fab fragment, a F(ab')₂ fragment, and a Fab' fragment. Additional examples of an antigen-binding fragment of an antibody is an antigen-binding fragment of an IgG (e.g., an antigen-binding fragment of IgGl, IgG2, IgG3, or IgG4) (e.g., an antigen-binding fragment of a human or humanized IgQ e.g., human or humanized IgGl, IgG2, IgG3, or IgG4); an antigen-binding fragment of an IgA (e.g., an antigen-binding fragment of IgAl or IgA2) (e.g., an antigen-binding fragment of a human or humanized IgA, e.g., a human or humanized IgAl or IgA2); an antigen-binding fragment of an IgD (e.g., an antigen-binding fragment of a human or humanized IgD); an antigen-binding fragment of an IgE (e.g., an antigen-binding fragment of a human or humanized IgE); or an antigen-binding fragment of an IgM (e.g., an antigen-binding fragment of a human or humanized IgM).

In some embodiments, the antibody is a humanized antibody, a chimeric antibody, a multivalent antibody, or a fragment thereof. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a humanized monoclonal antibody. See e.g., Hunter & Jones, Nat. Immunol. 16:448-457, 2015; Heo et al., Oncotarget 7(13): 15460-15473, 2016. Additional examples of antibodies and antigen-binding fragments thereof are described in U.S. Patent Nos. 8,440,196; 7,842, 144; 8,034,344; and 8,529,895; US 2013/0317203; US 2014/0322239; US 2015/0166666; US 2016/0152714; and US 2017/0002082, each of which is incorporated by reference in its entirety.

In certain embodiments, the antibody comprises or consists of an antigen-binding fragment or portion of tocilizumab (artlizumab, Actemra®; Sebba, Am. J. Health Syst.

Pharm. 65(15): 1413-1418, 2008; Tanaka et al., FEBS Letters 585(23):3699-3709, 2011; Nishimoto et al., Arthritis Rheum. 50: 1761-1769, 2004; Yokota et al., Lancet 371(9617):998- 1006, 2008; Emery et al., Ann. Rheum. Dis. 67(11): 1516-1523, 2008; Roll et al., Arthritis Rheum. 63(5): 1255-1264, 2011); lazakizumab (BMS945429; ALD518, a humanized monoclonal antibody that binds circulating IL-6 cytokine rather than the IL-6 receptor, blocking both classic signaling and trans-signaling (Weinblatt, Michael E., et al. "The Efficacy and Safety of Subcutaneous Clazakizumab in Patients With Moderate-to-Severe Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results From a Multinational, Phase lib, Randomized, Double-Blind, Placebo/ Active-Controlled,

Dose-Ranging Study." Arthritis & Rheumatology 67.10 (2015): 2591-2600.)); sarilumab (REGN88 or SAR153191; Huizinga et al., Ann. Rheum. Dis. 73(9): 1626-1634, 2014; Sieper et al., Ann. Rheum. £fe.74(6): 1051-1057, 2014; Cooper, Immunotherapy 8(3): 249-250, 2016); MR-16 (Hartman et al., PLosOne 1 l(12):e0167195, 2016; Fujita et al., Biochim.

Biophys. Acta. 10:3170-80, 2014; Okazaki et al., Immunol. Lett. 84(3):231-40, 2002;

Noguchi-Sasaki et al., BMC Cancer 16:270, 2016; Ueda et al., Sci. Rep. 3 : 1196, 2013);

rhPM-1 (MRA; Nishimoto et al., Blood 95: 56-61, 2000; Nishimoto et al., Blood 106: 2627- 2632, 2005; Nakahara et al., Arthritis Rheum. 48(6): 1521-1529, 2003); NI-1201 (Lacroix et al., J. Biol. Chem. 290(45):26943-26953, 2015); EBI-029 (Schmidt et al., Eleven

Biotherapeutics Poster #B0200, 2014). In some embodiments, the antibody is a nanobody (e.g., ALX-0061 (Van Roy et al., Arthritis Res. Ther. 17: 135, 2015; Kim et al., Arch. Pharm. Res. 38(5):575-584, 2015)). In some embodiments, the antibody is NRI or a variant thereof (Adachi et al., Mol. Ther. 1 l(l):S262-263, 2005; Hoshino et al., Can. Res. 67(3): 871-875, 2007). In some embodiments, the antibody is PF-04236921 (Pfizer) (Wallace et al., Ann. Rheum. Dis. 76(3):534-542, 2017).

In some embodiments, any of the antibodies or antigen-binding fragments described herein has a dissociation constant (KD) of less than 1 x 10^"5 M (e.g., less than 0.5 x 10^"5 M, less than 1 x 10^-6 M, less than 0.5 x 10^-6 M, less than 1 x 10^_7 M, less than 0.5 x 10^-7 M, less than 1 x 10^-8 M, less than 0.5 x 10^-8 M, less than 1 x 10^_9 M, less than 0.5 x 10^-9 M, less than 1 x 10-¹⁰ M, less than 0.5 x 10-¹⁰ M, less than 1 x 10^"11 M, less than 0.5 x 10-^U M, or less than 1 x 10^"12 M), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).

In some embodiments, any of the antibodies or antigen-binding fragments described herein has a KD of about 1 x 10^"12 M to about 1 x 10^"5 M, about 0.5 x 10^"5 M, about 1 x 10^"6

M, about 0.5 x 10^"6 M, about 1 x 10^"7 M, about 0.5 x 10^"7 M, about 1 x 10^"8 M, about 0.5 x 10^" ⁸ M, about 1 x 10^"9 M, about 0.5 x 10^"9 M, about 1 x 10-¹⁰ M, about 0.5 x 10-¹⁰ M, about 1 x 10^-11 M, or about 0.5 x 10^_11 M (inclusive); about 0.5 x 10^_11 M to about 1 x 10^_5 M, about 0.5 x 10^"5 M, about 1 x 10^"6 M, about 0.5 x 10^"6 M, about 1 x 10^"7 M, about 0.5 x 10^"7 M, about 1 x 10^"8 M, about 0.5 x 10^"8 M, about 1 x 10^"9 M, about 0.5 x 10^"9 M, about 1 x 10-¹⁰ M, about 0.5 x 10-¹⁰ M, or about 1 x 10^-11 M (inclusive); about 1 x 10^_11 M to about 1 x 10^_5 M, about 0.5 x 10^"5 M, about 1 x 10^"6 M, about 0.5 x 10^"6 M, about 1 x 10^"7 M, about 0.5 x 10^"7 M, about 1 x 10^"8 M, about 0.5 x 10^"8 M, about 1 x 10^"9 M, about 0.5 x 10^"9 M, about 1 x 10-¹⁰ M, or about 0.5 x 10-¹⁰ M (inclusive); about 0.5 x 10^-10 M to about 1 x 10^_5 M, about 0.5 x 10^-5 M, about 1 x 10^"6 M, about 0.5 x 10^"6 M, about 1 x 10^"7 M, about 0.5 x 10^"7 M, about 1 x 10^"8 M, about 0.5 x 10^"8 M, about 1 x 10^"9 M, about 0.5 x 10^"9 M, or about 1 x 10-¹⁰ M (inclusive); about 1 x 10-¹⁰ M to about 1 x 10^"5 M, about 0.5 x 10^"5 M, about 1 x 10^"6 M, about 0.5 x 10^"6 M, about 1 x 10^"7 M, about 0.5 x 10^"7 M, about 1 x 10^"8 M, about 0.5 x 10^"8 M, about 1 x 10^"9 M, or about 0.5 x 10^"9 M (inclusive); about 0.5 x 10^"9 M to about 1 x 10^"5 M, about 0.5 x 10^"5 M, about 1 x 10^"6 M, about 0.5 x 10^"6 M, about 1 x 10^"7 M, about 0.5 x 10^"7 M, about 1 x 10^"8 M, about 0.5 x 10^"8 M, or about 1 x 10^"9 M (inclusive); about 1 x 10^"9 M to about 1 x 10^"5 M, about 0.5 x 10^"5 M, about 1 x 10^"6 M, about 0.5 x 10^"6 M, about 1 x 10^"7 M, about 0.5 x 10^"7 M, about 1 x 10^"8 M, or about 0.5 x 10^"8 M (inclusive); about 0.5 x 10^"8 M to about 1 x 10^"5

M, about 0.5 x 10^"5 M, about 1 x 10^"6 M, about 0.5 x 10^"6 M, about 1 x 10^"7 M, about 0.5 x 10^" ⁷ M, or about 1 x 10^"8 M (inclusive); about 1 x 10^"8 M to about 1 x 10^"5 M, about 0.5 x 10^"5 M, about 1 x 10^"6 M, about 0.5 x 10^"6 M, about 1 x 10^"7 M, or about 0.5 x 10^"7 M (inclusive); about 0.5 x 10^"7 M to about 1 x 10^"5 M, about 0.5 x 10^"5 M, about 1 x 10^"6 M, about 0.5 x 10^"6 M, or about 1 x 10^"7 M (inclusive); about 1 x 10^"7 M to about 1 x 10^"5 M, about 0.5 x 10^"5 M, about 1 x 10^"6 M, or about 0.5 x 10^"6 M (inclusive); about 0.5 x 10^"6 M to about 1 x 10^"5 M, about 0.5 x 10^"5 M, or about 1 x 10^"6 M (inclusive); about 1 x 10^"6 M to about 1 x 10^"5 M or about 0.5 x 10^"5 M (inclusive); or about 0.5 x 10^"5 M to about 1 x 10^"5 M (inclusive), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).

In some embodiments, any of the antibodies or antigen-binding fragments described herein has a K₀ff of about 1 x 10^"6 s^"1 to about 1 x 10^"3 s^"1, about 0.5 x 10^"3 s^"1, about 1 x 10^"4 s^" about 0.5 x 10^"4 s^"1, about 1 x 10^"5 s^"1, or about 0.5 x 10^"5 s^_1 (inclusive); about 0.5 x 10^-5 s^_1 to about 1 x 10^"3 s^"1, about 0.5 x 10^"3 s^"1, about 1 x 10^"4 s^"1, about 0.5 x 10^"4 s^"1, or about 1 x 10^"5 s^"1 (inclusive); about 1 x 10^"5 s^"1 to about 1 x 10^"3 s^"1, about 0.5 x 10^"3 s^"1, about 1 x 10^"4 s^" or about 0.5 x 10^-4 s^_1 (inclusive); about 0.5 x 10^-4 s^_1 to about 1 x 10^-3 s^"1, about 0.5 x 10^-3 s^"1, or about 1 x 10^"4 s^"1 (inclusive); about 1 x 10^"4 s^_1 to about 1 x 10^"3 s^"1, or about 0.5 x 10^"3 s^"1 (inclusive); or about 0.5 x 10^"5 s^_1 to about 1 x 10^"3 s^"1 (inclusive), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).

In some embodiments, any of the antibodies or antigen-binding fragments described herein has a K₀n of about 1 x 10² M^'V¹ to about 1 x 10⁶ M^s^-1, about 0.5 x 10⁶ M^'V¹, about 1 x 10⁵ M-¹s^_1, about 0.5 x 10⁵ M^'V¹, about 1 x 10⁴ M^'V¹, about 0.5 x 10⁴ M^s^"1, about 1 x 10³ M^-1s^-1, or about 0.5 x 10³ M^s^-1 (inclusive); about 0.5 x 10³ M^s^-1 to about 1 x 10⁶ M^-1s^-1, about 0.5 x 10⁶ M^s^"1, about 1 x lO^^{' 1}, about 0.5 x 10⁵ M^s^"1, about 1 x 10⁴ M^s^"1, about 0.5 x 10⁴ M^'V¹, or about 1 x 10³ TvTV¹ (inclusive); about 1 x 10³ M^' ^o about 1 x 10⁶ M^_V about 0.5 x 10⁶ M^'V¹,

about 0.5 x 10⁵ M^'V¹, about 1 x 10⁴ M^'V¹, or about 0.5 x 10⁴ M^'V¹ (inclusive); about 0.5 x 10⁴ M^-1s^-1 to about 1 x 10⁶ M^-1s^-1, about 0.5 x 10⁶ M^'V¹,

about 0.5 x 10⁵ M^'V¹, or about 1 x 10⁴ M^'V¹ (inclusive); about 1 x 10⁴ M^'V¹ to about 1 x 10⁶ M^-1s^"1, about 0.5 x 10⁶ M^'V¹, about 1 x lO^^{' 1}, or about 0.5 x 10⁵ M^'V¹ (inclusive); about 0.5 x 10⁵ M^-1s^-1 to about 1 x 10⁶ M^-1s^-1, about 0.5 x 10⁶ M^'V¹, or about 1 x 10⁵ M^-1s^-1 (inclusive); about 1 x 10⁵ M^-1s^-1 to about 1 x 10⁶ M^-1s^-1, or about 0.5 x 10⁶ M^'V¹ (inclusive); or about 0.5 x 10⁶ M^'V¹ to about 1 x 10⁶ M^"1s^"1 (inclusive), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).

Fusion Proteins

In some embodiments, the IL-6 receptor inhibitor is a fusion protein, a soluble receptor, or a peptide (see e.g., U.S. Patent No. 5,591,827). In some embodiments, the IL-6 receptor fusion protein comprises or consists of soluble gpl30 (Jostock et al., Eur. J.

Biochem. 268(1): 160-167, 2001 ; Richards et al., Arthritis Rheum. 54(5): 1662-1672, 2006; Rose- John Qt a\., Exp. Opin. Ther. Targets 1 1(5):613-624, 2007).

In some embodiments, the IL-6 receptor fusion protein comprises or consists of FE999301 (Jostock et al., Eur. J. Biochem. 268(1): 160-167, 2001) or sgpl30Fc protein (Jones et al., J. Clin. Invest. 121(9):3375-3383, 201 1). In some embodiments, the IL-6 receptor inhibitor is a peptide (e.g., S7 (Su et al., Cancer Res. 65(1 1):4827-4835, 2005). In some embodiments, the IL-6 receptor inhibitor is a triterpenoid saponin (e.g., chikusetsuaponin IVa butyl ester (CS-Iva-Be) (Yang et al., Mol. Cancer. Ther. 15(6): 1 190-200, 2016).

Small Molecules

In some embodiments, the IL-6 receptor inhibitor is a small molecule (see, e.g., U. S.

Patent No. 9,409,990). In some embodiments, the small molecule is LMT-28 (Hong et al., J.

Immunol. 195(1): 237-245, 2015); ERBA (Enomoto et al., Biochem. Biophys. Res. Commun.

323 : 1096-1 102, 2004; Boos et al., J. Nat. Prod. 75(4):661-668, 2012), ERBF (TB-2-081)

(Hayashi et al., J. Pharmacol. Exp. Ther. 303 : 104-109, 2002; Vardanyan et al., Pain

151(2):257-265, 2010; Kino et al., J. Allergy Clin. Immunol. 120(2):437-444, 2007), or a variant thereof. Exemplary embodiments:

The following are exemplary embodiments provided herein:

Exemplary embodiment 1. A method of treating a disease of the gastro-intestinal tract in a subject, comprising:

delivering an IL-6R inhibitor at a location in the gastrointestinal tract of the subject, wherein the method comprises administering orally to the subject a pharmaceutical composition comprising a therapeutically effective amount of the IL-6R inhibitor. Exemplary embodiment 2. The method of exemplary embodiment 1, wherein the disease of the GI tract is an inflammatory bowel disease.

Exemplary embodiment 3. The method of exemplary embodiment 1, wherein the disease of the GI tract is ulcerative colitis.

Exemplary embodiment 4. The method of exemplary embodiment 1, wherein the disease of the GI tract is Crohn's disease.

Exemplary embodiment 5. The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the IL-6R inhibitor is delivered at a location in the large intestine of the subject.

Exemplary embodiment 6. The method of exemplary embodiment 5, wherein the location is in the proximal portion of the large intestine. Exemplary embodiment 7. The method of exemplary embodiment 5, wherein the location is in the distal portion of the large intestine.

Exemplary embodiment 8. The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the IL-6R inhibitor is delivered at a location in the ascending colon of the subject.

Exemplary embodiment 9. The method of exemplary embodiment 8, wherein the location is in the proximal portion of the ascending colon. Exemplary embodiment 10. The method of exemplary embodiment 8, wherein the location is in the distal portion of the ascending colon.

Exemplary embodiment 11. The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the IL-6R inhibitor is delivered at a location in the cecum of the subject.

Exemplary embodiment 12. The method of exemplary embodiment 11, wherein the location is in the proximal portion of the cecum. Exemplary embodiment 13. The method of exemplary embodiment 11, wherein the location is in the distal portion of the cecum.

Exemplary embodiment 14. The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the IL-6R inhibitor is delivered at a location in the sigmoid colon of the subject.

Exemplary embodiment 15. The method of exemplary embodiment 14, wherein the location is in the proximal portion of the sigmoid colon.

Exemplary embodiment 16. The method of exemplary embodiment 14, wherein the location is in the distal portion of the sigmoid colon.

Exemplary embodiment 17. The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the IL-6R inhibitor is delivered at a location in the transverse colon of the subject. Exemplary embodiment 18. The method of exemplary embodiment 17, wherein the location is in the proximal portion of the transverse colon.

Exemplary embodiment 19. The method of exemplary embodiment 17, wherein the location is in the distal portion of the transverse colon.

Exemplary embodiment 20. The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the IL-6R inhibitor is delivered at a location in the descending colon of the subject. Exemplary embodiment 21. The method of exemplary embodiment 20, wherein the location is in the proximal portion of the descending colon.

Exemplary embodiment 22. The method of exemplary embodiment 20, wherein the location is in the distal portion of the descending colon.

Exemplary embodiment 23. The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the IL-6R inhibitor is delivered at a location in the small intestine of the subject. Exemplary embodiment 24. The method of exemplary embodiment 23, wherein the location is in the proximal portion of the small intestine.

Exemplary embodiment 25. The method of exemplary embodiment 23, wherein the location is in the distal portion of the small intestine.

Exemplary embodiment 26. The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the IL-6R inhibitor is delivered at a location in the duodenum of the subject.

Exemplary embodiment 27. The method of exemplary embodiment 26, wherein the location is in the proximal portion of the duodenum.

Exemplary embodiment 28. The method of exemplary embodiment 26, wherein the location is in the distal portion of the duodenum. Exemplary embodiment 29. The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the IL-6R inhibitor is delivered at a location in the jejunum of the subject.

Exemplary embodiment 30. The method of exemplary embodiment 29, wherein the location is in the proximal portion of the jejunum.

Exemplary embodiment 31. The method of exemplary embodiment 29, wherein the location is in the distal portion of the jejunum. Exemplary embodiment 32. The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the IL-6R inhibitor is delivered at a location in the ileum of the subject.

Exemplary embodiment 33. The method of exemplary embodiment 32, wherein the location is in the proximal portion of the ileum.

Exemplary embodiment 34. The method of exemplary embodiment 32, wherein the location is in the distal portion of the ileum.

Exemplary embodiment 35. The method of any one of the preceding exemplary

embodiments, wherein the location is proximate to one or more sites of disease.

