WO2018111322A1

WO2018111322A1 - Methods and ingestible devices for the regio-specific release of integrin inhibitors at the site of gastrointestinal tract disease

Info

Publication number: WO2018111322A1
Application number: PCT/US2017/025059
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 integrin inhibitor.

Description

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

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Application Serial No. 62/434,369, 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 integrin inhibitor (e.g., an integrin ΟΑ Ί inhibitor).

Background

Integrins are proteins that function by attaching the cell cytoskeleton to the extracellular matrix (ECM). Integrins can also sense whether adhesion has occurred and transduce a signal to the interior of the cell. The integrin family of proteins consists of a variety of alpha and beta subtypes, which together form transmembrane heterodimers. One type of integrin heterodimer is the ΟΑ Ί integrin heterodimer

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 integrin inhibitor at a location in the gastrointestinal tract of the subj ect, wherein the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the integrin inhibitor.

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

delivering a integrin 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 integrin inhibitor.

releasing a integrin 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 integrin inhibitor.

releasing a integrin 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 integrin inhibitor, wherein the pharmaceutical composition is an ingestible device, and the method comprises administering orally to the subject the pharmaceutical composition.

releasing a integrin 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 integrin inhibitor, wherein the method provides a concentration of the integrin inhibitor in the plasma of the subj ect that is less than 3 μg/ml. Provided herein in one embodiment is a method of treating a disease of the large intestine in a subject, comprising:

releasing a integrin 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 integrin 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 integrin inhibitor, wherein the integrin 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 integrin inhibitor, for use in a method of treatment, wherein the method comprises orally administering the composition to the subject, wherein the integrin 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 integrin inhibitor, wherein the device is controllable to release the integrin 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 integrin inhibitor, wherein the integrin 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 integrin 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 integrin inhibitor (e.g., from a reservoir comprising the integrin 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 integrin inhibitor stored therein;

a release mechanism having a closed state which retains the integrin inhibitor in the reservoir and an open state which releases the integrin 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 integrin inhibitor wherein a first end of the reservoir is attached to the first end of the housing;

a mechanism for releasing the integrin inhibitor from the reservoir;

and

an exit valve configured to allow the integrin 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 integrin inhibitor in the reservoir and an open state which releases the integrin inhibitor from the reservoir to the exterior of the device, and the mechanism for releasing the integrin 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 predetermined 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 integrin 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 integrin inhibitor stored therein; a release mechanism having a closed state which retains the integrin inhibitor in the reservoir and an open state which releases the integrin 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:

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 integrin 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 integrin inhibitor. The signal may be sent from an extemal 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 integrin inhibitor stored therein;

a release mechanism having a closed state which retains the integrin inhibitor in the reservoir and an open state which releases the integrin 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 integrin 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 integrin inhibitor, wherein the ingestible device comprises an environmental sensor for determining the presence of diseased tissue in the GI tract, and wherein the integrin 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 integrin inhibitor, wherein the ingestible device comprises an environmental sensor for determining the presence of diseased tissue in the GI tract, and wherein the integrin 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 integrin 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 integrin inhibitor, a release mechanism for release of the integrin inhibitor (e.g., from a reservoir comprising the integrin 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 integrin 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 integrin 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 integrin inhibitor or composition for use in a method of treatment involving the device.

Brief Description of the Drawings

FIG. 1 provides an exemplary structural diagram 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 (TNF-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 TNF 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-inflammatory/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.

Integrin Inhibitors

The term "integrin inhibitor" refers to an agent which decreases the expression of one or more integrins and/or decreases the binding of an integrin ligand to one or more integrins that play a role in the recruitment, extravasation, and/or activation of a leukocyte. In some embodiments, the integrin inhibitor specifically binds to at least a portion of a ligand binding site on a target integrin. In some embodiments, the integrin inhibitor specifically binds to a target integrin at the same site as an endogenous ligand. In some embodiments, the integrin inhibitor decreases the level of expression of the target integrin in a mammalian cell. In some embodiments, the integrin inhibitor specifically binds to an integrin ligand.

Non-limiting examples of integrins that can be targeted by any of the integrin inhibitors described herein include: α2β1 integrin, αΐβΐ integrin, α4β7 integrin, integrin α4β1 (VLA-4), E-selectin, ICAM-1, α5β1 integrin, α4β1 integrin, VLA-4, α2β1 integrin, α5β3 integrin, α5β5 integrin, αΙ¾β3 integrin, and MAdCAM-1. A non-limiting example of integrin inhibitor that can decrease the expression and/or activity of α4β7 integrin is FTY720. A non-limiting example of an integrin inhibitor that specifically targets MAdCAM is PF- 547659 (Pfizer). Non-limiting examples of an integrin inhibitor that specifically targets α4β7 is AJM300 (Ajinomoto), etrolizumab (Genentech), and vedolizumab (Millenium/Takeda).

In some embodiments, the integrin inhibitor is an αΙΠ)β3 integrin inhibitor. In some embodiments, the αΙΠ)β3 integrin inhibitor is abciximab (ReoPro®, c7E3; Kononczuk et al, Curr. Drug Targets 16(13): 1429-1437, 2015; Jiang et ., ΑρρΙ. Microbiol. Biotechnol.

98(1): 105-114, 2014), eptifibatide (Integrum®; Scarborough et al, J. Biol. Chem. 268: 1066- 1073, 1993; Tcheng et al., Circulation 91 :2151-2157, 1995) or tirofiban (Aggrastat®;

Hartman et al, J. Med. Chem. 35:4640-4642, 1992; Pierro et al, Eur. J. Ophthalmol.

26(4):e74-76, 2016; Guan et al, Eur. J. Pharmacol 761 : 144-152, 2015). In some embodiments, the integrin inhibitor is an aL-selective integrin inhibitor. In some embodiments, the integrin inhibitor is a β2 integrin inhibitor.

In some embodiments, the integrin inhibitor is an a4 integrin (e.g., an α4β1 integrin (e.g., Very Late Antigen-4 (VLA-4), CD49d, or CD29)) inhibitor, an α4β7 integrin (e.g.,

Lymphocyte Peyer's Patch Adhesion Molecule (LP AM)) inhibitor. In some embodiments, the integrin inhibitor targets endothelial VCAM1, fibronectin, mucosal addressin cellular adhesion molecule-1 (MAdCAM-1), vitronectin, tenascin-C, osteopontin (OPN), nephronectin, agiostatin, tissue-type transglutaminase, factor XIII, Von Willebrand factor (VWF), an ADAM protein, an ICAM protein, collagen, e-cadherin, laminin, fibulin-5, or ΤϋΡβ. In some embodiments, the a4 integrin inhibitor is natalizumab (Tysabri®; Targan et al, Gastroenterology 132(5): 1672-1683, 2007; Sandborn et al, N. Engl. J. Med.

353(18): 1912-1925, 2005; Nakamura et al., Intern. Med. 56(2):211-214, 2017; and Singh et al., J. Pediatr. Gastroenterol. Nutr. 62(6): 863-866, 2016). In some embodiments, the integrin inhibitor is an endogenous integrin inhibitor (e.g., SHARPIN (Rantala et al., Nat. Cell. Biol. 13(11): 1315-1324, 2011).

In some embodiments, the integrin inhibitor is an av integrin (e.g., an α5β1 integrin, an α5β3 integrin, an α5β5 integrin inhibitor, and/or an α5β6 integrin) inhibitor. In some embodiments, the integrin inhibitor is an α5β1 integrin inhibitor.

In some embodiments, an integrin inhibitor is an inhibitory nucleic acid, an antibody or antigen-binding fragment thereof, a fusion protein, an integrin antagonist, a cyclic peptide, a disintegrin, a peptidomimetic, or a small molecule. In some embodiments, the inhibitory nucleic acid is a small hairpin RNA, a small interfering RNA, an antisense, an aptamer, or a microRNA. Inhibitory Nucleic Acids

As described herein, inhibitory nucleic acids specifically bind (e.g., hybridize) to a nucleic acid encoding an integrin or an integrin ligand to treat inflammatory diseases (e.g., chronic inflammation, irritable bowel syndrome (IBS), rheumatoid arthritis, ulcerative colitis, Crohn's Disease, or auto-inflammatory disease). In some embodiments, the inhibitory nucleic acid can be an antisense nucleic acid, a ribozyme, a small interfering RNA, a small hairpin RNA, or a microRNA. Examples of aspects of these different inhibitory nucleic acids are described below. Any of the examples of inhibitory nucleic acids that can decrease expression of a target integrin or a target integrin ligand (e.g., any of the exemplary target integrins or any of the exemplary integrin ligands described herein) in a mammalian cell can be synthesized in vitro.

Inhibitory nucleic acids that can decrease the expression of target integrin mRNA or a target integrin ligand mRNA (e.g., any of the exemplary integrins described herein or any of the exemplary integrin ligands described herein) in a mammalian cell include antisense nucleic acid molecules, i.e., nucleic acid molecules whose nucleotide sequence is complementary to all or part of target integrin mRNA or a target integrin ligand mRNA (e.g., complementary to all or a part of any one of SEQ ID NOs: 1-27).

Integrin a2 (ITGA) (NCBI Ref.: NM 002203.3) (SEQ ID NO: 1)

1 ttttccctgc tctcaccggg cgggggagag aagccctctg gacagcttct agagtgtgca

61 ggttctcgta tccctcggcc aagggtatcc tctgcaaacc tctgcaaacc cagcgcaact

121 acggtccccc ggtcagaccc aggatggggc cagaacggac aggggccgcg ccgctgccgc

181 tgctgctggt gttagcgctc agtcaaggca ttttaaattg ttgtttggcc tacaatgttg

241 gtctcccaga agcaaaaata ttttccggtc cttcaagtga acagtttggc tatgcagtgc

301 agcagtttat aaatccaaaa ggcaactggt tactggttgg ttcaccctgg agtggctttc

361 ctgagaaccg aatgggagat gtgtataaat gtcctgttga cctatccact gccacatgtg

421 aaaaactaaa tttgcaaact tcaacaagca ttccaaatgt tactgagatg aaaaccaaca

481 tgagcctcgg cttgatcctc accaggaaca tgggaactgg aggttttctc acatgtggtc

541 ctctgtgggc acagcaatgt gggaatcagt attacacaac gggtgtgtgt tctgacatca

601 gtcctgattt tcagctctca gccagcttct cacctgcaac tcagccctgc ccttccctca

661 tagatgttgt ggttgtgtgt gatgaatcaa atagtattta tccttgggat gcagtaaaga 721 attttttgga aaaatttgta caaggcctgg atataggccc cacaaagaca caggtggggt 781 taattcagta tgccaataat ccaagagttg tgtttaactt gaacacatat aaaaccaaag 841 aagaaatgat tgtagcaaca tcccagacat cccaatatgg tggggacctc acaaacacat 901 tcggagcaat tcaatatgca agaaaatatg cttattcagc agcttctggt gggcgacgaa 961 gtgctacgaa agtaatggta gttgtaactg acggtgaatc acatgatggt tcaatgttga

1021 aagctgtgat tgatcaatgc aaccatgaca atatactgag gtttggcata gcagttcttg 1081 ggtacttaaa cagaaacgcc cttgatacta aaaatttaat aaaagaaata aaagcaatcg 1141 ctagtattcc aacagaaaga tactttttca atgtgtctga tgaagcagct ctactagaaa 1201 aggctgggac attaggagaa caaattttca gcattgaagg tactgttcaa ggaggagaca 1261 actttcagat ggaaatgtca caagtgggat tcagtgcaga ttactcttct caaaatgata

1321 ttctgatgct gggtgcagtg ggagcttttg gctggagtgg gaccattgtc cagaagacat 1381 ctcatggcca tttgatcttt cctaaacaag cctttgacca aattctgcag gacagaaatc 1441 acagttcata tttaggttac tctgtggctg caatttctac tggagaaagc actcactttg 1501 ttgctggtgc tcctcgggca aattataccg gccagatagt gctatatagt gtgaatgaga 1561 atggcaatat cacggttatt caggctcacc gaggtgacca gattggctcc tattttggta

1621 gtgtgctgtg ttcagttgat gtggataaag acaccattac agacgtgctc ttggtaggtg 1681 caccaatgta catgagtgac ctaaagaaag aggaaggaag agtctacctg tttactatca 1741 aagagggcat tttgggtcag caccaatttc ttgaaggccc cgagggcatt gaaaacactc 1801 gatttggttc agcaattgca gctctttcag acatcaacat ggatggcttt aatgatgtga 1861 ttgttggttc accactagaa aatcagaatt ctggagctgt atacatttac aatggtcatc

1921 agggcactat ccgcacaaag tattcccaga aaatcttggg atccgatgga gcctttagga 1981 gccatctcca gtactttggg aggtccttgg atggctatgg agatttaaat ggggattcca 2041 tcaccgatgt gtctattggt gcctttggac aagtggttca actctggtca caaagtattg 2101 ctgatgtagc tatagaagct tcattcacac cagaaaaaat cactttggtc aacaagaatg 2161 ctcagataat tctcaaactc tgcttcagtg caaagttcag acctactaag caaaacaatc

2221 aagtggccat tgtatataac atcacacttg atgcagatgg attttcatcc agagtaacct 2281 ccagggggtt atttaaagaa aacaatgaaa ggtgcctgca gaagaatatg gtagtaaatc 2341 aagcacagag ttgccccgag cacatcattt atatacagga gccctctgat gttgtcaact 2401 ctttggattt gcgtgtggac atcagtctgg aaaaccctgg cactagccct gcccttgaag 2461 cctattctga gactgccaag gtcttcagta ttcctttcca caaagactgt ggtgaggacg

2521 gactttgcat ttctgatcta gtcctagatg tccgacaaat accagctgct caagaacaac 2581 cctttattgt cagcaaccaa aacaaaaggt taacattttc agtaacgctg aaaaataaaa 2641 gggaaagtgc atacaacact ggaattgttg ttgatttttc agaaaacttg ttttttgcat 2701 cattctccct gccggttgat gggacagaag taacatgcca ggtggctgca tctcagaagt 2761 ctgttgcctg cgatgtaggc taccctgctt taaagagaga acaacaggtg acttttacta

2821 ttaactttga cttcaatctt caaaaccttc agaatcaggc gtctctcagt ttccaagcct 2881 taagtgaaag ccaagaagaa aacaaggctg ataatttggt caacctcaaa attcctctcc 2941 tgtatgatgc tgaaattcac ttaacaagat ctaccaacat aaatttttat gaaatctctt 3001 cggatgggaa tgttccttca atcgtgcaca gttttgaaga tgttggtcca aaattcatct 3061 tctccctgaa ggtaacaaca ggaagtgttc cagtaagcat ggcaactgta atcatccaca