Exemplary embodiment 36. The method of exemplary embodiment 35, further comprising identifying the one or more sites of disease by a method comprising imaging of the gastrointestinal tract.

Exemplary embodiment 37. The method of any one of the preceding exemplary

embodiments, wherein the IL-6R inhibitor is delivered to the location by mucosal contact.

Exemplary embodiment 38. The method of any one of the preceding exemplary

embodiments, wherein the IL-6R inhibitor is delivered to the location by a process that does not comprise systemic transport of the IL-6R inhibitor.

Exemplary embodiment 39. The method of any one of the preceding exemplary

embodiments, wherein the amount of the IL-6R inhibitor that is administered is from about 1 mg to about 300 mg.

Exemplary embodiment 40. The method of exemplary embodiment 39, wherein the amount of the IL-6R inhibitor that is administered is from about 1 mg to about 100 mg.

Exemplary embodiment 41. The method of exemplary embodiment 40, wherein the amount of the IL-6R inhibitor that is administered is from about 5 mg to about 40 mg. Exemplary embodiment 42. The method of any one of exemplary embodiments 1 to 41, wherein the amount of the IL-6R inhibitor is less than an amount that is effective when the IL-6R inhibitor is administered systemically. Exemplary embodiment 43. The method of any one of the preceding exemplary

embodiments, comprising administering (i) an amount of the IL-6R inhibitor that is an induction dose.

Exemplary embodiment 44. The method of exemplary embodiment 43, further comprising (ii) administering an amount of the IL-6R inhibitor that is a maintenance dose following the administration of the induction dose.

Exemplary embodiment 45. The method of exemplary embodiment 43 or 44, wherein the induction dose is administered once a day.

Exemplary embodiment 46. The method of exemplary embodiment 43 or 44, wherein the induction dose is administered once every three days.

Exemplary embodiment 47. The method of exemplary embodiment 43 or 44, wherein the induction dose is administered once a week.

Exemplary embodiment 48. The method of exemplary embodiment 44, wherein step (ii) is repeated one or more times. Exemplary embodiment 49. The method of exemplary embodiment 44, wherein the induction dose is equal to the maintenance dose.

Exemplary embodiment 50. The method of exemplary embodiment 44, wherein the induction dose is greater than the maintenance dose.

Exemplary embodiment 51. The method of exemplary embodiment 44, wherein the induction dose is 5 greater than the maintenance dose.

Exemplary embodiment 52. The method of exemplary embodiment 44, wherein the induction dose is 2 greater than the maintenance dose. Exemplary embodiment 53. The method of any one of the preceding exemplary embodiments, wherein the method comprises delivering the IL-6R inhibitor at the location in the gastrointestinal tract as a single bolus. Exemplary embodiment 54. The method of any one of exemplary embodiments 1 to 52, wherein the method comprises delivering the IL-6R inhibitor at the location in the gastrointestinal tract as more than one bolus.

Exemplary embodiment 55. The method of any one of exemplary embodiments 1 to 52, wherein the method comprises delivering the IL-6R inhibitor at the location in the gastrointestinal tract in a continuous manner.

Exemplary embodiment 56. The method of exemplary embodiment 55, wherein the method comprises delivering the IL-6R inhibitor at the location in the gastrointestinal tract over a time period of 20 or more minutes.

Exemplary embodiment 57. The method of any one of the preceding exemplary

embodiments, wherein the method provides a concentration of the IL-6R inhibitor in the plasma of the subject that is less than 3 μg/ml.

Exemplary embodiment 58. The method of exemplary embodiment 57, wherein the method provides a concentration of the IL-6R inhibitor in the plasma of the subject that is less than 0.3 μg/ml. Exemplary embodiment 59. The method of exemplary embodiment 58, wherein the method provides a concentration of the IL-6R inhibitor in the plasma of the subject that is less than 0.01 μg/ml.

Exemplary embodiment 60. The method of any one of exemplary embodiments 1 to 59, wherein the method does not comprise delivering an IL-6R inhibitor rectally to the subject.

Exemplary embodiment 61. The method of any one of exemplary embodiments 1 to 59, wherein the method does not comprise delivering an IL-6R inhibitor via an enema to the subject. Exemplary embodiment 62. The method of any one of exemplary embodiments 1 to 59, wherein the method does not comprise delivering an IL-6R inhibitor via suppository to the subject.

Exemplary embodiment 63. The method of any one of exemplary embodiments 1 to 59, wherein the method does not comprise delivering an IL-6R inhibitor via instillation to the rectum of the subject. Exemplary embodiment 64. The method of exemplary embodiment 63, wherein the IL-6R inhibitor is selected from tocilizumab (Actemra®) and sarilumab (Sanofi and Regeneron); generic equivalents thereof; modifications thereof having at least 90% sequence homology; modifications thereof differing in the glycosylation pattern; and modifications thereof having at least 90% sequence homology and differing in the glycosylation pattern.

Exemplary embodiment 65. The method of exemplary embodiment 63, wherein the IL-6R inhibitor is selected from tocilizumab (Actemra®).

Exemplary embodiment 66. The method of any one of the preceding exemplary

embodiments, wherein the pharmaceutical composition is an ingestible device, comprising: a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end;

a storage reservoir located within the housing and containing the IL-6R inhibitor, wherein a first end of the storage reservoir is connected to the first end of the housing; a mechanism for releasing the IL-6R inhibitor from the storage reservoir;

and;

an exit valve configured to allow the IL-6R inhibitor to be released out of the housing from the storage reservoir.

Exemplary embodiment 67. The method of exemplary embodiment 66, wherein the ing device further comprises:

an electronic component located within the housing; and

a gas generating cell located within the housing and adjacent to the electronic component, wherein the electronic component is configured to activate the gas generating cell to generate gas.

Exemplary embodiment 68. The method of exemplary embodiment 66 or 67, wherein the ingestible device further comprises:

a safety device placed within or attached to the housing,

wherein the safety device is configured to relieve an internal pressure within the housing when the internal pressure exceeds a threshold level.

Exemplary embodiment 69. The method of exemplary embodiment 66, wherein the pharmaceutical composition is an ingestible device, comprising:

a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end;

an electronic component located within the housing;

a gas generating cell located within the housing and adjacent to the electronic component,

wherein the electronic component is configured to activate the gas generating cell to generate gas;

a storage reservoir located within the housing,

wherein the storage reservoir stores a dispensable substance and a first end of the storage reservoir is connected to the first end of the housing;

an exit valve located at the first end of the housing,

wherein the exit valve is configured to allow the dispensable substance to be released out of the first end of the housing from the storage reservoir; and

a safety device placed within or attached to the housing,

Exemplary embodiment 70. The method of exemplary embodiment 66, wherein the pharmaceutical composition is an ingestible device, comprising:

a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end; an electronic component located within the housing,

a storage reservoir located within the housing,

an injection device located at the first end of the housing,

wherein the j et inj ection device is configured to inj ect the dispensable substance out of the housing from the storage reservoir; and

a safety device placed within or attached to the housing,

wherein the safety device is configured to relieve an internal pressure within the housing.

Exemplary embodiment 71. The method of exemplary embodiment 66, wherein the pharmaceutical composition is an ingestible device, comprising:

an optical sensing unit located on a side of the housing,

wherein the optical sensing unit is configured to detect a reflectance from an environment external to the housing;

an electronic component located within the housing;

wherein the electronic component is configured to activate the gas generating cell to generate gas in response to identifying a location of the ingestible device based on the reflectance;

a storage reservoir located within the housing,

wherein the storage reservoir stores a dispensable substance and a first end of the storage reservoir is connected to the first end of the housing; a membrane in contact with the gas generating cell and configured to move or deform into the storage reservoir by a pressure generated by the gas generating cell; and

a dispensing outlet placed at the first end of the housing,

wherein the dispensing outlet is configured to deliver the dispensable substance out of the housing from the storage reservoir.

Exemplary embodiment 72. The method of any one of exemplary embodiments 1-71, wherein the pharmaceutical composition is an ingestible device as disclosed in US Patent Application Ser. No. 62/385,553, incorporated by reference herein in its entirety.

Exemplary embodiment 73. The method of any one of exemplary embodiments 1-71, wherein the pharmaceutical composition is an ingestible device comprising a localization mechanism as disclosed in international patent application PCT/US2015/052500, incorporated by reference herein in its entirety.

Exemplary embodiment 74. The method of any one of exemplary embodiments 1-73, wherein the pharmaceutical composition is not a dart-like dosage form.

Exemplary embodiment 75. A method of treating a disease of the large intestine of a subject, comprising:

delivering of an IL-6R inhibitor at a location in the proximal portion of the large intestine of the subject,

Exemplary embodiment 76. The method of exemplary embodiment 75, wherein the disease of the large intestine is an inflammatory bowel disease.

Exemplary embodiment 77. The method of exemplary embodiment 75, wherein the disease of the large intestine is ulcerative colitis.

Exemplary embodiment 78. The method of exemplary embodiment 75, wherein the disease the large intestine is Crohn's disease. Exemplary embodiment 79. The method of any one of exemplary embodiments 75 to 78, wherein the IL-6R inhibitor is delivered at a location in the proximal portion of the ascending colon.

Exemplary embodiment 80. The method of any one of exemplary embodiments 75 to 78, wherein the IL-6R inhibitor is delivered at a location in the proximal portion of the cecum.

Exemplary embodiment 81. The method of any one of exemplary embodiments 75 to 78, wherein the IL-6R inhibitor is delivered at a location in the proximal portion of the sigmoid colon.

Exemplary embodiment 82. The method of any one of exemplary embodiments 75 to 78, wherein the IL-6R inhibitor is delivered at a location in the proximal portion of the transverse colon.

Exemplary embodiment 83. The method of any one of exemplary embodiments 75 to 78, wherein the IL-6R inhibitor is delivered at a location in the proximal portion of the descending colon.

Exemplary embodiment 84. The method of any one of the preceding exemplary

embodiments, further comprising administering a second agent orally, intravenously or subcutaneously, wherein the second agent is the same IL-6R inhibitor as in exemplary embodiment 1 or 75; a different IL-6R inhibitor; or an agent having a different biological target from IL-6R.

Exemplary embodiment 85. The method of any one of the preceding exemplary

embodiments, further comprising administering a second agent orally, intravenously or subcutaneously, wherein the second agent is an agent suitable for treating an inflammatory bowel disease.

Exemplary embodiment 86. The method of exemplary embodiment 84 or 85, wherein the IL- 6R inhibitor is administered prior to the second agent. Exemplary embodiment 87. The method of exemplary embodiment 84 or 85, wherein the IL- 6R inhibitor is administered after the second agent.

Exemplary embodiment 88. The method of exemplary embodiment 84 or 85, wherein the IL- 6R inhibitor and the second agent are administered substantially at the same time.

Exemplary embodiment 89. The method of any one of exemplary embodiments 84 to 88, wherein the second agent is administered intravenously. Exemplary embodiment 90. The method of any one of exemplary embodiments 84 to 88, wherein the second agent is administered subcutaneously.

Exemplary embodiment 91. The method of any one of exemplary embodiments 84 to 90, wherein the amount of the second agent is less than the amount of the second agent when the IL-6R inhibitor and the second agent are both administered systemically.

Exemplary embodiment 92. The method of exemplary embodiment 91, wherein the second agent is an immunosuppressant. Exemplary embodiment 93. In some aspects of these embodiments, the second agent is methotrexate.

Exemplary embodiment 94. The method of any one of exemplary embodiments 1 to 83, wherein the method does not comprise administering a second agent.

Endoscopes, Ingestible Devices, and Reservoirs containing the drug

Direct visualization of the GI mucosa is useful to detect subtle mucosal alterations, as in inflammatory bowel diseases, as well as any flat or sessile lesions. The GI tract can be imaged using endoscopes, or more recently ingestible devices that are swallowed.

The technology behind standard colonoscopy consists of a long, semi-rigid insertion tube with a steerable tip (stiff if compared to the colon), which is pushed by the physician from the outside. However, invasiveness, patient discomfort, fear of pain, and -more often than not- the need for conscious sedation limit the take-up of screening colonoscopy.

Diagnosis and treatment in the GI tract are dominated by the use of flexible endoscopes. A few large companies, namely Olympus Medical Systems Co. (Tokyo, Japan), Pentax Medical Co. (Montvale, NJ, USA), Fujinon, Inc. (Wayne, NJ, USA) and Karl Storz GmbH & Co. KG (Tuttlingen, Germany), cover the majority of the market in flexible GI endoscopy.

In a review of robotic endoscopic capsules, Journal of Micro-Bio Robotics 11.1-4 (2016): 1-18, Ciuti et al. state that progress in micro-electromechanical systems (MEMS) technologies have led to the development of new endoscopic capsules with enhanced diagnostic capabilities, in addition to traditional visualization of mucosa (embedding, e.g. pressure, pH, blood detection and temperature sensors).

Endoscopes may comprise a catheter. As an example, the catheter may be a spray catheter. As an example, a spray catheter may be used to deliver dyes for diagnostic purposes. As an example, a spray catheter may be used to deliver a therapeutic agent at the site of disease in the GI tract. For example, the Olypmus PW-205V is a ready-to-use spray catheter that enables efficient spraying for maximal differentiation of tissue structures during endoscopy, but may also be used to deliver drugs diseased tissue.

FIG. 1, disclosed in US Provisional Application No. 62/385,553, incorporated by reference herein in its entirety, illustrates an example of an ingestible device for localized delivery of pharmaceutical compositions disclosed herein, in accordance with particular implementations. The ingestible device 100 includes a piston or drive element 134 to push for drug delivery, in accordance with particular implementations described herein. The ingestible device 100 may have one or more batteries 131 placed at one end 102a of a housing 101 to provide power for the ingestible device 100. A printed circuit board (PCB) 132 may be placed adjacent to a battery or other power source 131, and a gas generating cell 103 may be mounted on or above the PCB 132. The gas generating cell 103 may be sealed from the bottom chamber (e.g., space including 131 and 132) of the ingestible device 100. A movable piston 134 may be placed adjacent to the gas generating cell 103. In this way, gas generation from the gas generating cell 103 may propel a piston 134 to move towards another end 102b of the housing 101 such that the dispensable substance in a reservoir compartment 135 can be pushed out of the housing through a dispensing outlet 107, e.g., the movement is shown at 136, with the piston 134 at a position after dispensing the substance. The dispensing outlet 107 may comprise a plug. The reservoir compartment 135 can store the dispensable substance (e.g., drug substance), or alternatively the reservoir compartment can house a storage reservoir 161 which comprises the dispensable substance. The reservoir

compartment 135 or storage reservoir 161 may have a volume of approximately 600 μΙ_, or even more dispensable substance, which may be dispensed in a single bolus, or gradually over a period of time.

The battery cells 131 may have a height of 1.65 mm each, and one to three batteries may be used. The height of the piston may be reduced with custom molded part for around 1.5mm to save space. If the gas generating cell 103 is integrated with the piston 134, the overall height of the PCB, batteries and gas generating cell in total can be reduced to around 5 mm, thus providing more space for drug storage. For example, for an ingestible device of 7.8 mm in length (e.g., from end 102a to the other end 102b), a reservoir compartment 135 or a storage reservoir 161 of approximately 600μΙ. may be used for drug delivery. For another example, for an ingestible device of 17.5 mm in length, a reservoir compartment 135 or a storage reservoir 161 of approximately 1300μΙ. may be used for drug release.

In some implementations, at the reservoir 135 or 161 for storing a therapeutically effective amount of the IL-6R inhibitor forms at least a portion of the device housing 101. The therapeutically effective amount of the IL-6R inhibitor can be stored in the reservoir 135 or 161 at a particular pressure, for example, determined to be higher than a pressure inside the GI tract so that once the reservoir 135 or 161 is in fluid communication with the GI tract, the IL-6R inhibitor is automatically released. In certain implementations, the reservoir compartment 135 includes a plurality of chambers, and each of the plurality of the chambers stores a different dispensable substance or a different storage reservoir 161.

In certain embodiments, the storage reservoir 161 is a compressible component or has compressible side walls. In particular embodiments, the compressible component can be composed, at least in part, or coated (e.g., internally) with polyvinyl chloride (PVC), silicone, DEUP (di-2-ethylhexyl phthalate), Tyvek, polyester film, polyolefin, polyethylene, polyurethane, or other materials that inhibit the IL-6R inhibitor from sticking to the reservoir and provide a sterile reservoir environment for the IL-6R inhibitor. The storage reservoir 161 can be hermetically sealed. The reservoir compartment 135 or storage reservoir 161 can be configured to store IL-6R inhibitor in quantities in the range of 0.01 mL - 2 mL, such as 0.05 mL - 2 mL, such as 0.05 mL - 2 mL, such as 0.6mL - 2 mL. In some embodiments, the storage reservoir 161 is attachable to the device housing 101, for example, in the reservoir compartment. Accordingly, the storage reservoir 135 can be loaded with the IL-6R inhibitor prior to being positioned in and/or coupled to the ingestible device housing 101. The ingestible device housing 101 includes one or more openings configured as a loading port to load the dispensable substance into the reservoir compartment. In another embodiment, the ingestible device housing 101 includes one or more openings configured as a vent.

In certain embodiments, the ingestible device housing 101 includes one or more actuation systems (e.g., gas generating cell 103) for pumping the IL-6R inhibitor from the reservoir 135. In some embodiments, the actuation system can include a mechanical, electrical, electromechanical, hydraulic, and/or fluid actuation system. For example, a chemical actuation means may use chemical reaction of mixing one or more reagents to generate a sufficient volume of gas to propel the piston or drive element 134 for drug release. The actuation system can be integrated into the reservoir compartment 135 or can be an auxiliary system acting on or outside of the reservoir compartment 135. For example, the actuation system can include pumping system for pushing/pulling the IL-6R inhibitor out of the reservoir compartment 135 or the actuation system can be configured to cause the reservoir compartment 135 to change structurally so that the volume inside of the reservoir compartment 135 changes, thereby dispensing the IL-6R inhibitor from the reservoir compartment 135. The actuation system can include an energy storage component such as a battery or a capacitor for powering the actuation system. The actuation system can be actuated via gas pressure or a system storing potential energy, such as energy from an elastic reservoir component being expanded during loading of the reservoir and after being positioned in the ingestible device housing 101 being subsequently released from the expanded state when the ingestible device housing is at the location for release within the GI tract. In certain embodiments, the reservoir compartment 135 can include a membrane portion, whereby the IL-6R inhibitor is dispensed from the reservoir compartment 135 or storage reservoir 161 via osmotic pressure.

In particular embodiments the storage reservoir 161 is in a form of a bellow that is configured to be compressed via a pressure from the gas generating cell. The IL-6R inhibitor may be loaded into the bellow, which may be compressed by gas generation from the gas generating cell or other actuation means to dispense the dispensable substance through the dispensing outlet 107 and out of the housing 101. In some embodiments, the ingestible device includes a capillary plate placed between the gas generating cell and the first end of the housing, and a wax seal between the gas generating cell and the reservoir, wherein the wax seal is configured to melt and the dispensable substance is pushed through the capillary plate by a pressure from the gas generating cell. The shape of the bellow may aid in controlled delivery. The reservoir compartment 135 includes a dispensing outlet, such as a valve or dome slit 162 extending out of an end of the housing 101, in accordance with particular implementations. Thus when the bellow is being compressed, the dispensable substance may be propelled out of the bellow through the valve or the dome slit.

In certain embodiments, the reservoir compartment 135 includes one or more valves (e.g. a valve in the dispensing outlet 107) that are configured to move or open to fluidly couple the reservoir compartment 135 to the GI tract. In certain embodiments, a housing wall of the housing 101 can form a portion of the reservoir compartment 135. In certain embodiments, the housing walls of the reservoir serve as a gasket. One or more of the one or more valves are positioned in the housing wall of the device housing 101, in accordance with particular implementations. One or more conduits may extend from the reservoir 135 to the one or more valves, in certain implementations.

In certain embodiments, a housing wall of the housing 101 can be formed of a material that is configured to dissolve, for example, in response to contact at the disease site. In certain embodiments, a housing wall of the housing 101 can be configured to dissolve in response to a chemical reaction or an electrical signal. The one or more valves and/or the signals for causing the housing wall of the housing 101 to dissolve or dissipate can be controlled by one or more processors or controllers positioned on PCB 132 in the device housing 101. The controller is communicably coupled to one or more sensors or detectors configured to determine when the device housing 101 is proximate to a disease site. The sensors or detectors comprise a plurality of electrodes comprising a coating, in certain implementations. Releasing of the IL-6R inhibitor from the reservoir compartment 135 is triggered by an electric signal from the electrodes resulting from the interaction of the coating with the one or more sites of disease site. The one or more sensors can include a chemical sensor, an electrical sensor, an optical sensor, an electromagnetic sensor, a light sensor, and/or a radiofrequency sensor.

In particular embodiments, the device housing 101 can include one or more pumps configured to pump the therapeutically effective amount of the IL-6R inhibitor from the reservoir compartment 135. The pump is communicably coupled to the one or more controllers. The controller is configured to activate the pump in response to detection by the one or more detectors of the disease site and activation of the valves to allow the reservoir 135 to be in fluid communication with the GI tract. The pump can include a fluid actuated pump, an electrical pump, or a mechanical pump. In certain embodiments, the device housing 101 comprises one or more anchor systems for anchoring the device housing 101 or a portion thereof at a particular location in the GI tract adjacent the disease site. In some embodiments, a storage reservoir comprises an anchor system, and the storage reservoir comprising a releasable substance is anchored to the GI tract. The anchor system can be activated by the controller in response to detection by the one or more detectors of the disease site. In certain implementations, the anchor system includes legs or spikes configured to extend from the housing wall(s) of the device housing 101. The spikes can be configured to retract and/or can be configured to dissolve over time. An example of an attachable device that becomes fixed to the interior surface of the GI tract is described in PCT Patent Application PCT/US2015/012209, "Gastrointestinal Sensor Implantation System", filed January 21, 2015, which is hereby incorporated by reference herein in its entirety.

In certain embodiments, the reservoir is an anchorable reservoir, which is a reservoir comprising one or more anchor systems for anchoring the reservoir at a particular location in the GI tract adjacent the disease site. In certain embodiments, the anchor system includes legs or spikes or other securing means such as a piercing element, a gripping element, a magnetic-flux-guiding element, or an adhesive material, configured to extend from the anchorable reservoir of the device housing. The spikes can be configured to retract and/or can be configured to dissolve over time. In some embodiments, the anchorable reservoir is suitable for localizing positioning and/or anchoring. In some embodiments, the anchorable reservoir is suitable for localizing, and positioning and/or anchoring by an endoscope. In some embodiments, the anchorable reservoir is connected to the endoscope. In some embodiments, the anchorable reservoir is connected to the endoscope in a manner suitable for oral administration. In some embodiments, the anchorable reservoir is connected to the endoscope in a manner suitable for rectal administration. Accordingly, provided herein in some embodiments is an anchorable reservoir is connected to an endoscope wherein the anchorable reservoir comprises a therapeutically effective amount of the IL-6R inhibitor. In some embodiments the endoscope is fitted with a spray catheter.

Exemplary embodiments of anchorable reservoirs are as follows. In more particular examples of the following exemplary embodiments the reservoir is connected to an endoscope.

In one embodiment, the anchorable reservoir comprises an implant capsule for insertion into a body canal to apply radiation treatment to a selected portion of the body canal. The reservoir includes a body member defining at least one therapeutic treatment material receiving chamber and at least one resilient arm member associated with the body member for removably engaging the body canal when the device is positioned therein.

In one embodiment the anchorable reservoir has multiple suction ports and permits multiple folds of tissue to be captured in the suction ports with a single positioning of the device and attached together by a tissue securement mechanism such as a suture, staple or other form of tissue bonding. The suction ports may be arranged in a variety of configurations on the reservoir to best suit the desired resulting tissue orientation.

In some embodiments an anchorable reservoir comprises a tract stimulator and/or monitor IMD comprising a housing enclosing electrical stimulation and/or monitoring circuitry and a power source and an elongated flexible member extending from the housing to an active fixation mechanism adapted to be fixed into the GI tract wall is disclosed. After fixation is effected, the elongated flexible member bends into a preformed shape that presses the housing against the mucosa so that forces that would tend to dislodge the fixation mechanism are minimized. The EVID is fitted into an esophageal catheter lumen with the fixation mechanism aimed toward the catheter distal end opening whereby the bend in the flexible member is straightened. The catheter body is inserted through the esophagus into the GI tract cavity to direct the catheter distal end to the site of implantation and fix the fixation mechanism to the GI tract wall. The EVID is ejected from the lumen, and the flexible member assumes its bent configuration and lodges the hermetically sealed housing against the mucosa. A first stimulation/sense electrode is preferably an exposed conductive portion of the housing that is aligned with the bend of the flexible member so that it is pressed against the mucosa. A second stimulation/sense electrode is located at the fixation site.

In some embodiments a reservoir for sensing one or more parameters of a patient is anchored to a tissue at a specific site and is released from a device, using a single actuator operated during a single motion. As an example, a delivery device may anchor the capsule to the tissue site and release the reservoir from the delivery device during a single motion of the actuator.

In some embodiments a device is provided comprising: a reservoir configured to contain a fluid, the reservoir having at least one outlet through which the fluid may exit the reservoir; a fluid contained within the reservoir; a primary material contained within the reservoir and having a controllable effective concentration in the fluid; and at least one electromagnetically responsive control element located in the reservoir or in a wall of the reservoir and adapted for modifying the distribution of the primary material between a first active form carried in the fluid and a second form within the reservoir in response to an incident electromagnetic control signal, the effective concentration being the concentration of the first active form in the fluid, whereby fluid exiting the reservoir carries the primary material in the first active form at the effective concentration.

In some embodiments systems and methods are provided for implementing or deploying medical or veterinary devices or reservoirs (a) operable for anchoring at least partly within a digestive tract, (b) small enough to pass through the tract per vias naturales and including a wireless-control component, (c) having one or more protrusions positionable adjacent to a mucous membrane, (d) configured to facilitate redundant modes of anchoring, (e) facilitating a "primary" material supply deployable within a stomach for an extended and/or controllable period, (f) anchored by one or more adaptable extender modules supported by a subject's head or neck, and/or (g) configured to facilitate supporting at least a sensor within a subject's body lumen for up to a day or more.

In certain embodiments, the reservoir is attachable to an ingestible device. In certain embodiments, the ingestible device comprises a housing and the reservoir is attachable to the housing. In certain embodiments, the attachable reservoir is also an anchorable reservoir, such as an anchorable reservoir comprising one or more anchor systems for anchoring the reservoir at a particular location in the GI tract as disclosed hereinabove.

Accordingly, in certain embodiments, provided herein is an IL-6R inhibitor for use in a method of treating a disease of the gastrointestinal tract as disclosed herein, wherein the IL- 6R inhibitor is contained in a reservoir suitable for attachment to a device housing, and wherein the method comprises attaching the reservoir to the device housing to form the ingestible device, prior to orally administering the ingestible device to the subject.

In certain embodiments, provided herein is an attachable reservoir containing an IL-

6R inhibitor for use in a method of treating a disease of the gastrointestinal tract, wherein the method comprises attaching the reservoir to a device housing to form an ingestible device and orally administering the ingestible device to a subject, wherein the IL-6R inhibitor is released by device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.

In certain embodiments, provided herein is an attachable reservoir containing an IL- 6R inhibitor, wherein the reservoir is attachable to a device housing to form an ingestible device that is suitable for oral administration to a subject and that is capable of releasing the IL-6R inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.

In particular implementation the ingestible device includes cameras (e.g., video cameras) that affords inspection of the entire GI tract without discomfort or the need for sedation, thus avoiding many of the potential risks of conventional endoscopy. Video imaging can be used to help determine one or more characteristics of the GI tract, including the location of disease (e.g., presence or location of inflamed tissue and/or lesions associated with inflammatory bowel disease). In some embodiments, the ingestible device 101 may comprise a camera for generating video imaging data of the GI tract which can be used to determine, among other things, the location of the device. Examples of video imaging capsules include Medtronic' s PillCam™, Olympus' Endocapsule®, and IntroMedic's MicroCam™. For a review of imaging capsules, see Basar et al. "Ingestible Wireless Capsule Technology: A Review of Development and Future Indication" International Journal of Antennas and Propagation (2012); 1-14). Other imaging technologies implemented with the device 101 can include thermal imaging cameras, and those that employ ultrasound or Doppler principles to generate different images (see Chinese patent application

CN104473611 : "Capsule endoscope system having ultrasonic positioning function".

Ingestible devices can be equipped with sources for generating reflected light, including light in the Ultraviolet, Visible, Near-infrared and/or Mid-infrared spectrum, and the corresponding detectors for spectroscopy and hyperspectral imaging. Likewise, autofluorescense may be used to characterize GI tissue (e.g., subsurface vessel information), or low-dose radiation (see Check-Cap™) can be used to obtain 3D reconstructed images.

Device Components

An ingestible device in accordance with particular embodiments of the present invention may comprise a component made of a non-digestible material and containing the IL-6R inhibitor. In some embodiments, the material is plastic.

It is envisaged that the device is single-use. The device is loaded with a drug prior to the time of administration. In some embodiments, it may be preferred that there is provided a medicinal product comprising the device pre-filled with the drug. Localization components

Various implementations may be used for localization of ingestible devices within the GI tract. For example, certain implementations can include one or more electromagnetic sensor coils, magnetic fields, electromagnetic waves, electric potential values, ultrasound positioning systems, gamma scintigraphy techniques or other radio-tracker technology have been described by others. Alternatively, imaging can be used to localize, for example, using anatomical landmarks or more complex algorithms for 3D reconstruction based on multiple images. Other technologies rely on radio frequency, which relies on sensors placed externally on the body to receive the strength of signals emitted by the capsule. Ingestible devices may also be localized based on reflected light in the medium surrounding the device; pH;

temperature; time following ingestion; and/or acoustic signals.

Anchoring components

Several systems may actively actuate and control the capsule position and orientation in different sections of the GI tract. Examples include leg-like or anchor-like mechanisms that can be deployed by an ingestible device to resist peristaltic forces in narrowed sections of the GI tract, such as the intestine, and anchor the device to a location. Other systems employ magnetic shields of different shapes that can interact with external magnetic fields to move the device. These mechanisms may be particularly useful in areas outside of the small intestine, like the cecum and large intestine.

An anchoring mechanism may be a mechanical mechanism. For example, a device may be a capsule comprising a plurality of legs configured to steer the capsule. The number of legs in the capsule may be, for example, two, four, six, eight, ten or twelve. The aperture between the legs of the device may be up to about 35 mm; about 30 to about 35 mm; about 35 to about 75 mm; or about 70 to about 75 mm. The contact area of each leg may be varied to reduce impact on the tissue. One or more motors in the capsule may each actuate a set of legs independently from the other. The motors may be battery-powered motors.

An anchoring mechanism may be a non-mechanical mechanism. For example, a device may be a capsule comprising a permanent magnet located inside the capsule. The capsule may be anchored at the desired location of the GI tract by an external magnetic field. An anchoring mechanism may comprise a non-mechanical mechanism and a mechanical mechanism. For example, a device may be a capsule comprising one or more legs, one or more of which are coated with an adhesive material. Locomotion components

Ingestible devices can be active or passive, depending on whether they have controlled or non-controlled locomotion. Passive (non-controlled) locomotion is more commonly used among ingestible devices given the challenges of implementing a locomotion module. Active (controlled) locomotion is more common in endoscopic ingestible capsules. For example, a capsule may comprise a miniaturized locomotion system (internal locomotion). Internal locomotion mechanisms may employ independent miniaturized propellers actuated by DC brushed motors, or the use of water jets. As an example, a mechanism may comprise flagellar or flap-based swimming mechanisms. As an example, a mechanism may comprise cyclic compression/extension shape-memory alloy (SMA) spring actuators and anchoring systems based on directional micro-needles. As an example, a mechanism may comprise six SMA actuated units, each provided with two SMA actuators for enabling bidirectional motion. As an example, a mechanism may comprise a motor adapted to electrically stimulating the GI muscles to generate a temporary restriction in the bowel.

As an example, a capsule may comprise a magnet and motion of the capsule is caused by an external magnetic field. For example, a locomotion system may comprise an ingestible capsule and an external magnetic field source. For example, the system may comprise an ingestible capsule and magnetic guidance equipment such as, for example, magnetic resonance imaging and computer tomography, coupled to a dedicated control interface. In some embodiments drug release mechanisms may also be triggered by an external condition, such as temperature, pH, movement, acoustics, or combinations thereof.

Use of an endoscope or an ingestible device in biopsy and surgery

Ingestible devices may comprise a mechanism adapted to permit the collection of tissue samples. In some examples, this is achieved using electro-mechanical solutions to collect and store the sample inside an ingestible device. As an example, a biopsy mechanism may include a rotational tissue cutting razor fixed to a torsional spring or the use of microgrippers to fold and collect small biopsies. As an example, Over-the-scope clips (OTSC®) may be used to perform endoscopic surgery and/or biopsy. As an example of the methods disclosed herein, the method may comprise releasing an IL-6R inhibitor and collecting a sample inside the device. As an example, the method may comprise releasing an IL-6R inhibitor and collecting a sample inside the device in a single procedure.

Communication systems An ingestible device may be equipped with a communication system adapted to transmit and/or receive data, including imaging and/or localization data. As an example, a communication system may employ radiofrequency transmission. Ingestible devices using radiofrequency communication are attractive because of their efficient transmission through the layers of the skin. This is especially true for low frequency transmission (UHF-433 ISM and lower, including the Medical Device Radio Communication Service band (MDRS) band 402-406MHz). In another embodiment, acoustics are used for communications, including the transmission of data. For example, an ingestible capsule may be able to transmit information by applying one or more base voltages to an electromechanical transducer or piezoelectric (e.g., PZT, PVDF, etc.) device to cause the piezoelectric device to ring at particular frequencies, resulting in an acoustic transmission. A multi-sensor array for receiving the acoustic transmission may include a plurality of acoustic transducers that receive the acoustic transmission from a movable device such as an ingestible capsule as described in US Patent Application No. 11/851214 filed September 6, 2007, incorporated by reference herein in its entirety.

As an example, a communication system may employ human body communication technology. Human body communication technology uses the human body as a conductive medium, which generally requires a large number of sensor electrodes on the skin. As an example, a communication system may integrate a data storage system.

Environmental Sensors

In some embodiments the device may comprise environmental sensors to measure pH, temperature, transit times, or combinations thereof. Other examples of environmental sensors include, but are not limited to a capacitance sensor, an impedance sensor, a heart rate sensor, acoustic sensor such as a microphone or hydrophone, image sensor, and/or a movement sensor. In one embodiment, the ingestible device comprises a plurality of different environmental sensors for generating different kinds of environmental data.

In order to avoid the problem of capsule retention, a thorough past medical and surgical history should be undertaken. In addition, several other steps have been proposed, including performing investigations such as barium follow-through. In cases where it is suspected that there is a high risk of retention, the patient is given a patency capsule a few days before swallowing an ingestible device. Any dissolvable non-endoscopic capsule may be used to determine the patency of the GI tract. The patency capsule is usually the same size as the ingestible device and can be made of cellophane. In some embodiments, the patency capsule contains a mixture of barium and lactose, which allows visualization by x-ray.

The patency capsule may also include a radiotag or other label, which allows for it to be detected by radio-scanner externally. The patency capsule may comprise wax plugs, which allow for intestinal fluid to enter and dissolve the content, thereby dividing the capsule into small particles.

Accordingly, in some embodiments, the methods herein comprise (a) identifying a subject having a disease of the gastrointestinal tract and (b) evaluating the subject for suitability to treatment. In some embodiments, the methods herein comprise evaluating for suitability to treatment a subject identified as having a disease of the gastrointestinal tract. In some embodiments, evaluating the subject for suitability to treatment comprises determining the patency of the subject's GI tract.

In some embodiments, an ingestible device comprises a tissue anchoring mechanism for anchoring the ingestible device to a subject's tissue. For example, an ingestible device could be administered to a subject and once it reaches the desired location, the tissue attachment mechanism can be activated or deployed such that the ingestible device, or a portion thereof, is anchored to the desired location. In some embodiments, the tissue anchoring mechanism is reversible such that after initial anchoring, the tissue attachment device is retracted, dissolved, detached, inactivated or otherwise rendered incapable of anchoring the ingestible device to the subject's tissue. In some embodiments the attachment mechanism is placed endoscopically. In some embodiments, a tissue anchoring mechanism comprises an osmotically-driven sucker. In some embodiments, the osmotically-driven sucker comprises a first valve on the near side of the osmotically-driven sucker (e.g., near the subject's tissue) and a second oneway valve that is opened by osmotic pressure on the far side of the osmotically-driven sucker, and an internal osmotic pump system comprising salt crystals and semi-permeable

membranes positioned between the two valves. In such embodiments, osmotic pressure is used to adhere the ingestible device to the subject's tissue without generating a vacuum within the ingestible capsule. After the osmotic system is activated by opening the first valve, fluid is drawn in through the sucker and expelled through the second burst valve.

Fluid continues to flow until all the salt contained in the sucker is dissolved or until tissue is drawn into the sucker. As liminal fluid is drawn through the osmotic pump system, solutes build up between the tissue and the first valve, reducing osmotic pressure. In some embodiments, the solute buildup stalls the pump before the tissue contacts the valve, preventing tissue damage. In some embodiments, a burst valve is used on the far side of the osmotically-driven sucker rather than a one-way valve, such that luminal fluid eventually clears the saline chamber and the osmotic flow reverses, actively pushing the subject's tissue out of the sucker. In some embodiments, the ingestible device may be anchored to the interior surface of tissues forming the GI tract of a subject. In one embodiment, the ingestible device comprises a connector for anchoring the device to the interior surface of the GI tract. The connector may be operable to ingestible device to the interior surface of the GI tract using an adhesive, negative pressure and/or fastener.