3121 tccctcagta taccaaagaa aagaacccac tgatgtacct aactggggtg caaacagaca 3181 aggctggtga catcagttgt aatgcagata tcaatccact gaaaatagga caaacatctt 3241 cttctgtatc tttcaaaagt gaaaatttca ggcacaccaa agaattgaac tgcagaactg 3301 cttcctgtag taatgttacc tgctggttga aagacgttca catgaaagga gaatactttg 3361 ttaatgtgac taccagaatt tggaacggga ctttcgcatc atcaacgttc cagacagtac 3421 agctaacggc agctgcagaa atcaacacct ataaccctga gatatatgtg attgaagata 3481 acactgttac gattcccctg atgataatga aacctgatga gaaagccgaa gtaccaacag 3541 gagttataat aggaagtata attgctggaa tccttttgct gttagctctg gttgcaattt 3601 tatggaagct cggcttcttc aaaagaaaat atgaaaagat gaccaaaaat ccagatgaga 3661 ttgatgagac cacagagctc agtagctgaa ccagcagacc tacctgcagt gggaaccggc 3721 agcatcccag ccagggtttg ctgtttgcgt gaatggattt ctttttaaat cccatatttt 3781 ttttatcatg tcgtaggtaa actaacctgg tattttaaga gaaaactgca ggtcagtttg 3841 gaatgaagaa attgtggggg gtgggggagg tgcggggggc aggtagggaa ataataggga 3901 aaatacctat tttatatgat gggggaaaaa aagtaatctt taaactggct ggcccagagt 3961 ttacattcta atttgcattg tgtcagaaac atgaaatgct tccaagcatg acaactttta 4021 aagaaaaata tgatactctc agattttaag ggggaaaact gttctcttta aaatatttgt 4081 ctttaaacag caactacaga agtggaagtg cttgatatgt aagtacttcc acttgtgtat 4141 attttaatga atattgatgt taacaagagg ggaaaacaaa acacaggttt tttcaattta 4201 tgctgctcat ccaaagttgc cacagatgat acttccaagt gataatttta tttataaact 4261 aggtaaaatt tgttgttggt tccttttaga ccacggctgc cccttccaca ccccatcttg 4321 ctctaatgat caaaacatgc ttgaataact gagcttagag tatacctcct atatgtccat 4381 ttaagttagg agagggggcg atatagagaa taaggcacaa aattttgttt aaaactcaga 4441 atataacatg taaaatccca tctgctagaa gcccatcctg tgccagagga aggaaaagga 4501 ggaaatttcc tttctctttt aggaggcaca acagttctct tctaggattt gtttggctga 4561 ctggcagtaa cctagtgaat ttctgaaaga tgagtaattt ctttggcaac cttcctcctc 4621 ccttactgaa ccactctccc acctcctggt ggtaccatta ttatagaagc cctctacagc 4681 ctgactttct ctccagcggt ccaaagttat cccctccttt acccctcatc caaagttccc 4741 actccttcag gacagctgct gtgcattaga tattaggggg gaaagtcatc tgtttaattt 4801 acacacttgc atgaattact gtatataaac tccttaactt cagggagcta ttttcattta 4861 gtgctaaaca agtaagaaaa ataagctcga gtgaatttct aaatgttgga atgttatggg 4921 atgtaaacaa tgtaaagtaa gacatctcag gatttcacca gaagttacag atgaggcact 4981 ggaagccacc aaattagcag gtgcaccttc tgtggctgtc ttgtttctga agtacttaaa 5041 cttccacaag agtgaatttg acctaggcaa gtttgttcaa aaggtagatc ctgagatgat 5101 ttggtcagat tgggataagg cccagcaatc tgcattttaa caagcacccc agtcactagg 5161 atgcagatgg accacacttt gagaaacacc acccatttct actttttgca ccttattttc 5221 tctgttcctg agcccccaca ttctctagga gaaacttaga ggaaaagggc acagacacta 5281 catatctaaa gctttggaca agtccttgac ctctataaac ttcagagtcc tcattataaa 5341 atgggaagac tgagctggag ttcagcagtg atgcttttag ttttaaaagt ctatgatctg 5401 gacttcctat aatacaaata cacaatcctc caagaatttg acttggaaaa aaatgtcaaa 5461 ggaaaacagg ttatctgccc atgtgcatat ggacaacctt gactaccctg gcctggcccg 5521 tggtggcagt ccagggctat ctgtactgtt tacagaatta ctttgtagtt gacaacacaa 5581 aacaaacaaa aaaggcataa aatgccagcg gtttatagaa aaaacagcat ggtattctcc 5641 agttaggtat gccagagtcc aattctttta acagctgtga gaatttgctg cttcattcca 5701 acaaaatttt atttaaaaaa aaaaaaaaaa gactggagaa actagtcatt agcttgataa 5761 agaatattta acagctagtg gtgctggtgt gtacctgaag ctccagctac ttgagagact 5821 gagacaggaa gatcgcttga gcccaggagt tcaagtccag cctaagcaac atagcaagac 5881 cctgtctcaa aaaaatgact atttaaaaag acaatgtggc caggcacggt ggctcacacc 5941 tgtaatccca acactttggg aggctgaggc cggtggatca cgaggtcagg agtttgagac 6001 tagcctggcc aacatggtga aaccccatct ctaataatat aaaaattagc tgggcgtagt 6061 agcaggtgcc tgtaatccca gttactcggg aagctgaggc aggagaatca cttgaacccg 6121 ggaggcagag gtttcagtga gccgagatcg cgccactgca ctccagcctg ggtgacaggg 6181 caagactctg tctcaaacaa acaaacaaaa aaaaagttag tactgtatat gtaaatacta 6241 gcttttcaat gtgctataca aacaattata gcacatcctt ccttttactc tgtctcacct 6301 cctttaggtg agtacttcct taaataagtg ctaaacatac atatacggaa cttgaaagct 6361 ttggttagcc ttgccttagg taatcagcct agtttacact gtttccaggg agtagttgaa 6421 ttactataaa ccattagcca cttgtctctg caccatttat cacaccagga cagggtctct 6481 caacctgggc gctactgtca tttggggcca ggtgattctt ccttgcaggg gctgtcctgt 6541 accttgtagg acagcagccc tgtcctagaa ggtatgttta gcagcattcc tggcctctag 6601 ctacccgatg ccagagcatg ctccccccgc agtcatgaca atcaaaaaat gtctccagac 6661 attgtcaaat gcctcctggg gggcagtatt tctcaagcac ttttaagcaa aggtaagtat 6721 tcatacaaga aatttagggg gaaaaaacat tgtttaaata aaagctatgt gttcctattc 6781 aacaatattt ttgctttaaa agtaagtaga gggcataaaa gatgtcatat tcaaatttcc 6841 atttcataaa tggtgtacag acaaggtcta tagaatgtgg taaaaacttg actgcaacac 6901 aaggcttata aaatagtaag atagtaaaat agcttatgaa gaaactacag agatttaaaa 6961 ttgtgcatga ctcatttcag cagcaaaata agaactccta actgaacaga aatttttcta 7021 cctagcaatg ttattcttgt aaaatagtta cctattaaaa ctgtgaagag taaaactaaa 7081 gccaatttat tatagtcaca caagtgatta tactaaaaat tattataaag gttataattt 7141 tataatgtat ttacctgtcc tgatatatag ctataaccca atatatgaaa atctcaaaaa 7201 ttaagacatc atcatacaga aggcaggatt ccttaaactg agatccctga tccatcttta 7261 atatttcaat ttgcacacat aaaacaatgc ccttttgtgt acattcaggc atacccattt 7321 taatcaattt gaaaggttaa tttaaacctc tagaggtgaa tgagaaacat gggggaaaag 7381 tatgaaatag gtgaaaatct taactatttc tttgaactct aaagactgaa actgtagcca 7441 ttatgtaaat aaagtttcat atgtacctgt ttattttggc agattaagtc aaaatatgaa 7501 tgtatatatt gcataactat gttagaattg tatatatttt aaagaaattg tcttggatat

7561 tttcctttat acataataga taagtctttt ttcaaatgtg gtgtttgatg tttttgatta

7621 aatgtgtttt gcctctttcc acaaaaactg taaaaataaa tgcatgtttg tacaaaaagt 7681 tgcagaattc atttgattta tgagaaacaa aaattaaatt gtagtcaaca gttagtagtt 7741 tttctcatat ccaagtataa caaacagaaa agtttcatta ttgtaaccca cttttttcat 7801 accacattat tgaatattgt tacaattgtt ttgaaaataa agccattttc tttgggcttt

7861 tataagttaa aaaaaaaa

Integrin allb (a2b) (NCBI Ref.: NM 000419.4; SEQ ID NO: 2)

1 gctctgcccg ttgctcagca agttacttgg ggttccagtt tgataagaaa agacttcctg

61 tggaggaatc tgaagggaag gaggaggagc tggcccattc ctgcctggga ggttgtggaa 121 gaaggaagat ggccagagct ttgtgtccac tgcaagccct ctggcttctg gagtgggtgc 181 tgctgctctt gggaccttgt gctgcccctc cagcctgggc cttgaacctg gacccagtgc 241 agctcacctt ctatgcaggc cccaatggca gccagtttgg attttcactg gacttccaca 301 aggacagcca tgggagagtg gccatcgtgg tgggcgcccc gcggaccctg ggccccagcc

361 aggaggagac gggcggcgtg ttcctgtgcc cctggagggc cgagggcggc cagtgcccct 421 cgctgctctt tgacctccgt gatgagaccc gaaatgtagg ctcccaaact ttacaaacct 481 tcaaggcccg ccaaggactg ggggcgtcgg tcgtcagctg gagcgacgtc attgtggcct 541 gcgccccctg gcagcactgg aacgtcctag aaaagactga ggaggctgag aagacgcccg 601 taggtagctg ctttttggct cagccagaga gcggccgccg cgccgagtac tccccctgtc 661 gcgggaacac cctgagccgc atttacgtgg aaaatgattt tagctgggac aagcgttact 721 gtgaagcggg cttcagctcc gtggtcactc aggccggaga gctggtgctt ggggctcctg 781 gcggctatta tttcttaggt ctcctggccc aggctccagt tgcggatatt ttctcgagtt

841 accgcccagg catccttttg tggcacgtgt cctcccagag cctctccttt gactccagca 901 acccagagta cttcgacggc tactgggggt actcggtggc cgtgggcgag ttcgacgggg 961 atctcaacac tacagaatat gtcgtcggtg cccccacttg gagctggacc ctgggagcgg 1021 tggaaatttt ggattcctac taccagaggc tgcatcggct gcgcggagag cagatggcgt 1081 cgtattttgg gcattcagtg gctgtcactg acgtcaacgg ggatgggagg catgatctgc

1141 tggtgggcgc tccactgtat atggagagcc gggcagaccg aaaactggcc gaagtggggc 1201 gtgtgtattt gttcctgcag ccgcgaggcc cccacgcgct gggtgccccc agcctcctgc 1261 tgactggcac acagctctat gggcgattcg gctctgccat cgcacccctg ggcgacctcg 1321 accgggatgg ctacaatgac attgcagtgg ctgcccccta cgggggtccc agtggccggg 1381 gccaagtgct ggtgttcctg ggtcagagtg aggggctgag gtcacgtccc tcccaggtcc

1441 tggacagccc cttccccaca ggctctgcct ttggcttctc ccttcgaggt gccgtagaca 1501 tcgatgacaa cggataccca gacctgatcg tgggagctta cggggccaac caggtggctg 1561 tgtacagagc tcagccagtg gtgaaggcct ctgtccagct actggtgcaa gattcactga 1621 atcctgctgt gaagagctgt gtcctacctc agaccaagac acccgtgagc tgcttcaaca 1681 tccagatgtg tgttggagcc actgggcaca acattcctca gaagctatcc ctaaatgccg

1741 agctgcagct ggaccggcag aagccccgcc agggccggcg ggtgctgctg ctgggctctc 1801 aacaggcagg caccaccctg aacctggatc tgggcggaaa gcacagcccc atctgccaca 1861 ccaccatggc cttccttcga gatgaggcag acttccggga caagctgagc cccattgtgc 1921 tcagcctcaa tgtgtcccta ccgcccacgg aggctggaat ggcccctgct gtcgtgctgc 1981 atggagacac ccatgtgcag gagcagacac gaatcgtcct ggactgtggg gaagatgacg

2041 tatgtgtgcc ccagcttcag ctcactgcca gcgtgacggg ctccccgctc ctagttgggg 2101 cagataatgt cctggagctg cagatggacg cagccaacga gggcgagggg gcctatgaag 2161 cagagctggc cgtgcacctg ccccagggcg cccactacat gcgggcccta agcaatgtcg 2221 agggctttga gagactcatc tgtaatcaga agaaggagaa tgagaccagg gtggtgctgt 2281 gtgagctggg caaccccatg aagaagaacg cccagatagg aatcgcgatg ttggtgagcg

2341 tggggaatct ggaagaggct ggggagtctg tgtccttcca gctgcagata cggagcaaga 2401 acagccagaa tccaaacagc aagattgtgc tgctggacgt gccggtccgg gcagaggccc 2461 aagtggagct gcgagggaac tcctttccag cctccctggt ggtggcagca gaagaaggtg 2521 agagggagca gaacagcttg gacagctggg gacccaaagt ggagcacacc tatgagctcc 2581 acaacaatgg ccctgggact gtgaatggtc ttcacctcag catccacctt ccgggacagt

2641 cccagccctc cgacctgctc tacatcctgg atatacagcc ccaggggggc cttcagtgct 2701 tcccacagcc tcctgtcaac cctctcaagg tggactgggg gctgcccatc cccagcccct 2761 cccccattca cccggcccat cacaagcggg atcgcagaca gatcttcctg ccagagcccg 2821 agcagccctc gaggcttcag gatccagttc tcgtaagctg cgactcggcg ccctgtactg 2881 tggtgcagtg tgacctgcag gagatggcgc gcgggcagcg ggccatggtc acggtgctgg