In some embodiments a device comprises a tract stimulator and/or monitor IMD comprising a housing enclosing electrical stimulation and/or monitoring circuitry and a power source and an elongated flexible member extending from the housing to an active fixation mechanism adapted to be fixed into the GI tract wall is disclosed. After fixation is effected, the elongated flexible member bends into a preformed shape that presses the housing against the mucosa so that forces that would tend to dislodge the fixation mechanism are minimized. The IMD is fitted into an esophageal catheter lumen with the fixation mechanism aimed toward the catheter distal end opening whereby the bend in the flexible member is straightened. The catheter body is inserted through the esophagus into the GI tract cavity to direct the catheter distal end to the site of implantation and fix the fixation mechanism to the GI tract wall. The IMD is ejected from the lumen, and the flexible member assumes its bent configuration and lodges the hermetically sealed housing against the mucosa. A first stimulation/sense electrode is preferably an exposed conductive portion of the housing that is aligned with the bend of the flexible member so that it is pressed against the mucosa. A second stimulation/sense electrode is located at the fixation site.

In some embodiments a device includes a fixation mechanism to anchor the device to tissue within a body lumen, and a mechanism to permit selective de-anchoring of the device from the tissue anchoring site without the need for endoscopic or surgical intervention. An electromagnetic device may be provided to mechanically actuate the de-anchoring

mechanism. Alternatively, a fuse link may be electrically blown to de-anchor the device. As a further alternative, a rapidly degradable bonding agent may be exposed to a degradation agent to de-anchor the device from a bonding surface within the body lumen.

In some embodiments a device is as disclosed in patent publication

WO2015112575A1, incorporated by reference herein in its entirety. The patent publication is directed to a gastrointestinal sensor implantation system. In some embodiments an orally- administrable capsule comprises a tissue capture device or reservoir removably coupled to the orally-administrable capsule, where the tissue capture device including a plurality of fasteners for anchoring the tissue capture device to gastrointestinal tissue within a body

In some embodiments, the ingestible device contains an electric energy emitting means, a radio signal transmitting means, a medicament storage means and a remote actuatable medicament releasing means. The capsule signals a remote receiver as it progresses through the alimentary tract in a previously mapped route and upon reaching a specified site is remotely triggered to release a dosage of medicament. Accordingly, in some embodiments, releasing the IL-6R inhibitor is triggered by a remote electromagnetic signal.

In some embodiments, the ingestible device includes a housing introducible into a body cavity and of a material insoluble in the body cavity fluids, but formed with an opening covered by a material which is soluble in body cavity fluids. A diaphragm divides the interior of the housing into a medication chamber including the opening, and a control chamber. An electrolytic cell in the control chamber generates a gas when electrical current is passed therethrough to deliver medication from the medication chamber through the opening into the body cavity at a rate controlled by the electrical current. Accordingly, in some embodiments, releasing the IL-6R inhibitor is triggered by generation in the composition of a gas in an amount sufficient to expel the IL-6R inhibitor. In some embodiments, the ingestible device includes an oral drug delivery device having a housing with walls of water permeable material and having at least two chambers separated by a displaceable membrane. The first chamber receives drug and has an orifice through which the drug is expelled under pressure. The second chamber contains at least one of two spaced apart electrodes forming part of an electric circuit which is closed by the ingress of an aqueous ionic solution into the second chamber. When current flows through the circuit, gas is generated and acts on the displaceable membrane to compress the first chamber and expel the active ingredient through the orifice for progressive delivery to the gastrointestinal tract.

In some embodiments, the ingestible device includes an ingestible device for delivering a substance to a chosen location in the GI tract of a mammal includes a receiver of electromagnetic radiation for powering an openable part of the device to an opened position for dispensing of the substance. The receiver includes a coiled wire that couples the energy field, the wire having an air or ferrite core. In a further embodiment the invention includes an apparatus for generating the electromagnetic radiation, the apparatus including one or more pairs of field coils supported in a housing. The device optionally includes a latch defined by a heating resistor and a fusible restraint. The device may also include a flexible member that may serve one or both the functions of activating a transmitter circuit to indicate dispensing of the substance; and restraining of a piston used for expelling the substance.

In some embodiments, the ingestible device is a device a swallowable capsule. A sensing module is disposed in the capsule. A bioactive substance dispenser is disposed in the capsule. A memory and logic component is disposed in the capsule and in communication with the sensing module and the dispenser. In some embodiments, localized administration is implemented via an electronic probe which is introduced into the intestinal tract of a living organism and which operates autonomously therein, adapted to deliver one or more therapy agents. In one embodiment, the method includes loading the probe with one or more therapy agents, and selectively releasing the agents from the probe at a desired location of the intestinal tract in order to provide increased efficacy over traditional oral ingestion or intravenous introduction of the agent(s).

In some embodiments, the ingestible device includes electronic control means for dispensing the drug substantially to the diseased tissue sites of the GI tract, according to a pre-determined drug release profile obtained prior to administration from the specific mammal. Accordingly, in some embodiments, releasing the IL-6R inhibitor is triggered by an electromagnetic signal generated within the device. The releasing may occur according to a pre-determined drug release profile.

In some embodiments, the ingestible device can include at least one guide tube, one or more tissue penetrating members positioned in the guide tube, a delivery member, an actuating mechanism and a release element. The release element degrades upon exposure to various conditions in the intestine so as to release and actuate the actuating mechanism.

Embodiments of the invention are particularly useful for the delivery of drugs which are poorly absorbed, tolerated and/or degraded within the GI tract.

In some embodiments, the ingestible device includes an electronic pill comprising at least one reservoir with a solid powder or granulate medicament or formulation, a discharge opening and an actuator responsive to control circuitry for displacing medicine from the reservoir to the discharge opening. The medicament or formulation comprises a dispersion of one or more active ingredients~e.g., solids in powder or granulate form—in an inert carrier matrix. Optionally, the active ingredients are dispersed using intestinal moisture absorbed into the pill via a semi-permeable wall section.

In some embodiments, the ingestible device includes a sensor comprising a plurality of electrodes having a miniature size and a lower power consumption and a coating exterior to the electrodes, wherein the coating interacts with a target condition thereby producing a change in an electrical property of the electrodes, wherein the change is transduced into an electrical signal by the electrodes. Accordingly, in some embodiments, releasing the IL-6R inhibitor is triggered by an electric signal by the electrodes resulting from the interaction of the coating with the one or more sites of disease. Further provided herein is a system for medication delivery comprising such sensor and a pill. In some embodiments, the ingestible device includes an electronic pill comprising a plurality of reservoirs, each of the reservoirs comprising a discharge opening covered by a removable cover. The pill comprises at least one actuator responsive to control circuitry for removing the cover from the discharge opening. The actuator can for example be a spring loaded piston breaking a foil cover when dispensing the medicament. Alternatively, the cover can be a rotatable disk or cylinder with an opening which can be brought in line with the discharge opening of a reservoir under the action of the actuator.

In some embodiments, the ingestible device includes an electronically and remotely controlled pill or medicament delivery system. The pill includes a housing; a reservoir for storing a medicament; an electronically controlled release valve or hatch for dispensing one or more medicaments stored in the reservoir while traversing the gastrointestinal tract; control and timing circuitry for opening and closing the valve; and a battery. The control and timing circuitry opens and closes the valve throughout a dispensing time period in accordance with a preset dispensing timing pattern which is programmed within the control and timing circuitry. RF communication circuitry receives control signals for remotely overriding the preset dispensing timing pattern, reprogramming the control and timing circuitry or terminating the dispensing of the medicament within the body. The pill includes an RFID tag for tracking, identification, inventory and other purposes.

In some embodiments, the ingestible device includes an electronic capsule which has a discrete drive element comprising: a housing, electronics for making the electronic capsule operable, a pumping mechanism for dosing and displacing a substance, a power source for powering the electronic capsule and enabling the electronics and the pumping mechanism to operate, and a locking mechanism; and a discrete payload element comprising: a housing, a reservoir for storing the substance, one or more openings in the housing for releasing the substance from the reservoir and a locking mechanism for engaging the drive element locking mechanism. Engagement of the drive element locking mechanism with the payload element locking mechanism secures the drive element to the payload element, thereby making the electronic capsule operable and specific.

In some embodiments, the ingestible device may be a mucoadhesive device configured for release of an active agent.

In some embodiments, the ingestible device includes an apparatus that includes an ingestible medical treatment device, which is configured to initially assume a contracted state having a volume of less than 4 cm³. The device includes a gastric anchor, which initially assumes a contracted size, and which is configured to, upon coming in contact with a liquid, expand sufficiently to prevent passage of the anchor through a round opening having a diameter of between 1 cm and 3 cm. The device also includes a duodenal unit, which is configured to pass through the opening, and which is coupled to the gastric anchor such that the duodenal unit is held between 1 cm and 20 cm from the gastric anchor.

In some embodiments, the ingestible device includes a medical robotic system and method of operating such comprises taking intraoperative external image data of a patient anatomy, and using that image data to generate a modeling adjustment for a control system of the medical robotic system (e.g., updating anatomic model and/or refining instrument registration), and/or adjust a procedure control aspect (e.g., regulating substance or therapy delivery, improving targeting, and/or tracking performance).

In one embodiment the ingestible device may also include one or more environmental sensors. Environmental sensor may be used to generate environmental data for the environment external to device in the gastrointestinal (GI) tract of the subject. In some embodiments, environmental data is generated at or near the location within the GI tract of the subject where a drug is delivered. Examples of environmental sensor include, but are not limited to a capacitance sensor, a temperature sensor, an impedance sensor, a pH sensor, a heart rate sensor, acoustic sensor, image sensor (e.g., a hydrophone), and/or a movement sensor (e.g., an accelerometer). In one embodiment, the ingestible device comprises a plurality of different environmental sensors for generating different kinds of environmental data.

In one embodiment, the image sensor is a video camera suitable for obtaining images in vivo of the tissues forming the GI tract of the subject. In one embodiment, the

environmental data is used to help determine one or more characteristics of the GI tract, including the location of disease (e.g., presence or location of inflamed tissue and/or lesions associated with inflammatory bowel disease). In some embodiments, the ingestible device may comprise a camera for generating video imaging data of the GI tract which can be used to determine, among other things, the location of the device.

In another embodiment, the ingestible device described herein may be localized using a gamma scintigraphy technique or other radio-tracker technology as employed by Phaeton Research's Enterion™ capsule (See Teng, Renli, and Juan Maya. "Absolute bioavailability and regional absorption of ticagrelor in healthy volunteers." Journal of Drug Assessment 3.1 (2014): 43-50), or monitoring the magnetic field strength of permanent magnet in the ingestible device (see T. D. Than, et al., "A review of localization systems for robotic endoscopic capsules," IEEE Trans. Biomed. Eng., vol. 59, no. 9, pp. 2387-2399, Sep. 2012).

In one embodiment, drug delivery is triggered when it encounters the site of disease in the GI tract.

In one embodiment, the one or more environmental sensors measure pH, temperature, transit times, or combinations thereof.

In some embodiments, releasing the IL-6R inhibitor is dependent on the pH at or in the vicinity of the location. In some embodiments the pH in the jejunum is from 6.1 to 7.2, such as 6.6. In some embodiments the pH in the mid small bowel is from 7.0 to 7.8, such as 7.4. In some embodiments the pH in the ileum is from 7.0 to 8.0, such as 7.5. In some embodiments the pH in the right colon is from 5.7 to 7.0, such as 6.4. In some embodiments the pH in the mid colon is from 5.7 to 7.4, such as 6.6. In some embodiments the pH in the left colon is from 6.3 to 7.7, such as 7.0. In some embodiments, the gastric pH in fasting subjects is from about 1.1 to 2.1, such as from 1.4 to 2.1, such as from 1.1 to 1.6, such as from 1.4 to 1.6. In some embodiments, the gastric pH in fed subjects is from 3.9 to 7.0, such as from 3.9 to 6.7, such as from 3.9 to 6.4, such as from 3.9 to 5.8, such as from 3.9 to 5.5, such as from 3.9 to 5.4, such as from 4.3 to 7.0, such as from 4.3 to 6.7, such as from 4.3 to

6.4, such as from 4.3 to 5.8, such as from 4.3 to 5.5, such as from 4.3 to 5.4. In some embodiments, the pH in the duodenum is from 5.8 to 6.8, such as from 6.0 to 6.8, such as from 6.1 to 6.8, such as from 6.2 to 6.8, such as from 5.8 to 6.7, such as from 6.0 to 6.7, such as from 6.1 to 6.7, such as from 6.2 to 6.7, such as from 5.8 to 6.6, such as from 6.0 to 6.6, such as from 6.1 to 6.6, such as from 6.2 to 6.6, such as from 5.8 to 6.5, such as from 6.0 to

6.5, such as from 6.1 to 6.5, such as from 6.2 to 6.5.

In some embodiments, releasing the IL-6R inhibitor is not dependent on the pH at or in the vicinity of the location. In some embodiments, releasing the IL-6R inhibitor is triggered by degradation of a release component located in the capsule. In some

embodiments, the IL-6R inhibitor is not triggered by degradation of a release component located in the capsule. In some embodiments, wherein releasing the IL-6R inhibitor is not dependent on enzymatic activity at or in the vicinity of the location. In some embodiments, releasing the IL-6R inhibitor is not dependent on bacterial activity at or in the vicinity of the location.

In some embodiments, the pharmaceutical composition is an ingestible device, comprising: a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end;

a reservoir located within the housing and containing the IL-6R inhibitor, wherein a first end of the reservoir is attached to the first end of the housing;

a mechanism for releasing the IL-6R inhibitor from the reservoir;

and;

an exit valve configured to allow the IL-6R inhibitor to be released out of the housing from the reservoir.

In some embodiments, the ingestible device further comprises:

an electronic component located within the housing; and

wherein the electronic component is configured to activate the gas generating cell to generate gas.

In some embodiments, the ingestible device further comprises:

a safety device placed within or attached to the housing,

an electronic component located within the housing;

a reservoir located within the housing,

wherein the reservoir stores a dispensable substance and a first end of the reservoir is attached to the first end of the housing; an exit valve located at the first end of the housing,

wherein the exit valve is configured to allow the dispensable substance to be released out of the first end of the housing from the reservoir; and

a safety device placed within or attached to the housing,

an electronic component located within the housing,

a reservoir located within the housing,

wherein the reservoir stores a dispensable substance and a first end of the reservoir is attached to the first end of the housing;

an injection device located at the first end of the housing,

wherein the j et inj ection device is configured to inj ect the dispensable substance out of the housing from the reservoir; and

a safety device placed within or attached to the housing,

an optical sensing unit located on a side of the housing,

an electronic component located within the housing; a gas generating cell located within the housing and adjacent to the electronic component,

a reservoir located within the housing,

a membrane in contact with the gas generating cell and configured to move or deform into the reservoir by a pressure generated by the gas generating cell; and

a dispensing outlet placed at the first end of the housing,

wherein the dispensing outlet is configured to deliver the dispensable substance out of the housing from the reservoir.

In some embodiments, the pharmaceutical composition is an ingestible device as disclosed in US Patent Application Ser. No. 62/385,553, incorporated by reference herein in its entirety.

In some embodiments, the pharmaceutical composition is an ingestible device comprising a localization mechanism as disclosed in international patent application

PCT/US2015/052500, incorporated by reference herein in its entirety.

In some embodiments, the pharmaceutical composition is not a dart-like dosage form.

In case of conflict between the present specification and any subject matter incorporated by reference herein, the present specification, including definitions, will control.

Locations of treatment

In some embodiments, the IL-6R inhibitor is delivered at a location in the large intestine of the subject. In some embodiments, the location is in the proximal portion of the large intestine. In some embodiments, the location is in the distal portion of the large intestine.

In some embodiments, the IL-6R inhibitor is delivered at a location in the ascending colon of the subject. In some embodiments, the location is in the proximal portion of the ascending colon. In some embodiments, the location is in the distal portion of the ascending colon. In some embodiments, the IL-6R inhibitor is delivered at a location in the cecum of the subject. In some embodiments, the location is in the proximal portion of the cecum. In some embodiments, the location is in the distal portion of the cecum.

In some embodiments, the IL-6R inhibitor is delivered at a location in the sigmoid colon of the subject. In some embodiments, the location is in the proximal portion of the sigmoid colon. In some embodiments, the location is in the distal portion of the sigmoid colon.

In some embodiments, the IL-6R inhibitor is delivered at a location in the transverse colon of the subject. In some embodiments, the location is in the proximal portion of the transverse colon. In some embodiments, the location is in the distal portion of the transverse colon.

In some embodiments, the IL-6R inhibitor is delivered at a location in the descending colon of the subject. In some embodiments, the location is in the proximal portion of the descending colon. In some embodiments, the location is in the distal portion of the descending colon.

In some embodiments, the IL-6R inhibitor is delivered at a location in the small intestine of the subject. In some embodiments, the location is in the proximal portion of the small intestine. In some embodiments, the location is in the distal portion of the small intestine.

In some embodiments, the IL-6R inhibitor is delivered at a location in the duodenum of the subject. In some embodiments, the location is in the proximal portion of the duodenum. In some embodiments, the location is in the distal portion of the duodenum.

In some embodiments, the IL-6R inhibitor is delivered at a location in the jejunum of the subject. In some embodiments, the location is in the proximal portion of the jejunum. In some embodiments, the location is in the distal portion of the jejunum.

In some embodiments, the IL-6R inhibitor is delivered at a location in the duodenum of the subject and is not delivered at other locations in the gastrointestinal tract. In some

embodiments, the IL-6R inhibitor is delivered at a location in the duodenum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the duodenum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the duodenum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the duodenum and a second site of disease is in the stomach and no site of disease is present at other locations in the gastrointestinal tract.

In some embodiments, the IL-6R inhibitor is delivered at a location in the proximal duodenum of the subject and is not delivered at other locations in the gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the proximal duodenum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the duodenum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the proximal duodenum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the duodenum and a second site of disease is in the stomach and no site of disease is present at other locations in the

gastrointestinal tract.

In some embodiments, the IL-6R inhibitor is delivered at a location in the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the jejunum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the jejunum and a second site of disease is in the ileum and no site of disease is present at other locations in the gastrointestinal tract.

In some embodiments, the IL-6R inhibitor is delivered at a location in the proximal portion of the jejunum of the subject and is not delivered at other locations in the

gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the proximal portion of the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the jejunum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the proximal portion of the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the jejunum and a second site of disease is in the ileum and no site of disease is present at other locations in the gastrointestinal tract.

In some embodiments, the IL-6R inhibitor is delivered at a location in the distal portion of the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the distal portion of the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the jejunum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the distal portion of the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the jejunum and a second site of disease is in the ileum and no site of disease is present at other locations in the gastrointestinal tract.

In some embodiments, the IL-6R inhibitor is delivered at a location in the ileum of the subject. In some embodiments, the location is in the proximal portion of the ileum. In some embodiments, the location is in the distal portion of the ileum.

In some embodiments, the IL-6R inhibitor is delivered at a location in the ileum of the subject and is not delivered at other locations in the gastrointestinal tract. In some

embodiments, the IL-6R inhibitor is delivered at a location in the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the ileum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the ileum and a second site of disease is in the cecum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the ileum and a second site of disease is in the cecum and/or ascending colon, and no site of disease is present at other locations in the gastrointestinal tract.

In some embodiments, the IL-6R inhibitor is delivered at a location in the proximal portion of the ileum of the subject and is not delivered at other locations in the

gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the proximal portion of the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the ileum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the proximal portion of the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the ileum and a second site of disease is in the cecum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the proximal portion of the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the ileum and a second site of disease is in the cecum and/or ascending colon, and no site of disease is present at other locations in the gastrointestinal tract.

In some embodiments, the IL-6R inhibitor is delivered at a location in the distal portion of the ileum of the subject and is not delivered at other locations in the

gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the distal portion of the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the ileum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the distal portion of the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the ileum and a second site of disease is in the cecum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the distal portion of the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the ileum and a second site of disease is in the cecum and/or ascending colon, and no site of disease is present at other locations in the gastrointestinal tract.

In some embodiments, the IL-6R inhibitor is delivered at a location in the cecum of the subject and is not delivered at other locations in the gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the distal portion of the cecum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the cecum and/or ascending colon, and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the IL-6R inhibitor is delivered at a location in the distal portion of the ileum or the proximal portion of the ascending colon of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the cecum and a second site of disease is in the ascending colon, and no site of disease is present at other locations in the gastrointestinal tract.

In some embodiments, the location at which the IL-6R inhibitor is delivered is proximate to a site of disease. The site of disease may be, for example, an injury, inflamed tissue, or one or more lesions. In some embodiments, the location at which the IL-6R inhibitor is delivered is proximate to one or more sites of disease. In some embodiments, the IL-6R inhibitor is delivered 50 cm or less from the one or more sites of disease. In some embodiments, the IL-6R inhibitor is delivered 40 cm or less from the one or more sites of disease. In some embodiments, the IL-6R inhibitor is delivered 30 cm or less from the one or more sites of disease. In some embodiments, the IL-6R inhibitor is delivered 20 cm or less from the one or more sites of disease. In some embodiments, the IL-6R inhibitor is delivered 10 cm or less from the one or more sites of disease. In some embodiments, the IL-6R inhibitor is delivered 5 cm or less from the one or more sites of disease. In some

embodiments, the IL-6R inhibitor is delivered 2 cm or less from the one or more sites of disease. In some embodiments, the method further comprises identifying the one or more sites of disease by a method comprising imaging of the gastrointestinal tract. In some embodiments, imaging of the gastrointestinal tract comprises video imaging. In some embodiments, imaging of the gastrointestinal tract comprises thermal imaging. In some embodiments, imaging of the gastrointestinal tract comprises ultrasound imaging. In some embodiments, imaging of the gastrointestinal tract comprises Doppler imaging.

In some embodiments the method does not comprise releasing more than 20 % of the

IL-6R inhibitor at a location that is not proximate to a site of disease. In some embodiments the method does not comprise releasing more than 10 % of the IL-6R inhibitor at a location that is not proximate to a site of disease. In some embodiments the method does not comprise releasing more than 5 % of the IL-6R inhibitor at a location that is not proximate to a site of disease. In some embodiments the method does not comprise releasing more than 4 % of the IL-6R inhibitor at a location that is not proximate to a site of disease. In some embodiments the method does not comprise releasing more than 3 % of the IL-6R inhibitor at a location that is not proximate to a site of disease. In some embodiments the method does not comprise releasing more than 2 % of the IL-6R inhibitor at a location that is not proximate to a site of disease.

In some embodiments the method comprises releasing the IL-6R inhibitor at a location that is proximate to a site of disease, wherein the IL-6R inhibitor and, if applicable, any carriers, excipients or stabilizers admixed with the IL-6R inhibitor, are substantially unchanged, at the time of release of the IL-6R inhibitor at the location, relatively to the time of administration of the composition to the subject.

In some embodiments the method comprises releasing the IL-6R inhibitor at a location that is proximate to a site of disease, wherein the IL-6R inhibitor and, if applicable, any carriers, excipients or stabilizers admixed with the IL-6R inhibitor, are substantially unchanged by any physiological process (such as, but not limited to, degradation in the stomach), at the time of release of the IL-6R inhibitor at the location, relatively to the time of administration of the composition to the subject.

In some embodiments, the IL-6R inhibitor is delivered to the location by mucosal contact.

In some embodiments, the IL-6R inhibitor is delivered to the location by a process that does not comprise systemic transport of the IL-6R inhibitor.

In some embodiments, the amount of the IL-6R inhibitor that is administered is from about 1 mg to about 500 mg. In some embodiments, the amount of the IL-6R inhibitor that is administered is from about 1 mg to about 100 mg. In some embodiments, the amount of the IL-6R inhibitor that is administered is from about 5 mg to about 40 mg. In some

embodiments, the amount of the IL-6R inhibitor that is administered is from about 5 mg to about 50 mg. In some embodiments, the amount of PF-04236921 that is administered is about 50 mg.

In some embodiments, the amount of the IL-6R inhibitor that is administered is less than an amount that is effective when the IL-6R inhibitor is delivered systemically.

In some embodiments, the amount of the IL-6R inhibitor that is administered is an induction dose. In some embodiments, such induction dose is effective to induce remission of the TNF and cytokine storm and healing of acute inflammation and lesions. In some embodiments, the induction dose is administered once a day. In some embodiments, the induction dose is administered once every three days. In some embodiments, the induction dose is administered once a week. In some embodiments, the induction dose is administered once a day, once every three days, or once a week, over a period of about 6-8 weeks.

In some embodiments, the method comprises administering (i) an amount of the IL- 6R inhibitor that is an induction dose, and (ii) an amount of the IL-6R inhibitor that is a maintenance dose, in this order. In some embodiments, step (ii) is repeated one or more times. In some embodiments, the induction dose is equal to the maintenance dose. In some embodiments, the induction dose is greater than the maintenance dose. In some

embodiments, the induction dose is five times greater than the maintenance dose. In some embodiments, the induction dose is two times greater than the maintenance dose.

In some embodiments an induction dose of IL-6R inhibitor and a maintenance dose of IL-6R inhibitor are each administered to the subject by administering a pharmaceutical composition comprising a therapeutically effective amount of the IL-6R inhibitor, wherein the pharmaceutical composition is a device. In some embodiments an induction dose of IL- 6R inhibitor is administered to the subject in a different manner from the maintenance dose. As an example, the induction dose may be administered systemically. In some embodiments, the induction dose may be administered other than orally. As an example, the induction dose may be administered rectally. As an example, the induction dose may be administered intravenously. As an example, the induction dose may be administered subcutaneously. In some embodiments, the induction dose may be administered by spray catheter.

In some embodiments, the concentration of the IL-6R inhibitor delivered at the location in the gastrointestinal tract is 10%, 25%, 50%, 75%, 100%, 200%, 300%, 400%, 500%, 1000%, 2000% greater than the concentration of IL-6R inhibitor in plasma.

In some embodiments, the method provides a concentration of the IL-6R inhibitor at a location that is a site of disease or proximate to a site of disease that is 2-100 times greater than at a location that is not a site of disease or proximate to a site of disease.

In some embodiments, the method comprises delivering the IL-6R inhibitor at the location in the gastrointestinal tract as a single bolus.

In some embodiments, the method comprises delivering the IL-6R inhibitor at the location in the gastrointestinal tract as more than one bolus.

In some embodiments, the method comprises delivering the IL-6R inhibitor at the location in the gastrointestinal tract in a continuous manner.

In some embodiments, the method comprises delivering the IL-6R inhibitor at the location in the gastrointestinal tract over a time period of 20 or more minutes.

In some embodiments, the method provides a concentration of the IL-6R inhibitor in the plasma of the subject that is less than 10 μg/ml. In some embodiments, the method provides a concentration of the IL-6R inhibitor in the plasma of the subject that is less than 3 μg/ml. In some embodiments, the method provides a concentration of the IL-6R inhibitor in the plasma of the subject that is less than 1 μg/ml. In some embodiments, the method provides a concentration of the IL-6R inhibitor in the plasma of the subject that is less than 0.3 μg/ml. In some embodiments, the method provides a concentration of the IL-6R inhibitor in the plasma of the subject that is less than 0.1 μg/ml. In some embodiments, the method provides a concentration of the IL-6R inhibitor in the plasma of the subject that is less than 0.01 μg/ml. In some embodiments, the values of the concentration of the IL-6R inhibitor in the plasma of the subject provided herein refer to Ctrough, that is, the lowest value of the concentration prior to administration of the next dose. In some embodiments, the method does not comprise delivering an IL-6R inhibitor rectally to the subject.

In some embodiments, the method does not comprise delivering an IL-6R inhibitor via an enema to the subject.

In some embodiments, the method does not comprise delivering an IL-6R inhibitor via suppository to the subject.

In some embodiments, the method does not comprise delivering an IL-6R inhibitor via instillation to the rectum of a subject.

In some embodiments, the methods disclosed herein comprise producing a therapeutically effective degradation product of the IL-6R inhibitor in the gastrointestinal tract. In some embodiments, the degradation product is a therapeutic antibody fragment. In some embodiments, a therapeutically effective amount of the degradation product is produced.

In some embodiments, the methods comprising administering the IL-6R inhibitor in the manner disclosed herein disclosed herein result in a reduced immunosuppressive properties relative to methods of administration of the IL-6R inhibitor systemically.

In some embodiments, the methods comprising administering the IL-6R inhibitor in the manner disclosed herein disclosed herein result in reduced immunogenicity relative to methods of administration of the IL-6R inhibitor systemically.

Markers

In some embodiments, the methods provided herein comprise monitoring the progress of the disease. In some embodiments, monitoring the progress of the disease comprises measuring the levels of IBD serological markers. In some embodiments, monitoring the progress of the disease comprises determining mucosal healing at the location of release. In some embodiments, monitoring the progress of the disease comprises determining the Crohn's Disease Activity Index (CDAI) over a period of about 6-8 weeks, or over a period of about 52 weeks, following administration of the IL-6R inhibitor. In some embodiments, monitoring the progress of the disease comprises determining the Harvey-Bradshaw Index (HBI) following administration of the IL-6R inhibitor. Possible markers may include the following: anti-glycan antibodies: anti-Saccharomices cerevisiae (ASCA); anti- laminaribioside (ALCA); anti-chitobioside (ACCA); anti-mannobioside (AMCA); anti- laminarin (anti-L); anti-chitin (anti-C) antibodies: anti-outer membrane porin C (anti-OmpC), anti-Cbirl flagellin; anti-12 antibody; autoantibodies targeting the exocrine pancreas (PAB); perinuclear anti -neutrophil antibody (pANCA). In some embodiments, monitoring the progress of the disease comprises measuring IL-6R inhibitor levels in serum over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the IL-6R inhibitor, including at the 6-8 week time point. In some embodiments, monitoring the progress of the disease comprises measuring IL-6R inhibitor levels in serum over a period of about 52 weeks following administration of the IL-6R inhibitor, including at the 52 week time point.

Patients condition, diagnosis and treatment

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises one or more of the following:

a) identifying a subject having a disease of the gastrointestinal tract, for example by endoscopy or colonoscopy;

b) determination of the severity of the disease, for example with reference to the Mayo Clinic Score, the Crohn's Disease Activity Index (CDAI), the Harvey -Bradshaw Index (HBI), or a combination of the above;

c) determination of the location of the disease, for example as determined by the

presence of lesions indicative of the disease;

d) evaluating the subject for suitability to treatment, for example by determining the patency of the subject's GI tract, for example if the indication is small intestinal diseases, pancolitis, Crohn's disease, or if the patients has strictures or fistulae;

e) administration of an induction dose or of a maintenance dose of a drug, such as the IL-6R inhibitor or such as another drug that is effective in the treatment of IBD conditions;

f) monitoring the progress of the disease, for example with reference to the Mayo Clinic Score, the Crohn's Disease Activity Index (CDAI), the Harvey -Bradshaw Index (HBI), the PRO, PR02 or PR03 tools, or a combination of the above; and/or g) optionally repeating steps e) and f) one or more times, for example over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the IL-6R inhibitor, including at the 6-8 week time point, or over a period of about 52 weeks following administration of the IL-6R inhibitor, including at the 52 week time point. As used herein, an induction dose is a dose of drug that may be administered, for example, at the beginning of a course of treatment, and that is higher than the maintenance dose administered during treatment. An induction dose may also be administered during treatment, for example if the condition of the patients becomes worse.

As used herein, a maintenance dose is a dose of drug that is provided on a repetitive basis, for example at regular dosing intervals.

In some embodiments the IL-6R inhibitor is released from an ingestible device.

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises a) hereinabove.

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises b) hereinabove.

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises c) hereinabove.

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises d) hereinabove.

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises e) hereinabove.

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises f) hereinabove.

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises g) hereinabove.

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises a) and b) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises a) and c) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises a) and d) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises a) and e) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises a) and f) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises a) and g) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises b) and c) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises b) and d) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises b) and e) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises b) and f) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises b) and g) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises c) and d) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises c) and e) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises c) and f) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises c) and g) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises d) and e) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises d) and f) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises d) and g) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises e) and f) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing an IL-6R inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises g) hereinabove.

In some embodiments, one or more steps a) to e) herein comprise endoscopy of the gastrointestinal tract. In some embodiments, one or more steps a) to e) herein comprise colonoscopy of the gastrointestinal tract. In some embodiments, one or more steps a) to d) herein is performed one or more times. In some embodiments, such one or more of such one or more steps a) to d) is performed after releasing the IL-6R inhibitor at the location in the gastrointestinal tract that is proximate to one or more sites of disease.

In some embodiments, the method comprises administering one or more maintenance doses following administration of the induction dose in step e). In some embodiments an induction dose of IL-6R inhibitor and a maintenance dose of IL-6R inhibitor are each administered to the subject by administering a pharmaceutical composition comprising a therapeutically effective amount of the IL-6R inhibitor. In some embodiments an induction dose of IL-6R inhibitor is administered to the subject in a different manner from the maintenance dose. As an example, the maintenance dose may be administered systemically, while the maintenance dose is administered locally using a device. In one embodiment, a maintenance dose is administered systemically, and an induction dose is administered using a device every 1, 2, 3, 4, 5, 6, 7, 10, 15, 20, 25, 30, 35, 40, or 45 days. In another embodiment, a maintenance dose is administered systemically, and an induction dose is administered when a disease flare up is detected or suspected.

In some embodiments, the induction dose is a dose of the IL-6R inhibitor administered in an ingestible device as disclosed herein. In some embodiments, the maintenance dose is a dose of the IL-6R inhibitor administered in an ingestible device as disclosed herein.

In some embodiments, the induction dose is a dose of the IL-6R inhibitor

administered in an ingestible device as disclosed herein. In some embodiments, the maintenance dose is a dose of the IL-6R inhibitor delivered systemically, such as orally with a tablet or capsule, or subcutaneously, or intravenously.

In some embodiments, the induction dose is a dose of the IL-6R inhibitor delivered systemically, such as orally with a tablet or capsule, or subcutaneously, or intravenously. In some embodiments, the maintenance dose is a dose of the IL-6R inhibitor administered in an ingestible device as disclosed herein.

In some embodiments, the induction dose is a dose of the IL-6R inhibitor

administered in an ingestible device as disclosed herein. In some embodiments, the maintenance dose is a dose of a second agent as disclosed herein delivered systemically, such as orally with a tablet or capsule, or subcutaneously, or intravenously.

In some embodiments, the induction dose is a dose of a second agent as disclosed herein delivered systemically, such as orally with a tablet or capsule, or subcutaneously, or intravenously. In some embodiments, the maintenance dose is a dose of the IL-6R inhibitor administered in an ingestible device as disclosed herein.

In one embodiment of the methods provided herein, the patient is not previously treated with an IL-6R inhibitor. In one embodiment, the gastrointestinal inflammatory disorder is an inflammatory bowel disease. In one embodiment, the inflammatory bowel disease is ulcerative colitis or Crohn's disease. In one embodiment, the inflammatory bowel disease is ulcerative colitis and the response is selected from clinical response, mucosal healing and remission. In certain embodiments, remission in the patient is determined to be induced when the Mayo Clinic Score < 2 and no individual subscore >1, which is also referred to as clinical remission. In certain embodiments, mucosal healing is determined to have occurred when the patient is determined to have an endoscopy subscore of 0 or 1 as assessed by flexible sigmoidoscopy. In certain such embodiments, patients who experience mucosal healing are determined to have an endoscopy subscore of 0. In certain embodiments, clinical response is determined to have occurred when the patient experiences a 3 -point decrease and 30% reduction from baseline in MCS and > 1 -point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1.

In some embodiments, the method comprises identifying the disease site substantially at the same time as releasing the IL-6R inhibitor.

In some embodiments, the method comprises monitoring the progress of the disease. In some embodiments, monitoring the progress of the disease comprises measuring the weight of the subject over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the IL-6R inhibitor, including at the 6-8 week time point, or over a period of about 52 weeks following administration of the IL-6R inhibitor, including at the 52 week time point. In some embodiments, monitoring the progress of the disease comprises measuring the food intake of the subject; measuring the level of blood in the feces of the subject; measuring the level of abdominal pain of the subject; and/or a combination of the above, for example over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the IL-6R inhibitor, including at the 6-8 week time point, or over a period of about 52 weeks following administration of the IL-6R inhibitor, including at the 52 week time point.

In some embodiments, the method comprises administering an IL-6R inhibitor with a spray catheter. For example, administering an IL-6R inhibitor with a spray catheter may be performed in step (e) hereinabove.

In some embodiments, the method does not comprise administering an IL-6R inhibitor with a spray catheter.

Pharmaceutical Formulations

As used herein, a "formulation" of an IL-6R inhibitor may refer to either the IL-6R inhibitor in pure form - such as, for example, the lyophilized IL-6R inhibitor - or a mixture of the IL-6R inhibitor with one or more physiologically acceptable carriers, excipients or stabilizers. Thus, therapeutic formulations or medicaments can be prepared by mixing the IL-6R inhibitor having the desired degree of purity with optional physiologically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids;

antioxidants including ascorbic acid and methionine; preservatives (such as

octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) antibody; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt- forming counter-ions such as sodium; metal complexes (e.g. , Zn- protein complexes); and/or non- ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

Exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral -active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20

(HYLE EX<®>, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases. Exemplary lyophilized formulations are described in US Patent No. 6,267,958. Aqueous formulations include those described in US Patent No. 6,171,586 and WO2006/044908, the latter formulations including a histidine- acetate buffer.