2941 ccttcctgtg gctgcccagc ctctaccaga ggcctctgga tcagtttgtg ctgcagtcgc 3001 acgcatggtt caacgtgtcc tccctcccct atgcggtgcc cccgctcagc ctgccccgag 3061 gggaagctca ggtgtggaca cagctgctcc gggccttgga ggagagggcc attccaatct 3121 ggtgggtgct ggtgggtgtg ctgggtggcc tgctgctgct caccatcctg gtcctggcca 3181 tgtggaaggt cggcttcttc aagcggaacc ggccacccct ggaagaagat gatgaagagg 3241 gggagtgatg gtgcagccta cactattcta gcaggagggt tgggcgtgct acctgcaccg 3301 ccccttctcc aacaagttgc ctccaagctt tgggttggag ctgttccatt gggtcctctt 3361 ggtgtcgttt ccctcccaac agagctgggc taccccccct cctgctgcct aataaagaga 3421 ctgagccctg aaaaaaaaaa aaaaaaaaa

Integrin a4 (VLA-4) (NCBI Ref.: NM 000885.5; SEQ ID NO: 3)

1 ataacgtctt tgtcactaaa atgttcccca ggggccttcg gcgagtcttt ttgtttggtt

61 ttttgttttt aatctgtggc tcttgataat ttatctagtg gttgcctaca cctg aaaaac

121 aagacacagt gtttaactat caacgaaaga actggacggc tccccgccgc agtcccactc

181 cccgagtttg tggctggcat ttgggccacg ccgggctggg cggtcacagc gaggggcgcg 241 cagtttgggg tcacacagct ccgcttctag gccccaacca ccgttaaaag gggaagcccg 301 tgccccatca ggtccgctct tgctgagccc agagccatcc cgcgctctgc gggctgggag 361 gcccgggcca ggacgcgagt cctgcgcagc cgaggttccc cagcgccccc tgcagccgcg 421 cgtaggcaga gacggagccc ggccctgcgc ctccgcacca cgcccgggac cccacccagc

481 ggcccgtacc cggagaagca gcgcgagcac ccgaagctcc cggctggcgg cagaaaccgg 541 gagtggggcc gggcgagtgc gcggcatccc aggccggccc gaacgctccg cccgcggtgg 601 gccgacttcc cctcctcttc cctctctcct tcctttagcc cgctggcgcc ggacacgctg 661 cgcctcatct cttggggcgt tcttccccgt tggccaaccg tcgcatcccg tgcaactttg 721 gggtagtggc cgtttagtgt tgaatgttcc ccaccgagag cgcatggctt gggaagcgag

781 gcgcgaaccc ggcccccgaa gggccgccgt ccgggagacg gtgatgctgt tgctgtgcct 841 gggggtcccg accggccgcc cctacaacgt ggacactgag agcgcgctgc tttaccaggg 901 cccccacaac acgctgttcg gctactcggt cgtgctgcac agccacgggg cgaaccgatg 961 gctcctagtg ggtgcgccca ctgccaactg gctcgccaac gcttcagtga tcaatcccgg 1021 ggcgatttac agatgcagga tcggaaagaa tcccggccag acgtgcgaac agctccagct

1081 gggtagccct aatggagaac cttgtggaaa gacttgtttg gaagagagag acaatcagtg 1141 gttgggggtc acactttcca gacagccagg agaaaatgga tccatcgtga cttgtgggca 1201 tagatggaaa aatatatttt acataaagaa tgaaaataag ctccccactg gtggttgcta 1261 tggagtgccc cctgatttac gaacagaact gagtaaaaga atagctccgt gttatcaaga 1321 ttatgtgaaa aaatttggag aaaattttgc atcatgtcaa gctggaatat ccagttttta

1381 cacaaaggat ttaattgtga tgggggcccc aggatcatct tactggactg gctctctttt 1441 tgtctacaat ataactacaa ataaatacaa ggctttttta gacaaacaaa atcaagtaaa 1501 atttggaagt tatttaggat attcagtcgg agctggtcat tttcggagcc agcatactac 1561 cgaagtagtc ggaggagctc ctcaacatga gcagattggt aaggcatata tattcagcat 1621 tgatgaaaaa gaactaaata tcttacatga aatgaaaggt aaaaagcttg gatcgtactt

1681 tggagcttct gtctgtgctg tggacctcaa tgcagatggc ttctcagatc tgctcgtggg 1741 agcacccatg cagagcacca tcagagagga aggaagagtg tttgtgtaca tcaactctgg 1801 ctcgggagca gtaatgaatg caatggaaac aaacctcgtt ggaagtgaca aatatgctgc 1861 aagatttggg gaatctatag ttaatcttgg cgacattgac aatgatggct ttgaagatgt 1921 tgctatcgga gctccacaag aagatgactt gcaaggtgct atttatattt acaatggccg

1981 tgcagatggg atctcgtcaa ccttctcaca gagaattgaa ggacttcaga tcagcaaatc 2041 gttaagtatg tttggacagt ctatatcagg acaaattgat gcagataata atggctatgt 2101 agatgtagca gttggtgctt ttcggtctga ttctgctgtc ttgctaagga caagacctgt 2161 agtaattgtt gacgcttctt taagccaccc tgagtcagta aatagaacga aatttgactg 2221 tgttgaaaat ggatggcctt ctgtgtgcat agatctaaca ctttgtttct catataaggg 2281 caaggaagtt ccaggttaca ttgttttgtt ttataacatg agtttggatg tgaacagaaa 2341 ggcagagtct ccaccaagat tctatttctc ttctaatgga acttctgacg tgattacagg 2401 aagcatacag gtgtccagca gagaagctaa ctgtagaaca catcaagcat ttatgcggaa 2461 agatgtgcgg gacatcctca ccccaattca gattgaagct gcttaccacc ttggtcctca 2521 tgtcatcagt aaacgaagta cagaggaatt cccaccactt cagccaattc ttcagcagaa 2581 gaaagaaaaa gacataatga aaaaaacaat aaactttgca aggttttgtg cccatgaaaa 2641 ttgttctgct gatttacagg tttctgcaaa gattgggttt ttgaagcccc atgaaaataa 2701 aacatatctt gctgttggga gtatgaagac attgatgttg aatgtgtcct tgtttaatgc 2761 tggagatgat gcatatgaaa cgactctaca tgtcaaacta cccgtgggtc tttatttcat 2821 taagatttta gagctggaag agaagcaaat aaactgtgaa gtcacagata actctggcgt 2881 ggtacaactt gactgcagta ttggctatat atatgtagat catctctcaa ggatagatat 2941 tagctttctc ctggatgtga gctcactcag cagagcggaa gaggacctca gtatcacagt 3001 gcatgctacc tgtgaaaatg aagaggaaat ggacaatcta aagcacagca gagtgactgt 3061 agcaatacct ttaaaatatg aggttaagct gactgttcat gggtttgtaa acccaacttc 3121 atttgtgtat ggatcaaatg atgaaaatga gcctgaaacg tgcatggtgg agaaaatgaa 3181 cttaactttc catgttatca acactggcaa tagtatggct cccaatgtta gtgtggaaat 3241 aatggtacca aattctttta gcccccaaac tgataagctg ttcaacattt tggatgtcca 3301 gactactact ggagaatgcc actttgaaaa ttatcaaaga gtgtgtgcat tagagcagca 3361 aaagagtgca atgcagacct tgaaaggcat agtccggttc ttgtccaaga ctgataagag 3421 gctattgtac tgcataaaag ctgatccaca ttgtttaaat ttcttgtgta attttgggaa 3481 aatggaaagt ggaaaagaag ccagtgttca tatccaactg gaaggccggc catccatttt 3541 agaaatggat gagacttcag cactcaagtt tgaaataaga gcaacaggtt ttccagagcc 3601 aaatccaaga gtaattgaac taaacaagga tgagaatgtt gcgcatgttc tactggaagg 3661 actacatcat caaagaccca aacgttattt caccatagtg attatttcaa gtagcttgct 3721 acttggactt attgtacttc tgttgatctc atatgttatg tggaaggctg gcttctttaa 3781 aagacaatac aaatctatcc tacaagaaga aaacagaaga gacagttgga gttatatcaa 3841 cagtaaaagc aatgatgatt aaggacttct ttcaaattga gagaatggaa aacagactca 3901 ggttgtagta aagaaattta aaagacactg tttacaagaa aaaatgaatt ttgtttggac 3961 ttcttttact catgatcttg tgacatatta tgtcttcatg caaggggaaa atctcagcaa 4021 tgattactct ttgagataga agaactgcaa aggtaataat acagccaaag ataatctctc 4081 agcttttaaa tgggtagaga aacactaaag cattcaattt attcaagaaa agtaagccct 4141 tgaagatatc ttgaaatgaa agtataactg agttaaatta tactggagaa gtcttagact 4201 tgaaatacta cttaccatat gtgcttgcct cagtaaaatg aaccccactg ggtgggcaga 4261 ggttcatttc aaatacatct ttgatacttg ttcaaaatat gttctttaaa aatataattt 4321 tttagagagc tgttcccaaa ttttctaacg agtggaccat tatcacttta aagcccttta 4381 tttataatac atttcctacg ggctgtgttc caacaaccat tttttttcag cagactatga 4441 atattatagt attataggcc aaactggcaa acttcagact gaacatgtac actggtttga 4501 gcttagtgaa attacttctg gataattatt tttttataat tatggatttc accatctttc 4561 tttctgtata tatacatgtg tttttatgta ggtatatatt taccattctt cctatctatt

4621 cttcctataa cacaccttta tcaagcatac ccaggagtaa tcttcaaatc ttttgttata 4681 ttctgaaaca aaagattgtg agtgttgcac tttacctgat acacgctgat ttagaaaata 4741 cagaaaccat acctcactaa taactttaaa atcaaagctg tgcaaagact agggggccta 4801 tacttcatat gtattatgta ctatgtaaaa tattgactat cacacaacta tttccttgga 4861 tgtaattctt tgttaccctt tacaagtata agtgttacct tacatggaaa cgaagaaaca 4921 aaattcataa atttaaattc ataaatttag ctgaaagata ctgattcaat ttgtatacag 4981 tgaatataaa tgagacgaca gcaaaatttt catgaaatgt aaaatatttt tatagtttgt 5041 tcatactata tgaggttcta ttttaaatga ctttctggat tttaaaaaat ttctttaaat 5101 acaatcattt ttgtaatatt tattttatgc ttatgatcta gataattgca gaatatcatt 5161 ttatctgact ctgccttcat aagagagctg tggccgaatt ttgaacatct gttataggga 5221 gtgatcaaat tagaaggcaa tgtggaaaaa caattctggg aaagatttct ttatatgaag 5281 tccctgccac tagccagcca tcctaattga tgaaagttat ctgttcacag gcctgcagtg 5341 atggtgagga atgttctgag atttgcgaag gcatttgagt agtgaaatgt aagcacaaaa 5401 cctcctgaac ccagagtgtg tatacacagg aataaacttt atgacattta tgtattttta 5461 aaaaactttg tatcgttata aaaaggctag tcattctttc aggagaacat ctaggatcat 5521 agatgaaaaa tcaagccccg atttagaact gtcttctcca ggatggtctc taaggaaatt 5581 tacatttggt tctttcctac tcagaactac tcagaaacaa ctatatattt caggttatct 5641 gagcacagtg aaagcagagt actatggttg tccaacacag gcctctcaga tacaagggga 5701 acacaattac atattgggct agattttgcc cagttcaaaa tagtatttgt tatcaactta 5761 ctttgttact tgtatcatga attttaaaac cctaccactt taagaagaca gggatgggtt 5821 attctttttt ggcaggtagg ctatataact atgtgatttt gaaatttaac tgctctggat 5881 tagggagcag tgaatcaagg cagacttatg aaatctgtat tatatttgta acagaatata 5941 ggaaatttaa cataattgat gagctcaaat cctgaaaaat gaaagaatcc aaattatttc 6001 agaattatct aggttaaata ttgatgtatt atgatggttg caaagttttt ttgtgtgtcc 6061 aataaacaca ttgtaaaaaa aagaatttga attgatatct aaaaacagaa tttgaattga 6121 tatttcatct tgacttttaa agccctagag gctaattgtt agtaacatca atttctatta 6181 ggatatccgt ttggccacac agcaggaggt tagagcaatg gagcattact gagttcctcc 6241 ccctgtcaga tcagcagcag cattagattc tcatagaagt gcgaaccata tggtgaactg 6301 gtatgtgagg gatctagagt gccatgttcc tcaagagaat ctaatgcctg atgatctgag 6361 gtggaacagt tcatcctgaa accattcccc catccacgga aaaattgtct tccatgaaac 6421 tggtcccaaa aagggtgggg accacaggtt taaagcatgg ccacatttct ttatattaaa 6481 attctagttt gtacatttct tttagaaaca attacatgtt actttggaat catttcttcc 6541 atgcttcctc cataaagact gataagtctt ggatgcaatc tgtaaagaaa atacattatt 6601 tcatcaactt attttgttgt ttttcacata cacctaataa gtatggtaca caatgccaat 6661 gccaaataca aattgataac aaacacagca ttcccaacag agctgtaatc tagaaaactg 6721 agaaggtctg attgataaat catcaacaac aataattgct ctaaaacctc cttaactgac 6781 ttccttgatt gtccaatgct ctccattacc tctgtaaaac agtcagttat gcctctagaa 6841 cacccatgtc tagtgggcac ccctgcatgc ttcttctaac cactgagtgt cacaatgcct 6901 accaagaatg cgtttgcagg ttcctaaacc tgtttatacc agttgctatg taaaattgtt 6961 cccaagggaa gttgaatgct ctgtaaaggc ctaataaaag caaattactg aacaaaacat 7021 gttacagtaa ttatgagtga gaggaaacta agatggaagg ataaaaatct aacactttac 7081 tattcagatg gctccactaa aagatttaag atcttgatcc atttttaaaa atccaaaatg 7141 gaagttgtag acattatctg tagtttatgc acaacaataa attagaaagc caatgtagac 7201 acgcataacc aaagaaaatg ccttgggtct acataacagt tgaataaatg taaagttgct 7261 tttaaaaaaa aaaaaaaaaa a

Integrin a5 (NCBI Ref.: NM 002205.4; SEQ ID NO: 4) 1 attcgcctct gggaggttta ggaagcggct ccgggtcggt ggccccagga cagggaagag 61 cgggcgctat ggggagccgg acgccagagt cccctctcca cgccgtgcag ctgcgctggg 121 gcccccggcg ccgacccccg ctgctgccgc tgctgttgct gctgctgccg ccgccaccca 181 gggtcggggg cttcaactta gacgcggagg ccccagcagt actctcgggg cccccgggct 241 ccttcttcgg attctcagtg gagttttacc ggccgggaac agacggggtc agtgtgctgg