A formulation of an IL-6R inhibitor as disclosed herein, e.g., sustained-release formulations, can further include a mucoadhesive agent, e.g., one or more of polyvinyl pyrolidine, methyl cellulose, sodium carboxyl methyl cellulose, hydroxyl propyl cellulose, carbopol, a polyacrylate, chitosan, a eudragit analogue, a polymer, and a thiomer. Additional examples of mucoadhesive agents that can be included in a formulation with an IL-6R inhibitor are described in, e.g., Peppas et al., Biomaterials 17(16): 1553-1561, 1996; Kharenko et al., Pharmaceutical Chemistry J. 43(4):200-208, 2009; Salamat-Miller et al., Adv. DrugDeliv. Reviews 57(11): 1666-1691, 2005; Bernkop-Schnurch, Adv. DrugDeliv. Rev. 57(11): 1569-1582, 2005; and Harding et al., Biotechnol. Genet. Eng. News 16(l):41-86, 1999.

In some embodiments, components of a formulation may include any one of the following components, or any combination thereof:

Acacia, Alginate, Alginic Acid, Aluminum Acetate, an antiseptic, Benzyl Alcohol, Butyl Paraben, Butylated Hydroxy Toluene, an antioxidant. Citric acid, Calcium carbonate, Candelilla wax, a binder, Croscarmellose sodium, Confectioner sugar, Colloidal silicone dioxide, Cellulose, Carnuba wax, Corn starch, Carboxymethylcellulose calcium, Calcium stearate, Calcium disodium EDTA, Chelation agents, Copolyvidone, Castor oil hydrogenated, Calcium hydrogen phosphate dehydrate, Cetylpyridine chloride, Cysteine HC1,

Crosspovidone, Dibasic Calcium Phosphate, Disodium hydrogen phosphate, Dimethicone, Erythrosine Sodium, Ethyl Cellulose, Gelatin, Glyceryl monooleate, Glycerin, Glycine, Glyceryl monostearate, Glyceryl behenate, Hydroxy propyl cellulose, Hydroxyl propyl methyl cellulose, Hypromellose, HPMC Pthalate, Iron oxides or ferric oxide, Iron oxide yellow, Iron oxide red or ferric oxide, Lactose (hydrous or anhydrous or monohydrate or spray dried), Magnesium stearate, Microcrystalline cellulose, Mannitol, Methyl cellulose,, Magnesium carbonate, Mineral oil, Methacrylic acid copolymer, Magnesium oxide, Methyl paraben, PEG, Polysorbate 80, Propylene glycol, Polyethylene oxide, Propylene paraben, Polaxamer 407 or 188 or plain, Potassium bicarbonate, Potassium sorbate, Potato starch, Phosphoric acid, Polyoxyl40 stearate, Sodium starch glycolate, Starch pregelatinized, Sodium crossmellose, Sodium lauryl sulfate, Starch, Silicon dioxide, Sodium benzoate,, Stearic acid, Sucrose base for medicated confectionery, a granulating agent, Sorbic acid, Sodium carbonate, Saccharin sodium, Sodium alginate, Silica gel, Sorbiton monooleate,

Sodium stearyl fumarate, Sodium chloride, Sodium metabi sulfite, Sodium citrate dehydrate, Sodium starch, Sodium carboxy methyl cellulose, Succinic acid, Sodium propionate,

Titanium dioxide, Talc, Triacetin, Triethyl citrate.

Accordingly, in some embodiments of the method of treating a disease as disclosed herein, the method comprises administering to the subject a pharmaceutical composition that is a formulation as disclosed herein. In some embodiments the formulation is a dosage form, which may be, as an example, a solid form such as, for example, a capsule, a tablet, a sachet, or a lozenge; or which may be, as an example, a liquid form such as, for example, a solution, a suspension, an emulsion, or a syrup.

In some embodiments the formulation is not comprised in an ingestible device. In some embodiments wherein the formulation is not comprised in an ingestible device, the formulation may be suitable for oral administration. The formulation may be, for example, a solid dosage form or a liquid dosage form as disclosed herein. In some embodiments wherein the formulation is not comprised in an ingestible device, the formulation may be suitable for rectal administration. The formulation may be, for example, a dosage form such as a suppository or an enema. In embodiments where the formulation is not comprised in an ingestible device, the formulation releases the IL-6R inhibitor at a location in the

gastrointestinal tract of the subject that is proximate to one or more sites of disease. Such localized release may be achieved, for example, with a formulation comprising an enteric coating. Such localized release may be achieved, an another example, with a formulation comprising a core comprising one or more polymers suitable for controlled release of an active substance. A non-limiting list of such polymers includes: poly(2-(diethylamino)ethyl methacrylate, 2-(dimethylamino)ethyl methacrylate, poly(ethylene glycol), poly(2- aminoethyl methacrylate), (2-hydroxypropyl)methacrylamide, poly(P-benzyl-l-aspartate), poly(N-isopropylacrylamide), and cellulose derivatives.

In some embodiments the formulation is comprised in an ingestible device as disclosed herein. In some embodiments wherein the formulation is comprised in an ingestible device, the formulation may be suitable for oral administration. The formulation may be, for example, a solid dosage form or a liquid dosage form as disclosed herein. In some embodiments the formulation is suitable for introduction and optionally for storage in the device. In some embodiments the formulation is suitable for introduction and optionally for storage in the reservoir comprised in the device. In some embodiments the formulation is suitable for introduction and optionally for storage in the reservoir comprised in the device. Thus, in some embodiments, provided herein is a reservoir comprising a therapeutically effective amount of an IL-6R inhibitor, wherein the reservoir is configured to fit into an ingestible device. In some embodiments, the reservoir comprising a therapeutically effective amount of an IL-6R inhibitor is attachable to an ingestible device. In some embodiments, the reservoir comprising a therapeutically effective amount of an IL-6R inhibitor is capable of anchoring itself to the subject's tissue. As an example, the reservoir capable of anchoring itself to the subject's tissue comprises silicone. As an example, the reservoir capable of anchoring itself to the subject's tissue comprises polyvinyl chloride.

In some embodiments the formulation is suitable for introduction in the spray catheters disclosed herein.

The formulation/medicament herein may also contain more than one active compound as necessary for the particular indication being treated, for example, those with

complementary activities that do not adversely affect each other. For instance, the formulation may further comprise another IL-6R inhibitor or a chemotherapeutic agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.

The active ingredients may also be entrapped in microcapsule prepared, for example, by coacervation techniques or by interfacial polymerization, for

example, hydroxymethylcellulose or gelatin-microcapsule and poly-(methylmethacylate) microcapsule, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in

macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.

Sustained-release preparations may be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the IL-6R inhibitor, which matrices are in the form of shaped articles, e.g., films, or microcapsule. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2- hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γ ethyl -L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene- vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated IL-6R inhibitors remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37°C, resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for stabilization depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S-S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.

Pharmaceutical formulations may contain one or more IL-6R inhibitors. The pharmaceutical formulations may be formulated in any manner known in the art. In some embodiments the formulations include one or more of the following components: a sterile diluent (e.g., sterile water or saline), a fixed oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents, antibacterial or antifungal agents, such as benzyl alcohol or methyl parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like, antioxidants, such as ascorbic acid or sodium bisulfite, chelating agents, such as

ethylenediaminetetraacetic acid, buffers, such as acetates, citrates, or phosphates, and isotonic agents, such as sugars (e.g., dextrose), polyalcohols (e.g., mannitol or sorbitol), or salts (e.g., sodium chloride), or any combination thereof. Liposomal suspensions can also be used as pharmaceutically acceptable carriers (see, e.g., U.S. Patent No. 4,522,811, incorporated by reference herein in its entirety). The formulations can be formulated and enclosed in ampules, disposable syringes, or multiple dose vials. Where required, proper fluidity can be maintained by, for example, the use of a coating, such as lecithin, or a surfactant. Controlled release of the IL-6R inhibitor can be achieved by implants and microencapsulated delivery systems, which can include biodegradable, biocompatible polymers (e.g., ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid; Alza Corporation and Nova Pharmaceutical, Inc.).

In some embodiments, the IL-6R inhibitor is present in a pharmaceutical formulation within the device.

In some embodiments, the IL-6R inhibitor is present in solution within the device. In some embodiments, the IL-6R inhibitor is present in a suspension in a liquid medium within the device.

In some embodiments, data obtained from cell culture assays and animal studies can be used in formulating an appropriate dosage of any given IL-6R inhibitor. The effectiveness and dosing of any IL-6R inhibitor can be determined by a health care professional or veterinary professional using methods known in the art, as well as by the observation of one or more disease symptoms in a subject (e.g., a human). Certain factors may influence the dosage and timing required to effectively treat a subject (e.g., the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and the presence of other diseases).

In some embodiments, the subject is further administered an additional therapeutic agent (e.g., any of the additional therapeutic agents described herein). The additional therapeutic agent can be administered to the subject at substantially the same time as the IL- 6R inhibitor or pharmaceutical composition comprising it is administered and/or at one or more other time points. In some embodiments, the additional therapeutic agent is formulated together with the IL-6R inhibitor (e.g., using any of the examples of formulations described herein).

In some embodiments, the subject is administered a dose of the IL-6R inhibitor at least once a month (e.g., at least twice a month, at least three times a month, at least four times a month, at least once a week, at least twice a week, three times a week, once a day, or twice a day). The IL-6R inhibitor may be administered to a subject chronically. Chronic treatments include any form of repeated administration for an extended period of time, such as repeated administrations for one or more months, between a month and a year, one or more years, more than five years, more than 10 years, more than 15 years, more than 20 years, more than 25 years, more than 30 years, more than 35 years, more than 40 years, more than 45 years, or longer. Alternatively or in addition, chronic treatments may be administered. Chronic treatments can involve regular administrations, for example one or more times a day, one or more times a week, or one or more times a month. For example, chronic treatment can include administration (e.g., intravenous administration) about every two weeks (e.g., between about every 10 to 18 days).

A suitable dose may be the amount that is the lowest dose effective to produce a desired therapeutic effect. Such an effective dose will generally depend upon the factors described herein. If desired, an effective daily dose of IL-6R inhibitor can be administered as two, three, four, five, or six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Combination therapy:

The IL-6R inhibitors disclosed herein may be optionally be used with additional agents in the treatment of the diseases disclosed herein. Nonlimiting examples of such agents for treating or preventing inflammatory bowel disease in such adjunct therapy (e.g., Crohn's disease, ulcerative colitis) include substances that suppress cytokine production, down-regulate or suppress self-antigen expression, or mask the MHC antigens. Examples of such agents include 2- amino-6-aryl-5 -substituted pyrimidines (see U.S. Patent No. 4,665,077); nonsteroidal antiinflammatory drugs (NSAIDs); ganciclovir; tacrolimus; lucocorticoids such as Cortisol or aldosterone; anti-inflammatory agents such as a cyclooxygenase inhibitor; a 5 - lipoxygenase inhibitor; or a leukotriene receptor antagonist; purine antagonists such as azathioprine or mycophenolate mofetil (MMF); alkylating agents such as cyclophosphamide; bromocryptine; danazol; dapsone; glutaraldehyde (which masks the MHC antigens, as described in U.S. Patent No. 4, 120,649); anti -idiotypic antibodies for MHC antigens and MHC fragments; cyclosporine; 6-mercaptopurine; steroids such as corticosteroids or glucocorticosteroids or glucocorticoid analogs, e.g., prednisone, methylprednisolone, including SOLU-MEDROL®, methylprednisolone sodium succinate, and dexamethasone; dihydrofolate reductase inhibitors such as methotrexate (oral or subcutaneous); anti-malarial agents such as chloroquine and hydroxychloroquine; sulfasalazine; leflunomide; cytokine or cytokine receptor antibodies or antagonists including anti-interferon-alpha, -beta, or -gamma antibodies, anti-tumor necrosis factor(TNF)-alpha antibodies (infliximab (REMICADE®) or adalimumab), anti-TNF- alpha immunoadhesin (etanercept), anti-TNF-beta antibodies, anti- interleukin-2 (IL-2) antibodies and anti-IL-2 receptor antibodies, and anti-interleukin-6 (IL-6) receptor antibodies and antagonists; anti-LFA-1 antibodies, including anti-CD 1 la and anti- CD 18 antibodies; anti- L3T4 antibodies; heterologous anti -lymphocyte globulin; pan-T antibodies, anti-CD3 or anti- CD4/CD4a antibodies; soluble peptide containing a LFA-3 binding domain (WO 90/08187 published Jul. 26, 1990); streptokinase; transforming growth factor-beta (TGF-beta); streptodomase; RNA or DNA from the host; FK506; RS-61443; chlorambucil; deoxyspergualin; rapamycin; T-cell receptor (Cohen et al, U.S. Patent No. 5, 114,721); T-cell receptor fragments (Offner et al, Science, 251 : 430-432 (1991); WO

90/11294; laneway, Nature, 341 : 482 (1989); and WO 91/01133); BAFF antagonists such as BAFF or BR3 antibodies or immunoadhesins and zTNF4 antagonists (for review, see Mackay and Mackay, Trends Immunol, 23 : 113-5 (2002) and see also definition below); biologic agents that interfere with T cell helper signals, such as anti-CD40 receptor or anti- CD40 ligand (CD 154), including blocking antibodies to CD40-CD40 ligand.(e.g., Durie et al, Science, 261 : 1328-30 (1993); Mohan et al, J. Immunol, 154: 1470-80 (1995)) and CTLA4-Ig (Finck et al, Science, 265: 1225-7 (1994)); and T-cell receptor antibodies (EP 340, 109) such as T10B9. Non-limiting examples of adjunct agents also include the following: budenoside; epidermal growth factor; aminosalicylates; metronidazole;

mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor antagonists; anti-IL-1 monoclonal antibodies; growth factors; elastase inhibitors; pyridinyl- imidazole compounds; TNF antagonists; IL-4, IL-10, IL-13 and/or TGFP cytokines or agonists thereof (e.g., agonist antibodies); IL-11; glucuronide- or dextran-conjugated prodrugs of prednisolone, dexamethasone or budesonide; ICAM-I antisense phosphorothioate oligodeoxynucleotides (ISIS 2302; Isis Pharmaceuticals, Inc.); soluble complement receptor 1 (TPIO; T Cell Sciences, Inc.); slow-release mesalazine; antagonists of platelet activating factor (PAF); ciprofloxacin; and lignocaine. Examples of agents for UC are sulfasalazine and related salicylate-containing drugs for mild cases and corticosteroid drugs in severe cases. Topical administration of either salicylates or corticosteroids is sometimes effective, particularly when the disease is limited to the distal bowel, and is associated with decreased side effects compared with systemic use. Supportive measures such as administration of iron and antidiarrheal agents are sometimes indicated. Azathioprine, 6-mercaptopurine and methotrexate are sometimes also prescribed for use in refractory corticosteroid-dependent cases.

In other embodiments, an IL-6R inhibitor as described herein can be administered with one or more of: a CHST15 inhibitor, a TNF inhibitor, an IL-12/IL-23 inhibitor, an integrin inhibitor, a JAK inhibitor, a SMAD7 inhibitor, a IL-13 inhibitor, an IL-1 receptor inhibitor, a TLR agonist, an immunosuppressant, or a stem cell. In other embodiments, a IL- 6R inhibitor as described herein can be administered with a vitamin C infusion, one or more corticosteroids, and optionally thiamine.

In some embodiments, the methods disclosed herein comprise administering (i) the IL-6R inhibitor as disclosed herein, and (ii) a second agent orally, intravenously or subcutaneously, wherein the second agent in (ii) is the same IL-6R inhibitor in (i); a different IL-6R inhibitor; or an agent having a different biological target from the IL-6R inhibitor.

In some embodiments, the methods disclosed herein comprise administering (i) the IL-6R inhibitor in the manner disclosed herein, and (ii) a second agent orally, intravenously or subcutaneously, wherein the second agent in (ii) is an agent suitable for treating an inflammatory bowel disease.

In some embodiments, the IL-6R inhibitor is administered prior to the second agent. In some embodiments, the IL-6R inhibitor is administered after the second agent. In some embodiments, the IL-6R inhibitor and the second agent are administered substantially at the same time. In some embodiments, the IL-6R inhibitor is delivered prior to the second agent. In some embodiments, the IL-6R inhibitor is delivered after the second agent. In some embodiments, the IL-6R inhibitor and the second agent are delivered substantially at the same time.

In some embodiments, the second agent is an agent suitable for the treatment of a disease of the gastrointestinal tract. In some embodiments, the second agent is an agent suitable for the treatment of an inflammatory bowel disease. In some embodiments, the second agent is administered intravenously. In some embodiments, the second agent is administered subcutaneously. In some embodiments, the second agent is methotrexate.

In some embodiments, delivery of the IL-6R inhibitor to the location, such as delivery to the location by mucosal contact, results in systemic immunogenicity levels at or below systemic immunogenicity levels resulting from administration of the IL-6R inhibitor systemically. In some embodiments comprising administering the IL-6R inhibitor in the manner disclosed herein and a second agent systemically, delivery of the IL-6R inhibitor to the location, such as delivery to the location by mucosal contact, results in systemic immunogenicity levels at or below systemic immunogenicity levels resulting from

administration of the IL-6R inhibitor systemically and the second agent systemically. In some embodiments, the method comprises administering the IL-6R inhibitor in the manner disclosed herein and a second agent, wherein the amount of the second agent is less than the amount of the second agent when the IL-6R inhibitor and the second agent are both administered systemically. In some aspects of these embodiments, the second agent is an IL- 6R inhibitor.

In some embodiments, the method comprises administering the IL-6R inhibitor in the manner disclosed herein and does not comprise administering a second agent.

Examples:

Example 1 - Preclinical Murine Colitis Model

Experimental Induction of Colitis

Colitis is experimentally induced to in mice via the dextran sulfate sodium (DSS)- induced colitis model. This model is widely used because of its simplicity and many similarities with human ulcerative colitis. Briefly, mice are subjected to DSS via cecal catheterization, which is thought to be directly toxic to colonic epithelial cells of the basal crypts, for several days until colitis is induced.

Groups

Mice are allocated to one of seven cohorts, depending on the agent that is

administered:

1. Control (no agent)

2. Tocilizumab (2.5 mg/kg)

3. Tocilizumab (5 mg/kg)

4. Tocilizumab (10 mg/kg)

The control or agent is applied to a damaged mucosal surface of the bowel via administration through a cecal catheter at the dose levels described above.

Additionally, for each cohort, the animals are separated into two groups. One group receives a single dose of the control or agent on day 10 or 12. The other group receives daily (or similar) dosing of the control or agent.

Analysis

For each animal, efficacy is determined (e.g., by endoscopy, histology, etc.), and IL- 6R levels are determined in blood, feces, and tissue (tissue levels are determined after animal sacrifice). For tissue samples, levels FIER2 are additionally determined, and the level of IL- 6R is normalized to the level of FIER2. Additionally, other cytokine levels are determined in tissue (e.g., phospho STAT 1, STAT 3 and STAT 5), in plasma (e.g., VEGF, VCAM, ICAM, IL-6), or both.

Pharmacokinetics are determined both systemically (e.g., in the plasma) and locally (e.g., in colon tissue). For systemic pharmacokinetic analysis, blood and/or feces is collected from the animals at one or more timepoints after administration (e.g., plasma samples are collected at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and/or 8 hours after

administration). Local/colon tissue samples are collected once after animal sacrifice. Example 2a - Development of Preclinical Porcine Colitis Model

Experimental Induction of Colitis

Female swine weighing approximately 35 to 45 kg at study start are fasted at least 24 hours prior to intra-rectal administration of trinitrobenzene sulfonic acid (TNBS). Animals are lightly anesthetized during the dosing and endoscopy procedure. An enema to clean the colon is used, if necessary. One animal is administered 40 ml of 100% EtOH mixed with 5 grams of TNBS diluted in 10 ml of water via an enema using a ball-tipped catheter. The enema is deposited in the proximal portion of the descending colon just past the bend of the transverse colon. The TNBS is retained at the dose site for 12 minutes by use of two Foley catheters with 60-ml balloons placed in the mid-section of the descending colon below the dose site. A second animal is similarly treated, but with a solution containing 10 grams of TNBS. An Endoscope is employed to positively identify the dose site in both animals prior to TNBS administration. Dosing and endoscopy are performed by a veterinary surgeon

Seven (7) days after TNBS administration, after light anesthesia, the dose site and mucosal tissues above and below the dose site are evaluated by the veterinary surgeon using an endoscope. Pinch Biopsies are obtained necessary, as determined by the surgeon. Based on the endoscopy findings, the animals may be euthanized for tissue collection on that day, or may proceed on study pending the results of subsequent endoscopy exams for 1 to 4 more days. Macroscopic and microscopic alterations of colonic architecture, possible necrosis, thickening of the colon, and substantial histologic changes are observed at the proper TNBS dose.

Clinical signs (e.g., ill health, behavioral changes, etc.) are recorded at least daily during acclimation and throughout the study. Additional pen-side observations are conducted twice daily (once-daily on weekends). Body weight is measured for both animals Days 1 and 7 (and on the day of euthanasia if after Day 7).

On the day of necropsy, the animals are euthanized via injection of a veterinarian- approved euthanasia solution. Immediately after euthanasia in order to avoid autolytic changes, colon tissues are collected, opened, rinsed with saline, and a detailed macroscopic examination of the colon is performed to identify macroscopic finings related to TNBS- damage. Photos are taken. Tissue samples are taken from the proximal, mid, and distal transverse colon; the dose site; the distal colon; the rectum; and the anal canal. Samples are placed into NBF and evaluated by a board certified veterinary pathologist. Example 2b - Pharmacokinetic/Pharmacodynamic and Bioavailability of Tocilizumab After Topical Application Animal Model

Animals are subjected to intra-rectal administration of trinitrobenzene Sulfonic acid (TNBS) to induce chronic colitis on Day -6. All animals are fasted prior to colitis induction on Day -7. The TNBS is dissolved in 25% ethanol then instilled into the colon intra-rectally using a flexible plastic ball-tip gavage needle. Approximately seven (7) days after induction, macroscopic and microscopic alterations of colonic architecture are apparent: some necrosis, thickening of the colon, substantial histologic changes that only partially resolve by Day 60.

Groups

Sixteen (16) swine (approximately 35 to 45 kg at study start) are allocated to one of five groups:

1. Vehicle Control: (3.2 mL saline); intra-rectal; (n=2)

2. Treated Control: Tocilizumab (40mg in 3.2mL saline); subcutaneous; (n=2)

3. Tocilizumab (low): 4. Tocilizumab (40mg in 3.2mL saline); intra-rectal; (n=4)

4. Tocilizumab (med): Tocilizumab (80mg in 3.2 mL saline); intra-rectal; (n=4) 5. Tocilizumab (high): Tocilizumab (160mg in 3.2 mL saline); intra-rectal;

(n=4)

On Day 0, the test article is applied to a damaged mucosal surface of the bowel via intra-rectal administration or subcutaneous injection by a veterinary surgeon at the dose levels and volume described above.

Clinical Observations and Body Weight

Clinical observations are conducted at least once daily. Clinical signs (e.g., ill health, behavioral changes, etc.) are recorded on all appropriate animals at least daily prior to the initiation of experiment and throughout the study until termination. Additional clinical observations may be performed if deemed necessary. Animals whose health condition warrants further evaluation are examined by a Clinical Veterinarian. Body weight is measured for all animals Days -6, 0, and after the last blood collections. Samples

Blood:

Blood is collected (cephalic, jugular, and/or catheter) into EDTA tubes during acclimation on Day-7, just prior to dose on Day 0, and 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post-dose. The EDTA samples are split into two aliquots and one is centrifuged for pharmacokinetic plasma and either analyzed immediately, or stored frozen (-80°C) for later pharmacokinetic analyses. The remaining sample of whole blood is used for

pharmacodynamic analyses.

Feces:

Feces is collected Day -7, 0 and 0.5, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose, and either analyzed immediately, or flash-frozen on liquid nitrogen and stored frozen at -70°C pending later analysis of drug levels and inflammatory cytokines.

Tissue:

Immediately after euthanasia in order to avoid autolytic changes, colon tissues are collected, opened, rinsed with saline, and a detailed macroscopic examination of the colon is performed to identify macroscopic finings related to T BS-damage. Triplicate samples of normal and damaged tissues are either analyzed immediately, or are flash-frozen on liquid nitrogen and stored frozen at -70°C pending later analysis of drug concentration,

inflammatory cytokines and histology.

Samples are analyzed for tocilizumab levels (local mucosal tissue levels and systemic circulation levels), and for levels of IL-6R.

Terminal Procedures

Animals are euthanized as per the schedule in Table AA, where one animal each of Vehicle and Treated Control groups is euthanized at 6 and 48 hours post-dose, and one animal of each the tocilizumab groups are euthanized at 6, 12, 24 and 48 hours post-dose. Animals are discarded after the last blood collection unless retained for a subsequent study. Table AA

Claims

Claims:

1. A method of treating a disease of the gastrointestinal tract in a subject,

comprising:

releasing an IL-6R inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease,

wherein the method comprises administering to the subject a

pharmaceutical composition comprising a therapeutically effective amount of the IL-6R inhibitor,

wherein the pharmaceutical composition is an ingestible device and the method comprises administering orally to the subject the pharmaceutical composition.

2. The method of claim 1, wherein the pharmaceutical composition is an ingestible device and the method comprises administering orally to the subject the pharmaceutical composition.

3. The method of claim 1 or 2, wherein the method does not comprise releasing more than 10% of the IL-6R inhibitor at a location that is not proximate to a site of disease.

4. The method of claim 1 or 2, wherein the method provides a concentration of the IL-6R inhibitor at a location that is a site of disease or proximate to a site of disease that is 2-100 times greater than at a location that is not proximate to a site of disease.

5. The method of any one of the preceding claims, wherein the method provides a concentration of the IL-6R inhibitor in the plasma of the subject that is less than 3

6. The method of claim 5, wherein the method provides a concentration of the IL-6R inhibitor in the plasma of the subject that is less than 0.3 μg/ml.

7. The method of claim 6, wherein the method provides a concentration of the IL-6R inhibitor in the plasma of the subject that is less than 0.01 μ /ηι1.

8. The method of any one of claims 1 to 4, wherein the method provides a C24 value of the IL-6R inhibitor in the plasma of the subject that is less than 3 μ§/τηΙ.

9. The method of claim 8, wherein the method provides a C24 value of the IL-6R inhibitor in the plasma of the subject that is less than 0.3 μ§/τηΙ.

10. The method of claim 9, wherein the method provides a C24 value of the IL-6R inhibitor in the plasma of the subject that is less than 0.01 μ§/ΐηΙ.

1 1. The method of any one of claims 1 to 10, wherein the IL-6R inhibitor is an

inhibitory nucleic acid.

12. The method of any one of claims 1 to 10, wherein the IL-6R inhibitor is an

antibody.

13. The method of any one of claims 1 to 10, wherein the IL-6R inhibitor is an antigen- binding fragment thereof.

14. The method of any one of claims 1 to 10, wherein the IL-6R inhibitor is a fusion protein.

15. The method of any one of claims 1 to 10, wherein the IL-6R inhibitor is a small molecule.

16. The method of any one of claims 2 to 15, wherein the IL-6R inhibitor is present in a pharmaceutical formulation within the device.

17. The method of claim 16, wherein the formulation is a solution of the IL-6R

inhibitor in a liquid medium.

18. The method of claim 17, wherein the formulation is a suspension of the IL-6R inhibitor in a liquid medium.

19. The method of any one of claims 1 to 18, wherein the disease of the GI tract is an inflammatory bowel disease.

20. The method of any one of claims 1 to 18, wherein the disease of the GI tract is ulcerative colitis.

21. The method of any one of claims 1 to 18, wherein the disease of the GI tract is Crohn's disease.

22. The method of any one of claims 1 to 21, wherein the IL-6R inhibitor is released at a location in the large intestine of the subject.

23. The method of claim 22, wherein the location is in the proximal portion of the large intestine.

24. The method of claim 22, wherein the location is in the distal portion of the large intestine.

25. The method of any one of claims 1 to 21, wherein the IL-6R inhibitor is released at a location in the ascending colon of the subject.

26. The method of claim 25, wherein the location is in the proximal portion of the ascending colon.

27. The method of claim 25, wherein the location is in the distal portion of the

ascending colon.

28. The method of any one of claims 1 to 21, wherein the IL-6R inhibitor is released at a location in the cecum of the subject.

29. The method of claim 28, wherein the location is in the proximal portion of the cecum.

30. The method of claim 28, wherein the location is in the distal portion of the cecum.

31. The method of any one of claims 1 to 21, wherein the IL-6R inhibitor is released at a location in the sigmoid colon of the subject.

32. The method of claim 31, wherein the location is in the proximal portion of the sigmoid colon.

33. The method of claim 31, wherein the location is in the distal portion of the

sigmoid colon.

34. The method of any one of claims 1 to 21, wherein the IL-6R inhibitor is released at a location in the transverse colon of the subject.

35. The method of claim 34, wherein the location is in the proximal portion of the transverse colon.

36. The method of claim 34, wherein the location is in the distal portion of the

transverse colon.

37. The method of any one of claims 1 to 21, wherein the IL-6R inhibitor is released at a location in the descending colon of the subject.

38. The method of claim 37, wherein the location is in the proximal portion of the descending colon.

39. The method of claim 37, wherein the location is in the distal portion of the

descending colon.

40. The method of any one of claims 1 to 21, wherein the IL-6R inhibitor is released at a location in the small intestine of the subject.

41. The method of claim 40, wherein the location is in the proximal portion of the small intestine.

42. The method of claim 40, wherein the location is in the distal portion of the small intestine.

43. The method of any one of claims 1 to 21, wherein the IL-6R inhibitor is released at a location in the duodenum of the subject.

44. The method of claim 43, wherein the location is in the proximal portion of the duodenum.

45. The method of claim 43, wherein the location is in the distal portion of the

duodenum.

46. The method of any one of claims 1 to 21, wherein the IL-6R inhibitor is released at a location in the jejunum of the subject.

47. The method of claim 46, wherein the location is in the proximal portion of the jejunum.

48. The method of claim 46, wherein the location is in the distal portion of the

jejunum.

49. The method of any one of claims 1 to 21, wherein the IL-6R inhibitor is released at a location in the ileum of the subject.

50. The method of claim 49, wherein the location is in the proximal portion of the ileum.

51. The method of claim 49, wherein the location is in the distal portion of the ileum.

52. The method of any one of the preceding claims, wherein the location at which the IL-6R inhibitor is released is 10 cm or less from one or more sites of disease.

53. The method of any one of the preceding claims, wherein the location at which the IL-6R inhibitor is released is 5 cm or less from one or more sites of disease.

54. The method of any one of the preceding claims, wherein the location at which the IL-6R inhibitor is released is 2 cm or less from one or more sites of disease.

55. The method of any one of the preceding claims, wherein the IL-6R inhibitor is released by mucosal contact.

56. The method of any one of the preceding claims, wherein the IL-6R inhibitor is delivered to the location by a process that does not comprise systemic transport of the IL-6R inhibitor.

57. The method of any one of the preceding claims, further comprising identifying the one or more sites of disease by a method comprising imaging of the

gastrointestinal tract.

58. The method of claim any one of the preceding claims, wherein the method

comprises identifying the disease site prior to administering the pharmaceutical composition.

59. The method of claim 58, wherein the method comprises releasing the IL-6R

inhibitor substantially at the same time as identifying the disease site.

60. The method of any one of the preceding claims, comprising (a) identifying a subject having a disease of the gastrointestinal tract and (b) evaluating the subject for suitability to treatment.

61. The method of any one of claims 1 or 3 to 15 or 17 to 60, wherein releasing the IL-6R inhibitor is triggered by one or more of: a pH in the jejunum from 6.1 to 7.2, a pH in the mid small bowel from 7.0 to 7.8, a pH in the ileum from 7.0 to

8.0, a pH in the right colon from 5.7 to 7.0, a pH in the mid colon from 5.7 to 7.4, a pH in the left colon from 6.3 to 7.7, such as 7.0.

62. The method of any one of claims 1 to 60, wherein releasing the IL-6R inhibitor is not dependent on the pH at or in the vicinity of the location.

63. The method of any one of claims 1 or 3 to 15 or 17 to 60, wherein releasing the IL-6R inhibitor is triggered by degradation of a release component located in the device.

64. The method of any one of claims 1 to 60, wherein releasing the IL-6R inhibitor is not triggered by degradation of a release component located in the device.

65. The method of any one of claims 1 to 60, wherein releasing the IL-6R inhibitor is not dependent on enzymatic activity at or in the vicinity of the location.

66. The method of any one of claims 1 to 60, wherein releasing the IL-6R inhibitor is not dependent on bacterial activity at or in the vicinity of the location.

67. The method of any one of claims 1 to 60, wherein the composition comprises a plurality of electrodes comprising a coating, and releasing the IL-6R inhibitor is triggered by an electric signal by the electrodes resulting from the interaction of the coating with the one or more sites of disease.

68. The method of any one of claims 1 to 60, wherein releasing the IL-6R inhibitor is triggered by a remote electromagnetic signal.

69. The method of any one of claims 1 to 60, wherein releasing the IL-6R inhibitor is triggered by generation in the composition of a gas in an amount sufficient to expel the IL-6R inhibitor.

70. The method of any one of claims 1 to 60, wherein releasing the IL-6R inhibitor is triggered by an electromagnetic signal generated within the device according to a pre-determined drug release profile.

71. The method of any one of claims 2 to 60, wherein the ingestible device comprises an ingestible housing, wherein a reservoir storing the IL-6R inhibitor is attached to the housing.

72. The method of claim 71, further comprising:

detecting when the ingestible housing is proximate to a respective disease site of the one of the one or more sites of disease,

wherein releasing the IL-6R inhibitor comprises releasing the therapeutically effective amount of the IL-6R inhibitor from the reservoir proximate the respective disease site in response to the detection.

73. The method of claim72, wherein detecting comprises detecting via one or more sensors coupled to the ingestible housing.

74. The method of claim 73, wherein the one or more sensors comprise a plurality of coated electrodes and wherein detecting comprises receiving an electric signal by one or more of the coated electrodes responsive to the one or more electrode contacting the respective disease site.

75. The method of claim 72, wherein releasing comprises opening one or more valves in fluid communication with the reservoir.

76. The method of claim 75, wherein the one or more valves is communicably

coupled to a processor positioned in the housing, the processor communicably coupled to one or more sensors configured to detect the one or more sites of disease.

77. The method of claim 72, wherein releasing comprises pumping the therapeutically effective amount of the IL-6R inhibitor from the reservoir via pump positioned in the ingestible housing.

78. The method of claim 77, wherein the pump is communicably coupled to a

processor positioned in the housing, the processor communicably coupled to one or more sensors configured to detect the one or more sites of disease.

79. The method of claim 71, wherein the therapeutically effective amount of the IL- 6R inhibitor is stored in the reservoir at a reservoir pressure higher than a pressure in the gastrointestinal tract of the subject.

80. The method of claim 71, further comprising anchoring the ingestible housing at a location proximate to the respective disease site in response to the detection.

81. The method of claim 80, wherein anchoring the ingestible housing comprises one or more legs to extend from the ingestible housing.

82. The method of any one of the preceding claims, wherein the amount of the IL-6R inhibitor that is administered is from about 1 mg to about 500 mg.

83. The method of any one of the preceding claims, wherein the IL-6R inhibitor is selected from tocilizumab (Actemra®) and sarilumab (Sanofi and Regeneron); generic equivalents thereof; modifications thereof having at least 90% sequence homology; modifications thereof differing in the glycosylation pattern; and modifications thereof having at least 90% sequence homology and differing in the glycosylation pattern.

84. The method of claim 83, wherein the IL-6R inhibitor is selected from tocilizumab (Actemra®).

85. The method of any one of claims 1 to 84, wherein the amount of the IL-6R

inhibitor is less than an amount that is effective when IL-6R inhibitor is administered systemically.

86. The method of any one of the preceding claims, comprising administering (i) an amount of the IL-6R inhibitor that is an induction dose.

87. The method of claim 86, further comprising (ii) administering an amount of the IL-6R inhibitor that is a maintenance dose following the administration of the induction dose.

88. The method of claim 86 or 87, wherein the induction dose is administered once a day.

89. The method of claim 86 or 87, wherein the induction dose is administered once every three days.

90. The method of claim 86 or 87, wherein the induction dose is administered once a week.

91. The method of claim 87, wherein step (ii) is repeated one or more times.

92. The method of claim 87, wherein step (ii) is repeated once a day over a period of about 6-8 weeks.

93. The method of claim 87, wherein step (ii) is repeated once every three days over a period of about 6-8 weeks.

94. The method of claim 87, wherein step (ii) is repeated once a week over a period of about 6-8 weeks.

95. The method of claim 87, wherein the induction dose is equal to the maintenance dose.

96. The method of claim 87, wherein the induction dose is greater than the

maintenance dose.

97. The method of claim 87, wherein the induction dose is 5 times greater than the maintenance dose.

98. The method of claim 87, wherein the induction dose is 2 times greater than the maintenance dose.

99. The method of any one of the preceding claims, wherein the method comprises releasing the IL-6R inhibitor at the location in the gastrointestinal tract as a single bolus.

100. The method of any one of claims 1 to 98, wherein the method comprises releasing the IL-6R inhibitor at the location in the gastrointestinal tract as more than one bolus.

101. The method of any one of claims 1 to 98, wherein the method comprises

delivering the IL-6R inhibitor at the location in the gastrointestinal tract in a continuous manner.

102. The method of claim 101, wherein the method comprises delivering the IL-6R inhibitor at the location in the gastrointestinal tract over a time period of 20 or more minutes.

103. The method of any one of claims 1 to 102, wherein the method does not

comprise delivering an IL-6R inhibitor rectally to the subject.

104. The method of any one of claims 1 to 102, wherein the method does not

comprise delivering an IL-6R inhibitor via an enema to the subject.

105. The method of any one of claims 1 to 102, wherein the method does not

comprise delivering an IL-6R inhibitor via suppository to the subject.

106. The method of any one of claims 1 to 102, wherein the method does not

comprise delivering an IL-6R inhibitor via instillation to the rectum of the subject.