301 tgggagcacc caaggctaat accagccagc caggagtgct gcagggtggt gctgtctacc 361 tctgtccttg gggtgccagc cccacacagt gcacccccat tgaatttgac agcaaaggct 421 ctcggctcct ggagtcctca ctgtccagct cagagggaga ggagcctgtg gagtacaagt 481 ccttgcagtg gttcggggca acagttcgag cccatggctc ctccatcttg gcatgcgctc 541 cactgtacag ctggcgcaca gagaaggagc cactgagcga ccccgtgggc acctgctacc

601 tctccacaga taacttcacc cgaattctgg agtatgcacc ctgccgctca gatttcagct 661 gggcagcagg acagggttac tgccaaggag gcttcagtgc cgagttcacc aagactggcc 721 gtgtggtttt aggtggacca ggaagctatt tctggcaagg ccagatcctg tctgccactc 781 aggagcagat tgcagaatct tattaccccg agtacctgat caacctggtt caggggcagc 841 tgcagactcg ccaggccagt tccatctatg atgacagcta cctaggatac tctgtggctg

901 ttggtgaatt cagtggtgat gacacagaag actttgttgc tggtgtgccc aaagggaacc 961 tcacttacgg ctatgtcacc atccttaatg gctcagacat tcgatccctc tacaacttct 1021 caggggaaca gatggcctcc tactttggct atgcagtggc cgccacagac gtcaatgggg 1081 acgggctgga tgacttgctg gtgggggcac ccctgctcat ggatcggacc cctgacgggc 1141 ggcctcagga ggtgggcagg gtctacgtct acctgcagca cccagccggc atagagccca

1201 cgcccaccct taccctcact ggccatgatg agtttggccg atttggcagc tccttgaccc 1261 ccctggggga cctggaccag gatggctaca atgatgtggc catcggggct ccctttggtg 1321 gggagaccca gcagggagta gtgtttgtat ttcctggggg cccaggaggg ctgggctcta 1381 agccttccca ggttctgcag cccctgtggg cagccagcca caccccagac ttctttggct 1441 ctgcccttcg aggaggccga gacctggatg gcaatggata tcctgatctg attgtggggt

1501 cctttggtgt ggacaaggct gtggtataca ggggccgccc catcgtgtcc gctagtgcct 1561 ccctcaccat cttccccgcc atgttcaacc cagaggagcg gagctgcagc ttagagggga 1621 accctgtggc ctgcatcaac cttagcttct gcctcaatgc ttctggaaaa cacgttgctg 1681 actccattgg tttcacagtg gaacttcagc tggactggca gaagcagaag ggaggggtac 1741 ggcgggcact gttcctggcc tccaggcagg caaccctgac ccagaccctg ctcatccaga

1801 atggggctcg agaggattgc agagagatga agatctacct caggaacgag tcagaatttc 1861 gagacaaact ctcgccgatt cacatcgctc tcaacttctc cttggacccc caagccccag 1921 tggacagcca cggcctcagg ccagccctac attatcagag caagagccgg atagaggaca 1981 aggctcagat cttgctggac tgtggagaag acaacatctg tgtgcctgac ctgcagctgg 2041 aagtgtttgg ggagcagaac catgtgtacc tgggtgacaa gaatgccctg aacctcactt

2101 tccatgccca gaatgtgggt gagggtggcg cctatgaggc tgagcttcgg gtcaccgccc 2161 ctccagaggc tgagtactca ggactcgtca gacacccagg gaacttctcc agcctgagct 2221 gtgactactt tgccgtgaac cagagccgcc tgctggtgtg tgacctgggc aaccccatga 2281 aggcaggagc cagtctgtgg ggtggccttc ggtttacagt ccctcatctc cgggacacta 2341 agaaaaccat ccagtttgac ttccagatcc tcagcaagaa tctcaacaac tcgcaaagcg

2401 acgtggtttc ctttcggctc tccgtggagg ctcaggccca ggtcaccctg aacggtgtct 2461 ccaagcctga ggcagtgcta ttcccagtaa gcgactggca tccccgagac cagcctcaga 2521 aggaggagga cctgggacct gctgtccacc atgtctatga gctcatcaac caaggcccca 2581 gctccattag ccagggtgtg ctggaactca gctgtcccca ggctctggaa ggtcagcagc 2641 tcctatatgt gaccagagtt acgggactca actgcaccac caatcacccc attaacccaa 2701 agggcctgga gttggatccc gagggttccc tgcaccacca gcaaaaacgg gaagctccaa 2761 gccgcagctc tgcttcctcg ggacctcaga tcctgaaatg cccggaggct gagtgtttca 2821 ggctgcgctg tgagctcggg cccctgcacc aacaagagag ccaaagtctg cagttgcatt 2881 tccgagtctg ggccaagact ttcttgcagc gggagcacca gccatttagc ctgcagtgtg

2941 aggctgtgta caaagccctg aagatgccct accgaatcct gcctcggcag ctgccccaaa 3001 aagagcgtca ggtggccaca gctgtgcaat ggaccaaggc agaaggcagc tatggcgtcc 3061 cactgtggat catcatccta gccatcctgt ttggcctcct gctcctaggt ctactcatct 3121 acatcctcta caagcttgga ttcttcaaac gctccctccc atatggcacc gccatggaaa 3181 aagctcagct caagcctcca gccacctctg atgcctgagt cctcccaatt tcagactccc

3241 attcctgaag aaccagtccc cccaccctca ttctactgaa aaggaggggt ctgggtactt 3301 cttgaaggtg ctgacggcca gggagaagct cctctcccca gcccagagac atacttgaag 3361 ggccagagcc aggggggtga ggagctgggg atccctcccc cccatgcact gtgaaggacc 3421 cttgtttaca cataccctct tcatggatgg gggaactcag atccagggac agaggcccca 3481 gcctccctga agcctttgca ttttggagag tttcctgaaa caacttggaa agataactag

3541 gaaatccatt cacagttctt tgggccagac atgccacaag gacttcctgt ccagctccaa 3601 cctgcaaaga tctgtcctca gccttgccag agatccaaaa gaagccccca gctaagaacc 3661 tggaacttgg ggagttaaga cctggcagct ctggacagcc ccaccctggt gggccaacaa 3721 agaacactaa ctatgcatgg tgccccagga ccagctcagg acagatgcca cacaaggata 3781 gatgctggcc cagggcccag agcccagctc caaggggaat cagaactcaa atggggccag

3841 atccagcctg gggtctggag ttgatctgga acccagactc agacattggc acctaatcca 3901 ggcagatcca ggactatatt tgggcctgct ccagacctga tcctggaggc ccagttcacc 3961 ctgatttagg agaagccagg aatttcccag gaccctgaag gggccatgat ggcaacagat 4021 ctggaacctc agcctggcca gacacaggcc ctccctgttc cccagagaaa ggggagccca 4081 ctgtcctggg cctgcagaat ttgggttctg cctgccagct gcactgatgc tgcccctcat

4141 ctctctgccc aacccttccc tcaccttggc accagacacc caggacttat ttaaactctg 4201 ttgcaagtgc aataaatctg acccagtgcc cccactgacc agaactagaa aaaaaaaaaa 4261 aaaaaaa Integrin βΐ (NCBI Ref.: NM 002211.3; SEQ ID NO: 5)

1 atcagacgcg cagaggaggc ggggccgcgg ctggtttcct gccggggggc ggctctgggc 61 cgccgagtcc cctcctcccg cccctgagga ggaggagccg ccgccacccg ccgcgcccga 121 cacccgggag gccccgccag cccgcgggag aggcccagcg ggagtcgcgg aacagcaggc 181 ccgagcccac cgcgccgggc cccggacgcc gcgcggaaaa gatgaattta caaccaattt 241 tctggattgg actgatcagt tcagtttgct gtgtgtttgc tcaaacagat gaaaatagat

301 gtttaaaagc aaatgccaaa tcatgtggag aatgtataca agcagggcca aattgtgggt 361 ggtgcacaaa ttcaacattt ttacaggaag gaatgcctac ttctgcacga tgtgatgatt 421 tagaagcctt aaaaaagaag ggttgccctc cagatgacat agaaaatccc agaggctcca 481 aagatataaa gaaaaataaa aatgtaacca accgtagcaa aggaacagca gagaagctca 541 agccagagga tattactcag atccaaccac agcagttggt tttgcgatta agatcagggg

601 agccacagac atttacatta aaattcaaga gagctgaaga ctatcccatt gacctctact 661 accttatgga cctgtcttac tcaatgaaag acgatttgga gaatgtaaaa agtcttggaa 721 cagatctgat gaatgaaatg aggaggatta cttcggactt cagaattgga tttggctcat 781 ttgtggaaaa gactgtgatg ccttacatta gcacaacacc agctaagctc aggaaccctt 841 gcacaagtga acagaactgc accagcccat ttagctacaa aaatgtgctc agtcttacta 901 ataaaggaga agtatttaat gaacttgttg gaaaacagcg catatctgga aatttggatt 961 ctccagaagg tggtttcgat gccatcatgc aagttgcagt ttgtggatca ctgattggct 1021 ggaggaatgt tacacggctg ctggtgtttt ccacagatgc cgggtttcac tttgctggag

1081 atgggaaact tggtggcatt gttttaccaa atgatggaca atgtcacctg gaaaataata 1141 tgtacacaat gagccattat tatgattatc cttctattgc tcaccttgtc cagaaactga 1201 gtgaaaataa tattcagaca atttttgcag ttactgaaga atttcagcct gtttacaagg 1261 agctgaaaaa cttgatccct aagtcagcag taggaacatt atctgcaaat tctagcaatg 1321 taattcagtt gatcattgat gcatacaatt ccctttcctc agaagtcatt ttggaaaacg

1381 gcaaattgtc agaaggcgta acaataagtt acaaatctta ctgcaagaac ggggtgaatg 1441 gaacagggga aaatggaaga aaatgttcca atatttccat tggagatgag gttcaatttg 1501 aaattagcat aacttcaaat aagtgtccaa aaaaggattc tgacagcttt aaaattaggc 1561 ctctgggctt tacggaggaa gtagaggtta ttcttcagta catctgtgaa tgtgaatgcc 1621 aaagcgaagg catccctgaa agtcccaagt gtcatgaagg aaatgggaca tttgagtgtg

1681 gcgcgtgcag gtgcaatgaa gggcgtgttg gtagacattg tgaatgcagc acagatgaag 1741 ttaacagtga agacatggat gcttactgca ggaaagaaaa cagttcagaa atctgcagta 1801 acaatggaga gtgcgtctgc ggacagtgtg tttgtaggaa gagggataat acaaatgaaa 1861 tttattctgg caaattctgc gagtgtgata atttcaactg tgatagatcc aatggcttaa 1921 tttgtggagg aaatggtgtt tgcaagtgtc gtgtgtgtga gtgcaacccc aactacactg

1981 gcagtgcatg tgactgttct ttggatacta gtacttgtga agccagcaac ggacagatct 2041 gcaatggccg gggcatctgc gagtgtggtg tctgtaagtg tacagatccg aagtttcaag 2101 ggcaaacgtg tgagatgtgt cagacctgcc ttggtgtctg tgctgagcat aaagaatgtg 2161 ttcagtgcag agccttcaat aaaggagaaa agaaagacac atgcacacag gaatgttcct 2221 attttaacat taccaaggta gaaagtcggg acaaattacc ccagccggtc caacctgatc

2281 ctgtgtccca ttgtaaggag aaggatgttg acgactgttg gttctatttt acgtattcag 2341 tgaatgggaa caacgaggtc atggttcatg ttgtggagaa tccagagtgt cccactggtc 2401 cagacatcat tccaattgta gctggtgtgg ttgctggaat tgttcttatt ggccttgcat 2461 tactgctgat atggaagctt ttaatgataa ttcatgacag aagggagttt gctaaatttg 2521 aaaaggagaa aatgaatgcc aaatgggaca cgggtgaaaa tcctatttat aagagtgccg

2581 taacaactgt ggtcaatccg aagtatgagg gaaaatgagt actgcccgtg caaatcccac 2641 aacactgaat gcaaagtagc aatttccata gtcacagtta ggtagcttta gggcaatatt 2701 gccatggttt tactcatgtg caggttttga aaatgtacaa tatgtataat ttttaaaatg 2761 ttttattatt ttgaaaataa tgttgtaatt catgccaggg actgacaaaa gacttgagac 2821 aggatggtta ctcttgtcag ctaaggtcac attgtgcctt tttgaccttt tcttcctgga

2881 ctattgaaat caagcttatt ggattaagtg atatttctat agcgattgaa agggcaatag 2941 ttaaagtaat gagcatgatg agagtttctg ttaatcatgt attaaaactg atttttagct 3001 ttacaaatat gtcagtttgc agttatgcag aatccaaagt aaatgtcctg ctagctagtt 3061 aaggattgtt ttaaatctgt tattttgcta tttgcctgtt agacatgact gatgacatat 3121 ctgaaagaca agtatgttga gagttgctgg tgtaaaatac gtttgaaata gttgatctac

3181 aaaggccatg ggaaaaattc agagagttag gaaggaaaaa ccaatagctt taaaacctgt 3241 gtgccatttt aagagttact taatgtttgg taacttttat gccttcactt tacaaattca 3301 agccttagat aaaagaaccg agcaattttc tgctaaaaag tccttgattt agcactattt 3361 acatacaggc catactttac aaagtatttg ctgaatgggg accttttgag ttgaatttat 3421 tttattattt ttattttgtt taatgtctgg tgctttctgt cacctcttct aatcttttaa

3481 tgtatttgtt tgcaattttg gggtaagact ttttttatga gtactttttc tttgaagttt

3541 tagcggtcaa tttgcctttt taatgaacat gtgaagttat actgtggcta tgcaacagct 3601 ctcacctacg cgagtcttac tttgagttag tgccataaca gaccactgta tgtttacttc 3661 tcaccatttg agttgcccat cttgtttcac actagtcaca ttcttgtttt aagtgccttt

3721 agttttaaca gttcactttt tacagtgcta tttactgaag ttatttatta aatatgccta

3781 aaatacttaa atcggatgtc ttgactctga tgtattttat caggttgtgt gcatgaaatt 3841 tttatagatt aaagaagttg aggaaaagca aaaaaaaaa Integrin β3 (NCBI Ref.: NM 000212.2; SEQ ID NO: 6)

1 cgccgcggga ggcggacgag atgcgagcgc ggccgcggcc ccggccgctc tgggcgactg 61 tgctggcgct gggggcgctg gcgggcgttg gcgtaggagg gcccaacatc tgtaccacgc 121 gaggtgtgag ctcctgccag cagtgcctgg ctgtgagccc catgtgtgcc tggtgctctg 181 atgaggccct gcctctgggc tcacctcgct gtgacctgaa ggagaatctg ctgaaggata 241 actgtgcccc agaatccatc gagttcccag tgagtgaggc ccgagtacta gaggacaggc

301 ccctcagcga caagggctct ggagacagct cccaggtcac tcaagtcagt ccccagagga 361 ttgcactccg gctccggcca gatgattcga agaatttctc catccaagtg cggcaggtgg 421 aggattaccc tgtggacatc tactacttga tggacctgtc ttactccatg aaggatgatc 481 tgtggagcat ccagaacctg ggtaccaagc tggccaccca gatgcgaaag ctcaccagta 541 acctgcggat tggcttcggg gcatttgtgg acaagcctgt gtcaccatac atgtatatct

601 ccccaccaga ggccctcgaa aacccctgct atgatatgaa gaccacctgc ttgcccatgt 661 ttggctacaa acacgtgctg acgctaactg accaggtgac ccgcttcaat gaggaagtga 721 agaagcagag tgtgtcacgg aaccgagatg ccccagaggg tggctttgat gccatcatgc 781 aggctacagt ctgtgatgaa aagattggct ggaggaatga tgcatcccac ttgctggtgt 841 ttaccactga tgccaagact catatagcat tggacggaag gctggcaggc attgtccagc

901 ctaatgacgg gcagtgtcat gttggtagtg acaatcatta ctctgcctcc actaccatgg 961 attatccctc tttggggctg atgactgaga agctatccca gaaaaacatc aatttgatct 1021 ttgcagtgac tgaaaatgta gtcaatctct atcagaacta tagtgagctc atcccaggga 1081 ccacagttgg ggttctgtcc atggattcca gcaatgtcct ccagctcatt gttgatgctt 1141 atgggaaaat ccgttctaaa gtagagctgg aagtgcgtga cctccctgaa gagttgtctc

1201 tatccttcaa tgccacctgc ctcaacaatg aggtcatccc tggcctcaag tcttgtatgg 1261 gactcaagat tggagacacg gtgagcttca gcattgaggc caaggtgcga ggctgtcccc 1321 aggagaagga gaagtccttt accataaagc ccgtgggctt caaggacagc ctgatcgtcc 1381 aggtcacctt tgattgtgac tgtgcctgcc aggcccaagc tgaacctaat agccatcgct 1441 gcaacaatgg caatgggacc tttgagtgtg gggtatgccg ttgtgggcct ggctggctgg

1501 gatcccagtg tgagtgctca gaggaggact atcgcccttc ccagcaggac gaatgcagcc 1561 cccgggaggg tcagcccgtc tgcagccagc ggggcgagtg cctctgtggt caatgtgtct 1621 gccacagcag tgactttggc aagatcacgg gcaagtactg cgagtgtgac gacttctcct 1681 gtgtccgcta caagggggag atgtgctcag gccatggcca gtgcagctgt ggggactgcc 1741 tgtgtgactc cgactggacc ggctactact gcaactgtac cacgcgtact gacacctgca

1801 tgtccagcaa tgggctgctg tgcagcggcc gcggcaagtg tgaatgtggc agctgtgtct 1861 gtatccagcc gggctcctat ggggacacct gtgagaagtg ccccacctgc ccagatgcct 1921 gcacctttaa gaaagaatgt gtggagtgta agaagtttga ccggggagcc ctacatgacg 1981 aaaatacctg caaccgttac tgccgtgacg agattgagtc agtgaaagag cttaaggaca 2041 ctggcaagga tgcagtgaat tgtacctata agaatgagga tgactgtgtc gtcagattcc 2101 agtactatga agattctagt ggaaagtcca tcctgtatgt ggtagaagag ccagagtgtc 2161 ccaagggccc tgacatcctg gtggtcctgc tctcagtgat gggggccatt ctgctcattg 2221 gccttgccgc cctgctcatc tggaaactcc tcatcaccat ccacgaccga aaagaattcg 2281 ctaaatttga ggaagaacgc gccagagcaa aatgggacac agccaacaac ccactgtata 2341 aagaggccac gtctaccttc accaatatca cgtaccgggg cacttaatga taagcagtca 2401 tcctcagatc attatcagcc tgtgccacga ttgcaggagt ccctgccatc atgtttacag 2461 aggacagtat ttgtggggag ggatttgggg ctcagagtgg ggtaggttgg gagaatgtca 2521 gtatgtggaa gtgtgggtct gtgtgtgtgt atgtgggggt ctgtgtgttt atgtgtgtgt 2581 gttgtgtgtg ggagtgtgta atttaaaatt gtgatgtgtc ctgataagct gagctcctta 2641 gcctttgtcc cagaatgcct cctgcaggga ttcttcctgc ttagcttgag ggtgactatg 2701 gagctgagca ggtgttcttc attacctcag tgagaagcca gctttcctca tcaggccatt 2761 gtccctgaag agaagggcag ggctgaggcc tctcattcca gaggaaggga caccaagcct 2821 tggctctacc ctgagttcat aaatttatgg ttctcaggcc tgactctcag cagctatggt 2881 aggaactgct gggcttggca gcccgggtca tctgtacctc tgcctccttt cccctccctc 2941 aggccgaagg aggagtcagg gagagctgaa ctattagagc tgcctgtgcc ttttgccatc 3001 ccctcaaccc agctatggtt ctctcgcaag ggaagtcctt gcaagctaat tctttgacct 3061 gttgggagtg aggatgtctg ggccactcag gggtcattca tggcctgggg gatgtaccag 3121 catctcccag ttcataatca caacccttca gatttgcctt attggcagct ctactctgga 3181 ggtttgttta gaagaagtgt gtcaccctta ggccagcacc atctctttac ctcctaattc 3241 cacaccctca ctgctgtaga catttgctat gagctgggga tgtctctcat gaccaaatgc 3301 ttttcctcaa agggagagag tgctattgta gagccagagg tctggcccta tgcttccggc 3361 ctcctgtccc tcatccatag cacctccaca tacctggccc tgtgccttgg tgtgctgtat 3421 ccatccatgg ggctgattgt atttaccttc tacctcttgg ctgccttgtg aaggaattat 3481 tcccatgagt tggctgggaa taagtgccag gatggaatga tgggtcagtt gtatcagcac 3541 gtgtggcctg ttcttctatg ggttggacaa cctcatttta actcagtctt taatctgaga 3601 ggccacagtg caattttatt ttatttttct catgatgagg ttttcttaac ttaaaagaac 3661 atgtatataa acatgcttgc attatatttg taaatttatg tgatggcaaa gaaggagagc 3721 ataggaaacc acacagactt gggcagggta cagacactcc cacttggcat cattcacagc 3781 aagtcactgg ccagtggctg gatctgtgag gggctctctc atgatagaag gctatgggga 3841 tagatgtgtg gacacattgg acctttcctg aggaagaggg actgttcttt tgtcccagaa 3901 aagcagtggc tccattggtg ttgacataca tccaacatta aaagccaccc ccaaatgccc 3961 aagaaaaaaa gaaagactta tcaacatttg ttccatgagc agaaaactgg agctctggcc 4021 tcagtgttac agctaaataa tctttaatta aggcaagtca ctttcttctt cttaaagctg 4081 ttttctagtt tgagaaatga tgggatttta gcagccagtc ttgaaggtct ctttcagtat 4141 caacattcta agatgctggg acttactgtg tcatcaaatg tgcggttaag attctctggg 4201 atattgatac tgtttgtgtt tttagttggg agatctgaga gacctggctt tggcaagagc 4261 agatgtcatt ccatatcacc tttctcaatg aaagtctcat tctatcctct ctccaaaccc 4321 gttttccaac atttgttaat agttacgtct ctcctgatgt agcacttaag cttcatttag 4381 ttattatttc tttcttcact ttgcacacat ttgcatccac atattaggga agaggaatcc 4441 ataagtagct gaaatatcta ttctgtatta ttgtgttaac attgagaata agccttggaa 4501 ttagatatgg ggcaatgact gagccctgtc tcacccatgg attactcctt actgtaggga 4561 atggcagtat ggtagaggga taaatagggg gcggggaggg atagtcatgg atccaagaag 4621 tccttagaaa tagtggcagg gaacaggtgt ggaagctcat gcctgtaatt ataaccttca 4681 gctactaaga caggtgtggt ggctcacgcc tgtgattata atcttcagtt actaagacag 4741 agtccatgag agtgttaatg ggacattttc tttagataag atgttttata tgaagaaact 4801 gtatcaaagg gggaagaaaa tgtatttaac aggtgaatca aatcaggaat cttgtctgag 4861 ctactggaat gaagttcaca ggtcttgaag acca

Integrin β5 (NCBI Ref.: NM 002213.4; SEQ ID NO: 7)

1 gccgccgagc ggagccagcc cctcccctac ccggagcagc ccgctggggc cgtcccgagc 61 ggcgacacac taggagtccc ggccggccag ccagggcagc cgcggtcccg ggactcggcc 121 gtgagtgctg cgggacggat ggtggcggcg gggcgcgggc cagcgcgggc gccgtgagcc

181 ggagctgcgc gcggggcatg cggctgcggc ccccggccct cggcccccgc gctccggccc 241 cagccccggc cgccggcccc cgcggagtgc agcgaccgcg ccgccgctga gggaggcgcc 301 ccaccatgcc gcgggccccg gcgccgctgt acgcctgcct cctggggctc tgcgcgctcc 361 tgccccggct cgcaggtctc aacatatgca ctagtggaag tgccacctca tgtgaagaat 421 gtctgctaat ccacccaaaa tgtgcctggt gctccaaaga ggacttcgga agcccacggt

481 ccatcacctc tcggtgtgat ctgagggcaa accttgtcaa aaatggctgt ggaggtgaga 541 tagagagccc agccagcagc ttccatgtcc tgaggagcct gcccctcagc agcaagggtt 601 cgggctctgc aggctgggac gtcattcaga tgacaccaca ggagattgcc gtgaacctcc 661 ggcccggtga caagaccacc ttccagctac aggttcgcca ggtggaggac tatcctgtgg 721 acctgtacta cctgatggac ctctccctgt ccatgaagga tgacttggac aatatccgga

781 gcctgggcac caaactcgcg gaggagatga ggaagctcac cagcaacttc cggttgggat 841 ttgggtcttt tgttgataag gacatctctc ctttctccta cacggcaccg aggtaccaga 901 ccaatccgtg cattggttac aagttgtttc caaattgcgt cccctccttt gggttccgcc 961 atctgctgcc tctcacagac agagtggaca gcttcaatga ggaagttcgg aaacagaggg 1021 tgtcccggaa ccgagatgcc cctgaggggg gctttgatgc agtactccag gcagccgtct

1081 gcaaggagaa gattggctgg cgaaaggatg cactgcattt gctggtgttc acaacagatg 1141 atgtgcccca catcgcattg gatggaaaat tgggaggcct ggtgcagcca cacgatggcc 1201 agtgccacct gaacgaggcc aacgagtaca ctgcatccaa ccagatggac tatccatccc 1261 ttgccttgct tggagagaaa ttggcagaga acaacatcaa cctcatcttt gcagtgacaa 1321 aaaaccatta tatgctgtac aagaatttta cagccctgat acctggaaca acggtggaga

1381 ttttagatgg agactccaaa aatattattc aactgattat taatgcatac aatagtatcc

1441 ggtctaaagt ggagttgtca gtctgggatc agcctgagga tcttaatctc ttctttactg 1501 ctacctgcca agatggggta tcctatcctg gtcagaggaa gtgtgagggt ctgaagattg 1561 gggacacggc atcttttgaa gtatcattgg aggcccgaag ctgtcccagc agacacacgg 1621 agcatgtgtt tgccctgcgg ccggtgggat tccgggacag cctggaggtg ggggtcacct

1681 acaactgcac gtgcggctgc agcgtggggc tggaacccaa cagcgccagg tgcaacggga 1741 gcgggaccta tgtctgcggc ctgtgtgagt gcagccccgg ctacctgggc accaggtgcg 1801 agtgccagga tggggagaac cagagcgtgt accagaacct gtgccgggag gcagagggca 1861 agccactgtg cagcgggcgt ggggactgca gctgcaacca gtgctcctgc ttcgagagcg 1921 agtttggcaa gatctatggg cctttctgtg agtgcgacaa cttctcctgt gccaggaaca