107. The method of any one of claims 1 to 102, wherein the method does not

comprise surgical implantation.

108. The method of any one of the preceding claims, wherein the IL-6 receptor

inhibitor targets the IL-6 receptor β-subunit, glycoprotein 130 (sIL6gpl30).

109. The method of any one of claims 1 to 107, wherein the IL-6 receptor inhibitor targets the IL-6 receptor subunit (IL6R).

110. The method of any one of claims 1 to 107, wherein the IL-6 receptor inhibitor targets the complex consisting of both the IL-6 receptor subunit (IL6R) and the IL-6 receptor β-subunit, glycoprotein 130 (sIL6gpl30).

111. The method of any one of claims 1 to 107, wherein the IL-6 receptor inhibitor is an inhibitory nucleic acid that is a nucleic acid molecules whose nucleotide sequence is complementary to all or part of an IL6R, sIL6gpl30, or IL-6 mRNA.

112. The method of any one of claims 1 to 107, wherein the IL-6 receptor inhibitor is an inhibitory nucleic acid that is a nucleic acid molecules whose nucleotide sequence is complementary to all or part of any one of SEQ ID NOs: 1-6.

113. The method of any one of claims 1 to 67 or 69 to 112, wherein the composition is an autonomous device.

114. The method of any one of claims 1 to 113, wherein the composition comprises a mechanism capable of releasing the IL-6R inhibitor.

115. The method of any one of claims 1 to 114, wherein the composition comprises a tissue anchoring mechanism for anchoring the composition to the location.

116. The method of claim 115, wherein the tissue anchoring mechanism is capable of activation for anchoring to the location.

117. The method of claim 115 to 116, wherein the tissue anchoring mechanism

comprises an osmotically-driven sucker.

118. The method of claim 115, 116, or 117, wherein the tissue anchoring mechanism comprises a connector operable to anchor the composition to the location.

119. The method of claim 118, wherein the connector is operable to anchor the

composition to the location using an adhesive, negative pressure and/or fastener.

120. The method of claim 71, wherein the reservoir is an anchorable reservoir.

121. The method of any one of claims 1 to 60,

wherein the pharmaceutical composition is an ingestible device, comprising: a housing;

a reservoir located within the housing and containing the IL-6R inhibitor, a mechanism for releasing the IL-6R inhibitor from the reservoir;

and;

122. The method of claim 121, wherein the ingestible device further comprises: an electronic component located within the housing; and

123. The method of claim 121 or 122, wherein the ingestible device further

comprises:

a safety device placed within or attached to the housing,

124. The method of claim 1 to 60, wherein the pharmaceutical composition is an ingestible device, comprising:

a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end; an electronic component located within the housing;

a reservoir located within the housing,

a safety device placed within or attached to the housing,

125. The method of claim 1 to 60, wherein the pharmaceutical composition is an

ingestible device, comprising:

a reservoir located within the housing,

an injection device located at the first end of the housing,

wherein the jet injection device is configured to inject the dispensable substance out of the housing from the reservoir; and

a safety device placed within or attached to the housing,

126. The method of claim 1 to 60, wherein the pharmaceutical composition is an

ingestible device, comprising:

a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end; an optical sensing unit located on a side of the housing,

wherein the optical sensing unit is configured to detect a reflectance from an environment external to the housing; an electronic component located within the housing;

a reservoir located within the housing,

a membrane in contact with the gas generating cell and configured to move or deform into the reservoir by a pressure generated by the gas generating cell; and a dispensing outlet placed at the first end of the housing,

127. The method of any one of claims 1 to 60, wherein the pharmaceutical

composition is an ingestible device as disclosed in US Patent Application Ser. No. 62/385,553, incorporated by reference herein in its entirety.

128. The method of any one of claims 1 to 60, wherein the pharmaceutical

composition is an ingestible device comprising a localization mechanism as disclosed in international patent application PCT/US2015/052500, incorporated by reference herein in its entirety.

129. The method of any one of claims 1 to 60, wherein the pharmaceutical

composition is not a dart-like dosage form.

130. A method of treating a disease of the large intestine of a subject, comprising: releasing an IL-6R inhibitor at a location in the proximal portion of the large intestine of the subject that is proximate to one or more sites of disease,

wherein the method comprises administering endoscopically to the subject a therapeutically effective amount of the IL-6R inhibitor, wherein the method does not comprise releasing more than 20% of the IL-6R inhibitor at a location that is not proximate to a site of disease.

131. A method of treating a disease of the gastrointestinal tract in a subject,

comprising:

releasing an IL-6R inhibitor at a location in the proximal portion of the large intestine of the subject that is proximate to one or more sites of disease, wherein the method comprises administering endoscopically to the subject a

pharmaceutical composition comprising a therapeutically effective amount of the IL-6R inhibitor, wherein the pharmaceutical composition is an ingestible device.

132. The method of claim 130 or 131, wherein the method does not comprise

releasing more than 20% of the IL-6R inhibitor at a location that is not proximate to a site of disease

133. The method of claim 130, 131 or 132 wherein the method does not comprise releasing more than 10% of the IL-6R inhibitor at a location that is not proximate to a site of disease.

134. The method of any one of claims 130, 131 or 132, wherein the method provides a concentration of the IL-6R inhibitor at a location that is a site of disease or proximate to a site of disease that is 2-100 times greater than at a location that is not proximate to a site of disease.

135. The method of any one of claims 130 to 134, wherein the method provides a concentration of the IL-6R inhibitor in the plasma of the subject that is less than 3

136. The method of claim 135, wherein the method provides a concentration of the IL-6R inhibitor in the plasma of the subject that is less than 0.3 μg/ml.

137. The method of claim 136, wherein the method provides a concentration of the IL-6R inhibitor in the plasma of the subject that is less than 0.01 μg/ml.

138. The method of any one of claims 130 to 134, wherein the method provides a C24 value of the IL-6R inhibitor in the plasma of the subject that is less than 3 μg/ml.

139. The method of any one of claims 130 to 134, wherein the method provides a C24 value of the IL-6R inhibitor in the plasma of the subject that is less than 0.3

140. The method of any one of claims 130 to 134, wherein the method provides a C24 value of the IL-6R inhibitor in the plasma of the subject that is less than 0.01

141. The method of any one of claims 130 to 134, wherein the composition does not comprise an enteric coating.

142. The method of any one of claims 130 to 141, wherein the IL-6R inhibitor is not a cyclic peptide.

143. The method of any one of claims 130 to 141, wherein the IL-6R inhibitor is present in a pharmaceutical formulation within the device.

144. The method of claim 143, wherein the formulation is a solution of the IL-6R inhibitor in a liquid medium.

145. The method of claim 143, wherein the formulation is a suspension of the IL-6R inhibitor in a liquid medium.

146. The method of any one of claims 130 to 145, wherein the disease of the large intestine is an inflammatory bowel disease.

147. The method of any one of claims 130 to 145, wherein the disease of the large intestine is ulcerative colitis.

148. The method of any one of claims 130 to 145, wherein the disease the large

intestine is Crohn's disease.

149. The method of any one of claims 130 to 148, wherein the IL-6R inhibitor is released at a location in the proximal portion of the ascending colon.

150. The method of any one of claims 130 to 148, wherein the IL-6R inhibitor is released at a location in the proximal portion of the cecum.

151. The method of any one of claims 130 to 148, wherein the IL-6R inhibitor is released at a location in the proximal portion of the sigmoid colon.

152. The method of any one of claims 130 to 148, wherein the IL-6R inhibitor is released at a location in the proximal portion of the transverse colon.

153. The method of any one of claims 130 to 148, wherein the IL-6R inhibitor is released at a location in the proximal portion of the descending colon.

154. The method of any one of claims 130 to 148, wherein the method comprises

administering to the subject a reservoir comprising the therapeutically effective amount of the IL-6R inhibitor, wherein the reservoir is connected to the endoscope.

155. The method of any one of the preceding claims, further comprising administering a second agent orally, intravenously or subcutaneously, wherein the second agent is the same IL-6R inhibitor; a different IL-6R inhibitor; or an agent having a different biological target from the IL-6R inhibitor, wherein the second agent is an agent suitable for treating an inflammatory bowel disease.

156. The method of claim 155, wherein the IL-6R inhibitor is administered prior to the second agent.

157. The method of claim 155, wherein the IL-6R inhibitor is administered after the second agent.

158. The method of claim 155, wherein the IL-6R inhibitor and the second agent are administered substantially at the same time.

159. The method of any one of claims 155, wherein the second agent is administered intravenously.

160. The method of any one of claims 155, wherein the second agent is administered subcutaneously.

161. The method of any one of claims 155 to 160, wherein the amount of the second agent is less than the amount of the second agent when the IL-6R inhibitor and the second agent are both administered systemically.

162. The method of claim 161, wherein the second agent is an IL-6R inhibitor.

163. The method of claim 161, wherein second agent is methotrexate.

164. The method of any one of claims 1 to 154, wherein the method does not

comprise administering a second agent.

165. The method of any one of claims 119 to 164, wherein the method comprises identifying the disease site prior to endoscopic administration.

166. The method of any one of claims 119 to 164, wherein the method comprises identifying the disease site substantially at the same time as releasing the IL-6R inhibitor.

167. The method of any one of the preceding claims, wherein the method comprising monitoring the progress of the disease.

168. The method of claim 167, wherein monitoring the progress of the disease

comprises measuring the weight of the subject over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the IL-6R inhibitor.

169. The method of claim 167 or 168, wherein monitoring the progress of the disease comprises measuring the food intake of the subject over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the IL-6R inhibitor.

170. The method of claim 167, 168 or 169, wherein monitoring the progress of the disease comprises measuring the level of blood in the feces of the subject over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the IL-6R inhibitor.

171. The method of claim 167, 168 or 169, wherein monitoring the progress of the disease comprises measuring the level of abdominal pain of the subject over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the IL-6R inhibitor.

172. The method of any one of claims 1 to 171, wherein the method does not

comprise administering an IL-6R inhibitor with a spray catheter.

173. The method of any one of claims 1 to 172, wherein the method comprises

administering an IL-6R inhibitor with a spray catheter.

174. A method of treating a disease of the gastrointestinal tract in a subject,

comprising:

releasing an IL-6R inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease, wherein the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the IL-6R inhibitor the method comprising one or more of the following steps:

a) identifying a subject having a disease of the gastrointestinal tract;

b) determination of the severity of the disease;

c) determination of the location of the disease;

d) evaluating the subject for suitability to treatment;

e) administration of an induction dose of the IL-6R inhibitor;

f) monitoring the progress of the disease; and/or

g) optionally repeating steps e) and f) one or more times.

175. The method of claim 174, wherein the pharmaceutical composition is an

ingestible device and the method comprises administering orally to the subject the pharmaceutical composition.

176. The method of claim 174 or 175, wherein the method comprises administering one or more maintenance doses following administration of the induction dose in step e).

177. The method of claim 176, wherein the induction dose is a dose of the IL-6R inhibitor administered in an ingestible device.

178. The method of claim 176 or 177, wherein the maintenance dose is a dose of the IL-6R inhibitor administered in an ingestible device as disclosed herein.

179. The method of claim 176 or 177, wherein the maintenance dose is a dose of the IL-6R inhibitor delivered systemically.

180. The method of claim 176, wherein the induction dose is a dose of the IL-6R inhibitor delivered systemically.

181. The method of claim 176 or 180, wherein the maintenance dose is a dose of the IL-6R inhibitor administered in an ingestible device.

182. The method of claim 176, wherein the induction dose is a dose of a second agent as delivered systemically.

183. The method of claim 176 or 180, wherein the maintenance dose is a dose of the IL-6R inhibitor administered in an ingestible device.

184. An IL-6R inhibitor delivery apparatus comprising:

an ingestible housing comprising a reservoir having a pharmaceutical composition comprising a therapeutically effective amount of the IL-6R inhibitor stored therein;

a detector coupled to the ingestible housing, the detector configured to detect when the ingestible housing is proximate to a respective disease site of the one of the one or more sites of disease;

185. The IL-6R inhibitor delivery apparatus according to claim 184, further

comprising a pump positioned in the ingestible housing, the pump configured to pump the therapeutically effective amount of the IL-6R inhibitor from the reservoir in response to activation of the pump by the controller responsive to detection by the detector of the ingestible housing being proximate to the respective disease site.

186. The IL-6R inhibitor delivery apparatus according to claim 185, wherein the

controller is configured to cause the pump to pump the therapeutically effective amount of the IL-6R inhibitor from the reservoir according to the following protocol.

187. The IL-6R inhibitor delivery apparatus according to claim 184, wherein the valve system comprises a dissolvable coating.

188. The IL-6R inhibitor delivery apparatus according to claim 184, wherein the valve system comprises one or more doors configured for actuation by at least one of sliding, pivoting, and rotating.

189. The IL-6R inhibitor delivery apparatus according to claim 184, wherein the valve system comprises an electrostatic shield.

190. The IL-6R inhibitor delivery apparatus according to claim 184, wherein the

reservoir comprises a pressurized cell.

191. The IL-6R inhibitor delivery apparatus according to claim 184, further comprising at least one actuatable anchor configured to retain the ingestible housing at the respective disease site upon actuation.

192. The IL-6R inhibitor delivery apparatus according to claim 184, herein the

actuatable anchor is retractable.

193. A composition comprising a therapeutically effective amount of the IL-6R

inhibitor of any one of the preceding claims, wherein the composition is capable of releasing the IL-6R inhibitor at a location in the gastrointestinal tract of the subject.

194. The composition of claim 193, wherein the composition comprises a tissue anchoring mechanism for anchoring the composition to the location.

195. The composition of claim 194, wherein the tissue anchoring mechanism is capable of anchoring for anchoring to the location.

196. The composition of claim 194 or 195, wherein the tissue anchoring mechanism comprises an osmotically-driven sucker.

197. The composition of claim 194, 195 or 196, wherein the tissue anchoring

mechanism comprises a connector operable to anchor the composition to the location.

198. The composition of claim 197, wherein the connector is operable to anchor the composition to the location using an adhesive, negative pressure and/or fastener.

199. An IL-6R inhibitor for use in a method of treating a disease of the

gastrointestinal tract in a subject, wherein the method comprises orally administering to the subject an ingestible device loaded with the IL-6R inhibitor, wherein the IL-6R inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.

200. The IL-6R inhibitor for use of claim 199, wherein the IL-6R inhibitor is contained in a reservoir suitable for attachment to a device housing, and wherein the method comprises attaching the reservoir to the device housing to form the ingestible device, prior to orally administering the ingestible device to the subject.

201. An attachable reservoir containing an IL-6R inhibitor for use in a method of treating a disease of the gastrointestinal tract, wherein the method comprises attaching the reservoir to a device housing to form an ingestible device and orally administering the ingestible device to a subject, wherein the IL-6R inhibitor is released by device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.

202. A composition comprising or consisting of an ingestible device loaded with a therapeutically effective amount of an IL-6R inhibitor, for use in a method of treatment, wherein the method comprises orally administering the composition to the subject, wherein the IL-6R inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.

203. The IL-6R inhibitor for use according to claim 199 or 200, the attachable

reservoir compartment for use according to claim 201, or the composition for use according to claim 202, wherein the sites of disease have been pre-determined.

204. The IL-6R inhibitor for use according to claim 199 or 200, the attachable

reservoir compartment for use according to claim 201, or the composition for use according to claim 202, wherein the ingestible device further comprises an environmental sensor and the method further comprises using the environmental sensor to identify the location of one or more sites of disease.

205. The IL-6R inhibitor for use, the attachable reservoir compartment for use the composition for use, according to claim 204, wherein the environmental sensor is an imaging sensor and the method further comprising imaging the gastrointestinal tract to identify the location of one or more sites of disease.

206. The IL-6R inhibitor for use, the attachable reservoir compartment for use, or the composition for use, according to claim 205, wherein the imaging detects inflamed tissue and/or lesions associated with a disease of the gastrointestinal tract.

207. The IL-6R inhibitor for use, the attachable reservoir compartment for use or the composition for use, according to any one of claims 199 to 205, wherein the disease of the GI tract is one or more of an inflammatory bowel disease, ulcerative colitis and Crohn's disease.

208. An ingestible device loaded with a therapeutically effective amount of an IL-6R inhibitor, wherein the device is controllable to release the IL-6R inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.

209. The device of claim 208 for use in a method of treatment of the human or animal body.

210. The IL-6R inhibitor for use, the attachable reservoir compartment for use or the composition for use according to any one of claims 199 to 207, or the device according to claim 208 or claim 209, wherein the ingestible device comprises: a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end; a reservoir located within the housing and containing the IL-6R inhibitor wherein a first end of the reservoir is connected to the first end of the housing; a mechanism for releasing the IL-6R inhibitor from the reservoir;

and

an exit value configured to allow the IL-6R inhibitor to be released out of the housing from the reservoir.

211. The IL-6R inhibitor for use, the attachable reservoir compartment for use or the composition for use according to any one of claims 199 to 207, or the device according to claim 208 or claim 209, wherein the ingestible device comprises: an ingestible housing comprising a reservoir compartment having a

therapeutically effective amount of the IL-6R inhibitor stored therein;

212. The IL-6R inhibitor for use, the attachable reservoir compartment for use, the composition for use, or the device according to claims 210 or 211, wherein the ingestible device further comprises an environmental sensor for detecting the location of the device in the gut and/or for detecting the presence of disease in the GI tract.

213. The IL-6R inhibitor for use, the attachable reservoir compartment for use, the composition for use, or the device according to claim 212, wherein the ingestible device further comprises a communication system for transmitting data from the environmental sensor to an external receiver.

214. The IL-6R inhibitor for use, the attachable reservoir compartment for use, the composition for use, or the device according to claim 212 or 213, wherein the ingestible device further comprises a processor or controller which is coupled to the environmental sensor and to the actuator and which triggers the actuator to cause the release mechanism to transition from its closed state to its open state when it is determined that the device is in the presence of diseased tissue and/or is in a location in the gut that has been predetermined to be proximal to diseased tissue.

215. The IL-6R inhibitor for use, the attachable reservoir compartment for use, the composition for use, or the device according to claim 213, wherein the communication system further comprises means for receiving a signal from an external transmitter, and wherein the actuator is adapted to be triggered in response to the signal.

216. The IL-6R inhibitor for use, the attachable reservoir compartment for use, the composition for use, or the device according to any one of claims 210 to 215, wherein the ingestible device further comprises a communication system for transmitting localization data to an external receiver.

217. The IL-6R inhibitor for use, the attachable reservoir compartment for use, the composition for use, or the device according to any one of claims 210 to 213, wherein the ingestible device further comprises a communication system for transmitting localization data to an external receiver and for receiving a signal from an external transmitter; wherein the actuator is adapted to be triggered in response to the signal.

218. The IL-6R inhibitor for use, the attachable reservoir compartment for use, the composition for use, or the device according to any one of claims 119 to 217, wherein the ingestible device further comprises a deployable anchoring system and an actuator for deploying the anchoring system, wherein the anchoring system is capable of anchoring or attaching the ingestible device to the subject's tissue.