1981 agggagtcct ctgctcaggc catggcgagt gtcactgcgg ggaatgcaag tgccatgcag 2041 gttacatcgg ggacaactgt aactgctcga cagacatcag cacatgccgg ggcagagatg 2101 gccagatctg cagcgagcgt gggcactgtc tctgtgggca gtgccaatgc acggagccgg 2161 gggcctttgg ggagatgtgt gagaagtgcc ccacctgccc ggatgcatgc agcaccaaga 2221 gagattgcgt cgagtgcctg ctgctccact ctgggaaacc tgacaaccag acctgccaca 2281 gcctatgcag ggatgaggtg atcacatggg tggacaccat cgtgaaagat gaccaggagg 2341 ctgtgctatg tttctacaaa accgccaagg actgcgtcat gatgttcacc tatgtggagc 2401 tccccagtgg gaagtccaac ctgaccgtcc tcagggagcc agagtgtgga aacaccccca 2461 acgccatgac catcctcctg gctgtggtcg gtagcatcct ccttgttggg cttgcactcc 2521 tggctatctg gaagctgctt gtcaccatcc acgaccggag ggagtttgca aagtttcaga 2581 gcgagcgatc cagggcccgc tatgaaatgg cttcaaatcc attatacaga aagcctatct 2641 ccacgcacac tgtggacttc accttcaaca agttcaacaa atcctacaat ggcactgtgg 2701 actgatgttt ccttctccga ggggctggag cggggatctg atgaaaaggt cagactgaaa 2761 cgccttgcac ggctgctcgg cttgatcaca gctccctagg taggcaccac agagaagacc 2821 ttctagtgag cctgggccag gagcccacag tgcctgtaca ggaaggtgcc tggccatgtc 2881 acctggctgc taggccagag ccatgccagg ctgcgtccct ccgagcttgg gataaagcaa 2941 ggggaccttg gcgctctcag ctttccctgc cacatccagc ttgttgtccc aatgaaatac 3001 tgagatgctg ggctgtctct cccttccagg aatgctgggc ccccagcctg gccagacaag 3061 aagactgtca ggaagggtcg gagtctgtaa aaccagcata cagtttggct tttttcacat 3121 tgatcatttt tatatgaaat aaaaagatcc tgcatttatg gtgtagttct gagtcctgag 3181 acttttctgc gtgatggcta tgccttgcac acaggtgttg gtgatggggc tgttgagatg 3241 cctgttgaag gtacatcgtt tgcaaatgtc agtttcctct cctgtccgtg tttgtttagt 3301 acttttataa tgaaaagaaa caagattgtt tgggattgga agtaaagatt aaaaccaaaa 3361 gaatttgtgt ttgtctgata ctctctgtgt gtttctttct ttctgagcgg acttaaaatg 3421 gtgcccccag tggggattga agcggccgtg tacttcctca gggatgggac acaggctggt 3481 ctgatactcc agactgcagc ttgtcaagta agcatgaggt gctcggggca gtgagggctg 3541 tgcaaggggg aacactgagc agataccttt ggccccttcc agcttttact gacagagagt 3601 tccaggctag acaccataaa aaccacccct tgttctgagg ggctgaggct ggaaatagat 3661 tgtacagaca agcaagggtt gagtggtggt tcccacacga agtcatctct taatcatcat 3721 tagcaatagc agttcccttc caaggcctcc cctcactccc gaaacactta cgtcccatgc 3781 aggcccaatg caaaaaaaca catttgagct tttttcccgc agggccatga agtcccctta 3841 agttcccata tctaagatgg ttgactgacc ctctcccctt atgtacagaa gaggaaactg 3901 attctcagag aggggaagtg gcttgcccga gtgtttgtta ggaggttact gaatgacaaa 3961 ctgttcctaa gaccccatct catgctggcc agagggccag cctcctcatt cctgcttgct 4021 cttagaaaat ctttcactga tcattttttg tcactggaat aacttcaagg ttattatgct 4081 ttcattccaa atggatctgt cctcagctct ggacccaatt ccccttactt cattttggca 4141 aacactaagt caaatagtga aatgcctgtc actacataga acctattacc tggggcaaat 4201 acgaacagat tgagtttcct tcatcttgtg taaatatgat gaaacagaga cctggtaact 4261 tggtgacact gttaaaccct ttttgggata aagccaaatg taaatgaaaa cattaaacag 4321 ataaattgtg gtgttgagac ttttctgaat tgagaaaaat aaatgtaatt ttggaagaaa 4381 aaaaaaaaaa aa

Integrin β7 (NCBI Ref.: NM 000889.2; SEQ ID NO: 8)

1 aaatcttccc caccctgggg agtgtcactt cctcctctgc cgtctcccag atcagtacac 61 aaaggctgct gctgccgcca gaggaaggac tgctctgcac gcacctatgt ggaaactaaa 121 gcccagagag aaagtctgac ttgccccaca gccagtgagt gactgcagca gcaccagaat 181 ctggtctgtt tcctgtttgg ctcttctacc actacggctt gggatctcgg gcatggtggc 241 tttgccaatg gtccttgttt tgctgctggt cctgagcaga ggtgagagtg aattggacgc 301 caagatccca tccacagggg atgccacaga atggcggaat cctcacctgt ccatgctggg 361 gtcctgccag ccagccccct cctgccagaa gtgcatcctc tcacacccca gctgtgcatg 421 gtgcaagcaa ctgaacttca ccgcgtcggg agaggcggag gcgcggcgct gcgcccgacg

481 agaggagctg ctggctcgag gctgcccgct ggaggagctg gaggagcccc gcggccagca 541 ggaggtgctg caggaccagc cgctcagcca gggcgcccgc ggagagggtg ccacccagct 601 ggcgccgcag cgggtccggg tcacgctgcg gcctggggag ccccagcagc tccaggtccg 661 cttccttcgt gctgagggat acccggtgga cctgtactac cttatggacc tgagctactc 721 catgaaggac gacctggaac gcgtgcgcca gctcgggcac gctctgctgg tccggctgca

781 ggaagtcacc cattctgtgc gcattggttt tggttccttt gtggacaaaa cggtgctgcc 841 ctttgtgagc acagtaccct ccaaactgcg ccacccctgc cccacccggc tggagcgctg 901 ccagtcacca ttcagctttc accatgtgct gtccctgacg ggggacgcac aagccttcga 961 gcgggaggtg gggcgccaga gtgtgtccgg caatctggac tcgcctgaag gtggcttcga 1021 tgccattctg caggctgcac tctgccagga gcagattggc tggagaaatg tgtcccggct

1081 gctggtgttc acttcagacg acacattcca tacagctggg gacgggaagt tgggcggcat 1141 tttcatgccc agtgatgggc actgccactt ggacagcaat ggcctctaca gtcgcagcac 1201 agagtttgac tacccttctg tgggtcaggt agcccaggcc ctctctgcag caaatatcca 1261 gcccatcttt gctgtcacca gtgccgcact gcctgtctac caggagctga gtaaactgat 1321 tcctaagtct gcagttgggg agctgagtga ggactccagc aacgtggtac agctcatcat

1381 ggatgcttat aatagcctgt cttccaccgt gacccttgaa cactcttcac tccctcctgg 1441 ggtccacatt tcttacgaat cccagtgtga gggtcctgag aagagggagg gtaaggctga 1501 ggatcgagga cagtgcaacc acgtccgaat caaccagacg gtgactttct gggtttctct 1561 ccaagccacc cactgcctcc cagagcccca tctcctgagg ctccgggccc ttggcttctc 1621 agaggagctg attgtggagt tgcacacgct gtgtgactgt aattgcagtg acacccagcc

1681 ccaggctccc cactgcagtg atggccaggg acacctacaa tgtggtgtat gcagctgtgc 1741 ccctggccgc ctaggtcggc tctgtgagtg ctctgtggca gagctgtcct ccccagacct 1801 ggaatctggg tgccgggctc ccaatggcac agggcccctg tgcagtggaa agggtcactg 1861 tcaatgtgga cgctgcagct gcagtggaca gagctctggg catctgtgcg agtgtgacga 1921 tgccagctgt gagcgacatg agggcatcct ctgcggaggc tttggtcgct gccaatgtgg

1981 agtatgtcac tgtcatgcca accgcacggg cagagcatgc gaatgcagtg gggacatgga 2041 cagttgcatc agtcccgagg gagggctctg cagtgggcat ggacgctgca aatgcaaccg 2101 ctgccagtgc ttggacggct actatggtgc tctatgcgac caatgcccag gctgcaagac 2161 accatgcgag agacaccggg actgtgcaga gtgtggggcc ttcaggactg gcccactggc 2221 caccaactgc agtacagctt gtgcccatac caatgtgacc ctggccttgg cccctatctt

2281 ggatgatggc tggtgcaaag agcggaccct ggacaaccag ctgttcttct tcttggtgga 2341 ggatgacgcc agaggcacgg tcgtgctcag agtgagaccc caagaaaagg gagcagacca 2401 cacgcaggcc attgtgctgg gctgcgtagg gggcatcgtg gcagtggggc tggggctggt 2461 cctggcttac cggctctcgg tggaaatcta tgaccgccgg gaatacagtc gctttgagaa 2521 ggagcagcaa caactcaact ggaagcagga cagtaatcct ctctacaaaa gtgccatcac

2581 gaccaccatc aatcctcgct ttcaagaggc agacagtccc actctctgaa ggagggaggg 2641 acacttaccc aaggctcttc tccttggagg acagtgggaa ctggagggtg agaggaaggg 2701 tgggtctgta agaccttggt aggggactaa ttcactggcg aggtgcggcc accaccctac 2761 ttcattttca gagtgacacc caagagggct gcttcccatg cctgcaacct tgcatccatc 2821 tgggctaccc cacccaagta tacaataaag tcttacctca gaccacaaaa aaaaaaaa

E-selectin (NCBI Ref.: NM 000450.2; SEQ ID NO: 9)

1 agctgttctt ggctgacttc acatcaaaac tcctatactg acctgagaca gaggcagcag 61 tgatacccac ctgagagatc ctgtgtttga acaactgctt cccaaaacgg aaagtatttc

121 aagcctaaac ctttgggtga aaagaactct tgaagtcatg attgcttcac agtttctctc 181 agctctcact ttggtgcttc tcattaaaga gagtggagcc tggtcttaca acacctccac 241 ggaagctatg acttatgatg aggccagtgc ttattgtcag caaaggtaca cacacctggt 301 tgcaattcaa aacaaagaag agattgagta cctaaactcc atattgagct attcaccaag 361 ttattactgg attggaatca gaaaagtcaa caatgtgtgg gtctgggtag gaacccagaa

421 acctctgaca gaagaagcca agaactgggc tccaggtgaa cccaacaata ggcaaaaaga 481 tgaggactgc gtggagatct acatcaagag agaaaaagat gtgggcatgt ggaatgatga 541 gaggtgcagc aagaagaagc ttgccctatg ctacacagct gcctgtacca atacatcctg 601 cagtggccac ggtgaatgtg tagagaccat caataattac acttgcaagt gtgaccctgg 661 cttcagtgga ctcaagtgtg agcaaattgt gaactgtaca gccctggaat cccctgagca

721 tggaagcctg gtttgcagtc acccactggg aaacttcagc tacaattctt cctgctctat 781 cagctgtgat aggggttacc tgccaagcag catggagacc atgcagtgta tgtcctctgg 841 agaatggagt gctcctattc cagcctgcaa tgtggttgag tgtgatgctg tgacaaatcc 901 agccaatggg ttcgtggaat gtttccaaaa ccctggaagc ttcccatgga acacaacctg 961 tacatttgac tgtgaagaag gatttgaact aatgggagcc cagagccttc agtgtacctc

1021 atctgggaat tgggacaacg agaagccaac gtgtaaagct gtgacatgca gggccgtccg 1081 ccagcctcag aatggctctg tgaggtgcag ccattcccct gctggagagt tcaccttcaa 1141 atcatcctgc aacttcacct gtgaggaagg cttcatgttg cagggaccag cccaggttga 1201 atgcaccact caagggcagt ggacacagca aatcccagtt tgtgaagctt tccagtgcac 1261 agccttgtcc aaccccgagc gaggctacat gaattgtctt cctagtgctt ctggcagttt

1321 ccgttatggg tccagctgtg agttctcctg tgagcagggt tttgtgttga agggatccaa 1381 aaggctccaa tgtggcccca caggggagtg ggacaacgag aagcccacat gtgaagctgt 1441 gagatgcgat gctgtccacc agcccccgaa gggtttggtg aggtgtgctc attcccctat 1501 tggagaattc acctacaagt cctcttgtgc cttcagctgt gaggagggat ttgaattaca 1561 tggatcaact caacttgagt gcacatctca gggacaatgg acagaagagg ttccttcctg

1621 ccaagtggta aaatgttcaa gcctggcagt tccgggaaag atcaacatga gctgcagtgg 1681 ggagcccgtg tttggcactg tgtgcaagtt cgcctgtcct gaaggatgga cgctcaatgg 1741 ctctgcagct cggacatgtg gagccacagg acactggtct ggcctgctac ctacctgtga 1801 agctcccact gagtccaaca ttcccttggt agctggactt tctgctgctg gactctccct 1861 cctgacatta gcaccatttc tcctctggct tcggaaatgc ttacggaaag caaagaaatt

1921 tgttcctgcc agcagctgcc aaagccttga atcagatgga agctaccaaa agccttctta 1981 catcctttaa gttcaaaaga atcagaaaca ggtgcatctg gggaactaga gggatacact 2041 gaagttaaca gagacagata actctcctcg ggtctctggc ccttcttgcc tactatgcca 2101 gatgccttta tggctgaaac cgcaacaccc atcaccactt caatagatca aagtccagca 2161 ggcaaggacg gccttcaact gaaaagactc agtgttccct ttcctactct caggatcaag

2221 aaagtgttgg ctaatgaagg gaaaggatat tttcttccaa gcaaaggtga agagaccaag 2281 actctgaaat ctcagaattc cttttctaac tctcccttgc tcgctgtaaa atcttggcac 2341 agaaacacaa tattttgtgg ctttctttct tttgcccttc acagtgtttc gacagctgat 2401 tacacagttg ctgtcataag aatgaataat aattatccag agtttagagg aaaaaaatga 2461 ctaaaaatat tataacttaa aaaaatgaca gatgttgaat gcccacaggc aaatgcatgg 2521 agggttgtta atggtgcaaa tcctactgaa tgctctgtgc gagggttact atgcacaatt 2581 taatcacttt catccctatg ggattcagtg cttcttaaag agttcttaag gattgtgata 2641 tttttacttg cattgaatat attataatct tccatacttc ttcattcaat acaagtgtgg

2701 tagggactta aaaaacttgt aaatgctgtc aactatgata tggtaaaagt tacttattct 2761 agattacccc ctcattgttt attaacaaat tatgttacat ctgttttaaa tttatttcaa

2821 aaagggaaac tattgtcccc tagcaaggca tgatgttaac cagaataaag ttctgagtgt 2881 ttttactaca gttgtttttt gaaaacatgg tagaattgga gagtaaaaac tgaatggaag 2941 gtttgtatat tgtcagatat tttttcagaa atatgtggtt tccacgatga aaaacttcca

3001 tgaggccaaa cgttttgaac taataaaagc ataaatgcaa acacacaaag gtataatttt 3061 atgaatgtct ttgttggaaa agaatacaga aagatggatg tgctttgcat tcctacaaag 3121 atgtttgtca gatatgatat gtaaacataa ttcttgtata ttatggaaga ttttaaattc

3181 acaatagaaa ctcaccatgt aaaagagtca tctggtagat ttttaacgaa tgaagatgtc 3241 taatagttat tccctatttg ttttcttctg tatgttaggg tgctctggaa gagaggaatg

3301 cctgtgtgag caagcattta tgtttattta taagcagatt taacaattcc aaaggaatct 3361 ccagttttca gttgatcact ggcaatgaaa aattctcagt cagtaattgc caaagctgct 3421 ctagccttga ggagtgtgag aatcaaaact ctcctacact tccattaact tagcatgtgt 3481 tgaaaaaaaa gtttcagaga agttctggct gaacactggc aacaacaaag ccaacagtca 3541 aaacagagat gtgataagga tcagaacagc agaggttctt ttaaaggggc agaaaaactc

3601 tgggaaataa gagagaacaa ctactgtgat caggctatgt atggaataca gtgttatttt 3661 ctttgaaatt gtttaagtgt tgtaaatatt tatgtaaact gcattagaaa ttagctgtgt 3721 gaaataccag tgtggtttgt gtttgagttt tattgagaat tttaaattat aacttaaaat 3781 attttataat ttttaaagta tatatttatt taagcttatg tcagacctat ttgacataac

3841 actataaagg ttgacaataa atgtgcttat gttta

ICAM-1(NCBI Ref.: NM 000201.2; SEQ ID NO: 10)

1 caagcttagc ctggccggga aacgggaggc gtggaggccg ggagcagccc ccggggtcat 61 cgccctgcca ccgccgcccg attgctttag cttggaaatt ccggagctga agcggccagc 121 gagggaggat gaccctctcg gcccgggcac cctgtcagtc cggaaataac tgcagcattt

181 gttccggagg ggaaggcgcg aggtttccgg gaaagcagca ccgccccttg gcccccaggt 241 ggctagcgct ataaaggatc acgcgcccca gtcgacgctg agctcctctg ctactcagag 301 ttgcaacctc agcctcgcta tggctcccag cagcccccgg cccgcgctgc ccgcactcct 361 ggtcctgctc ggggctctgt tcccaggacc tggcaatgcc cagacatctg tgtccccctc 421 aaaagtcatc ctgccccggg gaggctccgt gctggtgaca tgcagcacct cctgtgacca

481 gcccaagttg ttgggcatag agaccccgtt gcctaaaaag gagttgctcc tgcctgggaa 541 caaccggaag gtgtatgaac tgagcaatgt gcaagaagat agccaaccaa tgtgctattc 601 aaactgccct gatgggcagt caacagctaa aaccttcctc accgtgtact ggactccaga 661 acgggtggaa ctggcacccc tcccctcttg gcagccagtg ggcaagaacc ttaccctacg 721 ctgccaggtg gagggtgggg caccccgggc caacctcacc gtggtgctgc tccgtgggga

781 gaaggagctg aaacgggagc cagctgtggg ggagcccgct gaggtcacga ccacggtgct 841 ggtgaggaga gatcaccatg gagccaattt ctcgtgccgc actgaactgg acctgcggcc 901 ccaagggctg gagctgtttg agaacacctc ggccccctac cagctccaga cctttgtcct 961 gccagcgact cccccacaac ttgtcagccc ccgggtccta gaggtggaca cgcaggggac 1021 cgtggtctgt tccctggacg ggctgttccc agtctcggag gcccaggtcc acctggcact 1081 gggggaccag aggttgaacc ccacagtcac ctatggcaac gactccttct cggccaaggc 1141 ctcagtcagt gtgaccgcag aggacgaggg cacccagcgg ctgacgtgtg cagtaatact 1201 ggggaaccag agccaggaga cactgcagac agtgaccatc tacagctttc cggcgcccaa

1261 cgtgattctg acgaagccag aggtctcaga agggaccgag gtgacagtga agtgtgaggc 1321 ccaccctaga gccaaggtga cgctgaatgg ggttccagcc cagccactgg gcccgagggc 1381 ccagctcctg ctgaaggcca ccccagagga caacgggcgc agcttctcct gctctgcaac 1441 cctggaggtg gccggccagc ttatacacaa gaaccagacc cgggagcttc gtgtcctgta 1501 tggcccccga ctggacgaga gggattgtcc gggaaactgg acgtggccag aaaattccca

1561 gcagactcca atgtgccagg cttgggggaa cccattgccc gagctcaagt gtctaaagga 1621 tggcactttc ccactgccca tcggggaatc agtgactgtc actcgagatc ttgagggcac 1681 ctacctctgt cgggccagga gcactcaagg ggaggtcacc cgcaaggtga ccgtgaatgt 1741 gctctccccc cggtatgaga ttgtcatcat cactgtggta gcagccgcag tcataatggg 1801 cactgcaggc ctcagcacgt acctctataa ccgccagcgg aagatcaaga aatacagact

1861 acaacaggcc caaaaaggga cccccatgaa accgaacaca caagccacgc ctccctgaac 1921 ctatcccggg acagggcctc ttcctcggcc ttcccatatt ggtggcagtg gtgccacact 1981 gaacagagtg gaagacatat gccatgcagc tacacctacc ggccctggga cgccggagga 2041 cagggcattg tcctcagtca gatacaacag catttggggc catggtacct gcacacctaa 2101 aacactaggc cacgcatctg atctgtagtc acatgactaa gccaagagga aggagcaaga

2161 ctcaagacat gattgatgga tgttaaagtc tagcctgatg agaggggaag tggtggggga 2221 gacatagccc caccatgagg acatacaact gggaaatact gaaacttgct gcctattggg 2281 tatgctgagg ccccacagac ttacagaaga agtggccctc catagacatg tgtagcatca 2341 aaacacaaag gcccacactt cctgacggat gccagcttgg gcactgctgt ctactgaccc 2401 caacccttga tgatatgtat ttattcattt gttattttac cagctattta ttgagtgtct

2461 tttatgtagg ctaaatgaac ataggtctct ggcctcacgg agctcccagt cctaatcaca 2521 ttcaaggtca ccaggtacag ttgtacaggt tgtacactgc aggagagtgc ctggcaaaaa 2581 gatcaaatgg ggctgggact tctcattggc caacctgcct ttccccagaa ggagtgattt 2641 ttctatcggc acaaaagcac tatatggact ggtaatggtt acaggttcag agattaccca 2701 gtgaggcctt attcctccct tccccccaaa actgacacct ttgttagcca cctccccacc

2761 cacatacatt tctgccagtg ttcacaatga cactcagcgg tcatgtctgg acatgagtgc 2821 ccagggaata tgcccaagct atgccttgtc ctcttgtcct gtttgcattt cactgggagc 2881 ttgcactatg cagctccagt ttcctgcagt gatcagggtc ctgcaagcag tggggaaggg 2941 ggccaaggta ttggaggact ccctcccagc tttggaagcc tcatccgcgt gtgtgtgtgt 3001 gtgtatgtgt agacaagctc tcgctctgtc acccaggctg gagtgcagtg gtgcaatcat

3061 ggttcactgc agtcttgacc ttttgggctc aagtgatcct cccacctcag cctcctgagt 3121 agctgggacc ataggctcac aacaccacac ctggcaaatt tgattttttt tttttttcca 3181 gagacggggt ctcgcaacat tgcccagact tcctttgtgt tagttaataa agctttctca 3241 actgccaaa

TGF-P (NCBI Ref.: NM 000660.6; SEQ ID NO: 11)

1 acctccctcc gcggagcagc cagacagcga gggccccggc cgggggcagg ggggacgccc 61 cgtccggggc acccccccgg ctctgagccg cccgcggggc cggcctcggc ccggagcgga 121 ggaaggagtc gccgaggagc agcctgaggc cccagagtct gagacgagcc gccgccgccc 181 ccgccactgc ggggaggagg gggaggagga gcgggaggag ggacgagctg gtcgggagaa 241 gaggaaaaaa acttttgaga cttttccgtt gccgctggga gccggaggcg cggggacctc 301 ttggcgcgac gctgccccgc gaggaggcag gacttgggga ccccagaccg cctccctttg 361 ccgccgggga cgcttgctcc ctccctgccc cctacacggc gtccctcagg cgcccccatt

421 ccggaccagc cctcgggagt cgccgacccg gcctcccgca aagacttttc cccagacctc 481 gggcgcaccc cctgcacgcc gccttcatcc ccggcctgtc tcctgagccc ccgcgcatcc 541 tagacccttt ctcctccagg agacggatct ctctccgacc tgccacagat cccctattca 601 agaccaccca ccttctggta ccagatcgcg cccatctagg ttatttccgt gggatactga 661 gacacccccg gtccaagcct cccctccacc actgcgccct tctccctgag gacctcagct

721 ttccctcgag gccctcctac cttttgccgg gagaccccca gcccctgcag gggcggggcc 781 tccccaccac accagccctg ttcgcgctct cggcagtgcc ggggggcgcc gcctccccca 841 tgccgccctc cgggctgcgg ctgctgccgc tgctgctacc gctgctgtgg ctactggtgc 901 tgacgcctgg ccggccggcc gcgggactat ccacctgcaa gactatcgac atggagctgg 961 tgaagcggaa gcgcatcgag gccatccgcg gccagatcct gtccaagctg cggctcgcca

1021 gccccccgag ccagggggag gtgccgcccg gcccgctgcc cgaggccgtg ctcgccctgt 1081 acaacagcac ccgcgaccgg gtggccgggg agagtgcaga accggagccc gagcctgagg 1141 ccgactacta cgccaaggag gtcacccgcg tgctaatggt ggaaacccac aacgaaatct 1201 atgacaagtt caagcagagt acacacagca tatatatgtt cttcaacaca tcagagctcc 1261 gagaagcggt acctgaaccc gtgttgctct cccgggcaga gctgcgtctg ctgaggctca

1321 agttaaaagt ggagcagcac gtggagctgt accagaaata cagcaacaat tcctggcgat 1381 acctcagcaa ccggctgctg gcacccagcg actcgccaga gtggttatct tttgatgtca 1441 ccggagttgt gcggcagtgg ttgagccgtg gaggggaaat tgagggcttt cgccttagcg 1501 cccactgctc ctgtgacagc agggataaca cactgcaagt ggacatcaac gggttcacta 1561 ccggccgccg aggtgacctg gccaccattc atggcatgaa ccggcctttc ctgcttctca

1621 tggccacccc gctggagagg gcccagcatc tgcaaagctc ccggcaccgc cgagccctgg 1681 acaccaacta ttgcttcagc tccacggaga agaactgctg cgtgcggcag ctgtacattg 1741 acttccgcaa ggacctcggc tggaagtgga tccacgagcc caagggctac catgccaact 1801 tctgcctcgg gccctgcccc tacatttgga gcctggacac gcagtacagc aaggtcctgg 1861 ccctgtacaa ccagcataac ccgggcgcct cggcggcgcc gtgctgcgtg ccgcaggcgc

1921 tggagccgct gcccatcgtg tactacgtgg gccgcaagcc caaggtggag cagctgtcca 1981 acatgatcgt gcgctcctgc aagtgcagct gaggtcccgc cccgccccgc cccgccccgg 2041 caggcccggc cccaccccgc cccgcccccg ctgccttgcc catgggggct gtatttaagg 2101 acacccgtgc cccaagccca cctggggccc cattaaagat ggagagagga ctgcggatct 2161 ctgtgtcatt gggcgcctgc ctggggtctc catccctgac gttcccccac tcccactccc

2221 tctctctccc tctctgcctc ctcctgcctg tctgcactat tcctttgccc ggcatcaagg

2281 cacaggggac cagtggggaa cactactgta gttagatcta tttattgagc accttgggca 2341 ctgttgaagt gccttacatt aatgaactca ttcagtcacc atagcaacac tctgagatgc 2401 agggactctg ataacaccca ttttaaaggt gaggaaacaa gcccagagag gttaagggag 2461 gagttcctgc ccaccaggaa cctgctttag tgggggatag tgaagaagac aataaaagat

2521 agtagttcag gccaggcggg gtggctcacg cctgtaatcc tagcactttt gggaggcaga 2581 gatgggagga ttacttgaat ccaggcattt gagaccagcc tgggtaacat agtgagaccc 2641 tatctctaca aaacactttt aaaaaatgta cacctgtggt cccagctact ctggaggcta 2701 aggtgggagg atcacttgat cctgggaggt caaggctgca g MadCAM-1 (NCBI Ref.: NM 130760.2; SEQ ID NO: 12)

1 gggactgagc atggatttcg gactggccct cctgctggcg gggcttctgg ggctcctcct 61 cggccagtcc ctccaggtga agcccctgca ggtggagccc ccggagccgg tggtggccgt 121 ggccttgggc gcctcgcgcc agctcacctg ccgcctggcc tgcgcggacc gcggggcctc 181 ggtgcagtgg cggggcctgg acaccagcct gggcgcggtg cagtcggaca cgggccgcag

241 cgtcctcacc gtgcgcaacg cctcgctgtc ggcggccggg acccgcgtgt gcgtgggctc 301 ctgcgggggc cgcaccttcc agcacaccgt gcagctcctt gtgtacgcct tcccggacca 361 gctgaccgtc tccccagcag ccctggtgcc tggtgacccg gaggtggcct gtacggccca 421 caaagtcacg cccgtggacc ccaacgcgct ctccttctcc ctgctcgtcg ggggccagga 481 actggagggg gcgcaagccc tgggcccgga ggtgcaggag gaggaggagg agccccaggg

541 ggacgaggac gtgctgttca gggtgacaga gcgctggcgg ctgccgcccc tggggacccc 601 tgtcccgccc gccctctact gccaggccac gatgaggctg cctggcttgg agctcagcca 661 ccgccaggcc atccccgtcc tgcacagccc gacctccccg gagcctcccg acaccacctc 721 cccggagtct cccgacacca cctccccgga gtctcccgac accacctccc aggagcctcc 781 cgacaccacc tccccggagc ctcccgacaa gacctccccg gagcccgccc cccagcaggg

841 ctccacacac acccccagga gcccaggctc caccaggact cgccgccctg agatctccca 901 ggctgggccc acgcagggag aagtgatccc aacaggctcg tccaaacctg cgggtgacca 961 gctgcccgcg gctctgtgga ccagcagtgc ggtgctggga ctgctgctcc tggccttgcc 1021 cacctatcac ctctggaaac gctgccggca cctggctgag gacgacaccc acccaccagc 1081 ttctctgagg cttctgcccc aggtgtcggc ctgggctggg ttaaggggga ccggccaggt

1141 cgggatcagc ccctcctgag tggccagcct ttccccctgt gaaagcaaaa tagcttggac 1201 cccttcaagt tgagaactgg tcagggcaaa cctgcctccc attctactca aagtcatccc 1261 tctgttcaca gagatggatg catgttctga ttgcctcttt ggagaagctc atcagaaact 1321 caaaagaagg ccactgtttg tctcacctac ccatgacctg aagcccctcc ctgagtggtc 1381 cccacctttc tggacggaac cacgtacttt ttacatacat tgattcatgt ctcacgtctc

1441 cctaaaaatg cgtaagacca agctgtgccc tgaccaccct gggcccctgt cgtcaggacc 1501 tcctgaggct ttggcaaata aacctcctaa aatgataaaa

VCAM-1 (NCBI Ref.: NM 001078.3; SEQ ID NO: 13)

1 aaactttttt ccctggctct gccctgggtt tccccttgaa gggatttccc tccgcctctg

61 caacaagacc ctttataaag cacagacttt ctatttcact ccgcggtatc tgcatcgggc 121 ctcactggct tcaggagctg aataccctcc caggcacaca caggtgggac acaaataagg 181 gttttggaac cactattttc tcatcacgac agcaacttaa aatgcctggg aagatggtcg 241 tgatccttgg agcctcaaat atactttgga taatgtttgc agcttctcaa gcttttaaaa

301 tcgagaccac cccagaatct agatatcttg ctcagattgg tgactccgtc tcattgactt

361 gcagcaccac aggctgtgag tccccatttt tctcttggag aacccagata gatagtccac 421 tgaatgggaa ggtgacgaat gaggggacca catctacgct gacaatgaat cctgttagtt 481 ttgggaacga acactcttac ctgtgcacag caacttgtga atctaggaaa ttggaaaaag 541 gaatccaggt ggagatctac tcttttccta aggatccaga gattcatttg agtggccctc 601 tggaggctgg gaagccgatc acagtcaagt gttcagttgc tgatgtatac ccatttgaca

661 ggctggagat agacttactg aaaggagatc atctcatgaa gagtcaggaa tttctggagg 721 atgcagacag gaagtccctg gaaaccaaga gtttggaagt aacctttact cctgtcattg 781 aggatattgg aaaagttctt gtttgccgag ctaaattaca cattgatgaa atggattctg 841 tgcccacagt aaggcaggct gtaaaagaat tgcaagtcta catatcaccc aagaatacag 901 ttatttctgt gaatccatcc acaaagctgc aagaaggtgg ctctgtgacc atgacctgtt 961 ccagcgaggg tctaccagct ccagagattt tctggagtaa gaaattagat aatgggaatc 1021 tacagcacct ttctggaaat gcaactctca ccttaattgc tatgaggatg gaagattctg 1081 gaatttatgt gtgtgaagga gttaatttga ttgggaaaaa cagaaaagag gtggaattaa

1141 ttgttcaaga gaaaccattt actgttgaga tctcccctgg accccggatt gctgctcaga 1201 ttggagactc agtcatgttg acatgtagtg tcatgggctg tgaatcccca tctttctcct 1261 ggagaaccca gatagacagc cctctgagcg ggaaggtgag gagtgagggg accaattcca 1321 cgctgaccct gagccctgtg agttttgaga acgaacactc ttatctgtgc acagtgactt 1381 gtggacataa gaaactggaa aagggaatcc aggtggagct ctactcattc cctagagatc

1441 cagaaatcga gatgagtggt ggcctcgtga atgggagctc tgtcactgta agctgcaagg 1501 ttcctagcgt gtaccccctt gaccggctgg agattgaatt acttaagggg gagactattc 1561 tggagaatat agagtttttg gaggatacgg atatgaaatc tctagagaac aaaagtttgg 1621 aaatgacctt catccctacc attgaagata ctggaaaagc tcttgtttgt caggctaagt 1681 tacatattga tgacatggaa ttcgaaccca aacaaaggca gagtacgcaa acactttatg

1741 tcaatgttgc ccccagagat acaaccgtct tggtcagccc ttcctccatc ctggaggaag 1801 gcagttctgt gaatatgaca tgcttgagcc agggctttcc tgctccgaaa atcctgtgga 1861 gcaggcagct ccctaacggg gagctacagc ctctttctga gaatgcaact ctcaccttaa 1921 tttctacaaa aatggaagat tctggggttt atttatgtga aggaattaac caggctggaa 1981 gaagcagaaa ggaagtggaa ttaattatcc aagttactcc aaaagacata aaacttacag

2041 cttttccttc tgagagtgtc aaagaaggag acactgtcat catctcttgt acatgtggaa 2101 atgttccaga aacatggata atcctgaaga aaaaagcgga gacaggagac acagtactaa 2161 aatctataga tggcgcctat accatccgaa aggcccagtt gaaggatgcg ggagtatatg 2221 aatgtgaatc taaaaacaaa gttggctcac aattaagaag tttaacactt gatgttcaag 2281 gaagagaaaa caacaaagac tatttttctc ctgagcttct cgtgctctat tttgcatcct

2341 ccttaataat acctgccatt ggaatgataa tttactttgc aagaaaagcc aacatgaagg 2401 ggtcatatag tcttgtagaa gcacagaagt caaaagtgta gctaatgctt gatatgttca 2461 actggagaca ctatttatct gtgcaaatcc ttgatactgc tcatcattcc ttgagaaaaa 2521 caatgagctg agaggcagac ttccctgaat gtattgaact tggaaagaaa tgcccatcta 2581 tgtcccttgc tgtgagcaag aagtcaaagt aaaacttgct gcctgaagaa cagtaactgc

2641 catcaagatg agagaactgg aggagttcct tgatctgtat atacaataac ataatttgta 2701 catatgtaaa ataaaattat gccatagcaa gattgcttaa aatagcaaca ctctatattt 2761 agattgttaa aataactagt gttgcttgga ctattataat ttaatgcatg ttaggaaaat 2821 ttcacattaa tatttgctga cagctgacct ttgtcatctt tcttctattt tattcccttt

2881 cacaaaattt tattcctata tagtttattg acaataattt caggttttgt aaagatgccg

2941 ggttttatat ttttatagac aaataataag caaagggagc actgggttga ctttcaggta 3001 ctaaatacct caacctatgg tataatggtt gactgggttt ctctgtatag tactggcatg 3061 gtacggagat gtttcacgaa gtttgttcat cagactcctg tgcaactttc ccaatgtggc 3121 ctaaaaatgc aacttctttt tattttcttt tgtaaatgtt taggtttttt tgtatagtaa

3181 agtgataatt tctggaatta gaaaaaaaaa aaaaaaaaaa Fibronectin (NCBI Ref.: NM 001306129.1; SEQ ID NO: 14)

1 acgcccgcgc cggctgtgct gcacaggggg aggagaggga accccaggcg cgagcgggaa 61 gaggggacct gcagccacaa cttctctggt cctctgcatc ccttctgtcc ctccacccgt 121 ccccttcccc accctctggc ccccaccttc ttggaggcga caacccccgg gaggcattag 181 aagggatttt tcccgcaggt tgcgaaggga agcaaacttg gtggcaactt gcctcccggt

241 gcgggcgtct ctcccccacc gtctcaacat gcttaggggt ccggggcccg ggctgctgct 301 gctggccgtc cagtgcctgg ggacagcggt gccctccacg ggagcctcga agagcaagag 361 gcaggctcag caaatggttc agccccagtc cccggtggct gtcagtcaaa gcaagcccgg 421 ttgttatgac aatggaaaac actatcagat aaatcaacag tgggagcgga cctacctagg 481 caatgcgttg gtttgtactt gttatggagg aagccgaggt tttaactgcg agagtaaacc

541 tgaagctgaa gagacttgct ttgacaagta cactgggaac acttaccgag tgggtgacac 601 ttatgagcgt cctaaagact ccatgatctg ggactgtacc tgcatcgggg ctgggcgagg 661 gagaataagc tgtaccatcg caaaccgctg ccatgaaggg ggtcagtcct acaagattgg 721 tgacacctgg aggagaccac atgagactgg tggttacatg ttagagtgtg tgtgtcttgg 781 taatggaaaa ggagaatgga cctgcaagcc catagctgag aagtgttttg atcatgctgc

841 tgggacttcc tatgtggtcg gagaaacgtg ggagaagccc taccaaggct ggatgatggt 901 agattgtact tgcctgggag aaggcagcgg acgcatcact tgcacttcta gaaatagatg 961 caacgatcag gacacaagga catcctatag aattggagac acctggagca agaaggataa 1021 tcgaggaaac ctgctccagt gcatctgcac aggcaacggc cgaggagagt ggaagtgtga 1081 gaggcacacc tctgtgcaga ccacatcgag cggatctggc cccttcaccg atgttcgtgc

1141 agctgtttac caaccgcagc ctcaccccca gcctcctccc tatggccact gtgtcacaga 1201 cagtggtgtg gtctactctg tggggatgca gtggctgaag acacaaggaa ataagcaaat 1261 gctttgcacg tgcctgggca acggagtcag ctgccaagag acagctgtaa cccagactta 1321 cggtggcaac tcaaatggag agccatgtgt cttaccattc acctacaatg gcaggacgtt 1381 ctactcctgc accacagaag ggcgacagga cggacatctt tggtgcagca caacttcgaa

1441 ttatgagcag gaccagaaat actctttctg cacagaccac actgttttgg ttcagactcg 1501 aggaggaaat tccaatggtg ccttgtgcca cttccccttc ctatacaaca accacaatta 1561 cactgattgc acttctgagg gcagaagaga caacatgaag tggtgtggga ccacacagaa 1621 ctatgatgcc gaccagaagt ttgggttctg ccccatggct gcccacgagg aaatctgcac 1681 aaccaatgaa ggggtcatgt accgcattgg agatcagtgg gataagcagc atgacatggg

1741 tcacatgatg aggtgcacgt gtgttgggaa tggtcgtggg gaatggacat gcattgccta 1801 ctcgcagctt cgagatcagt gcattgttga tgacatcact tacaatgtga acgacacatt 1861 ccacaagcgt catgaagagg ggcacatgct gaactgtaca tgcttcggtc agggtcgggg 1921 caggtggaag tgtgatcccg tcgaccaatg ccaggattca gagactggga cgttttatca 1981 aattggagat tcatgggaga agtatgtgca tggtgtcaga taccagtgct actgctatgg

2041 ccgtggcatt ggggagtggc attgccaacc tttacagacc tatccaagct caagtggtcc 2101 tgtcgaagta tttatcactg agactccgag tcagcccaac tcccacccca tccagtggaa 2161 tgcaccacag ccatctcaca tttccaagta cattctcagg tggagaccta aaaattctgt 2221 aggccgttgg aaggaagcta ccataccagg ccacttaaac tcctacacca tcaaaggcct 2281 gaagcctggt gtggtatacg agggccagct catcagcatc cagcagtacg gccaccaaga

2341 agtgactcgc tttgacttca ccaccaccag caccagcaca cctgtgacca gcaacaccgt 2401 gacaggagag acgactccct tttctcctct tgtggccact tctgaatctg tgaccgaaat 2461 cacagccagt agctttgtgg tctcctgggt ctcagcttcc gacaccgtgt cgggattccg 2521 ggtggaatat gagctgagtg aggagggaga tgagccacag tacctggatc ttccaagcac 2581 agccacttct gtgaacatcc ctgacctgct tcctggccga aaatacattg taaatgtcta 2641 tcagatatct gaggatgggg agcagagttt gatcctgtct acttcacaaa caacagcgcc 2701 tgatgcccct cctgacccga ctgtggacca agttgatgac acctcaattg ttgttcgctg 2761 gagcagaccc caggctccca tcacagggta cagaatagtc tattcgccat cagtagaagg 2821 tagcagcaca gaactcaacc ttcctgaaac tgcaaactcc gtcaccctca gtgacttgca 2881 acctggtgtt cagtataaca tcactatcta tgctgtggaa gaaaatcaag aaagtacacc 2941 tgttgtcatt caacaagaaa ccactggcac cccacgctca gatacagtgc cctctcccag 3001 ggacctgcag tttgtggaag tgacagacgt gaaggtcacc atcatgtgga caccgcctga 3061 gagtgcagtg accggctacc gtgtggatgt gatccccgtc aacctgcctg gcgagcacgg 3121 gcagaggctg cccatcagca ggaacacctt tgcagaagtc accgggctgt cccctggggt 3181 cacctattac ttcaaagtct ttgcagtgag ccatgggagg gagagcaagc ctctgactgc 3241 tcaacagaca accaaactgg atgctcccac taacctccag tttgtcaatg aaactgattc 3301 tactgtcctg gtgagatgga ctccacctcg ggcccagata acaggatacc gactgaccgt 3361 gggccttacc cgaagaggac agcccaggca gtacaatgtg ggtccctctg tctccaagta 3421 cccactgagg aatctgcagc ctgcatctga gtacaccgta tccctcgtgg ccataaaggg 3481 caaccaagag agccccaaag ccactggagt ctttaccaca ctgcagcctg ggagctctat 3541 tccaccttac aacaccgagg tgactgagac caccattgtg atcacatgga cgcctgctcc 3601 aagaattggt tttaagctgg gtgtacgacc aagccaggga ggagaggcac cacgagaagt 3661 gacttcagac tcaggaagca tcgttgtgtc cggcttgact ccaggagtag aatacgtcta 3721 caccatccaa gtcctgagag atggacagga aagagatgcg ccaattgtaa acaaagtggt 3781 gacaccattg tctccaccaa caaacttgca tctggaggca aaccctgaca ctggagtgct 3841 cacagtctcc tgggagagga gcaccacccc agacattact ggttatagaa ttaccacaac 3901 ccctacaaac ggccagcagg gaaattcttt ggaagaagtg gtccatgctg atcagagctc 3961 ctgcactttt gataacctga gtcccggcct ggagtacaat gtcagtgttt acactgtcaa 4021 ggatgacaag gaaagtgtcc ctatctctga taccatcatc ccagaggtgc cccaactcac 4081 tgacctaagc tttgttgata taaccgattc aagcatcggc ctgaggtgga ccccgctaaa 4141 ctcttccacc attattgggt accgcatcac agtagttgcg gcaggagaag gtatccctat 4201 ttttgaagat tttgtggact cctcagtagg atactacaca gtcacagggc tggagccggg 4261 cattgactat gatatcagcg ttatcactct cattaatggc ggcgagagtg cccctactac 4321 actgacacaa caaacggctg ttcctcctcc cactgacctg cgattcacca acattggtcc 4381 agacaccatg cgtgtcacct gggctccacc cccatccatt gatttaacca acttcctggt 4441 gcgttactca cctgtgaaaa atgaggaaga tgttgcagag ttgtcaattt ctccttcaga 4501 caatgcagtg gtcttaacaa atctcctgcc tggtacagaa tatgtagtga gtgtctccag 4561 tgtctacgaa caacatgaga gcacacctct tagaggaaga cagaaaacag gtcttgattc 4621 cccaactggc attgactttt ctgatattac tgccaactct tttactgtgc actggattgc 4681 tcctcgagcc accatcactg gctacaggat ccgccatcat cccgagcact tcagtgggag 4741 acctcgagaa gatcgggtgc cccactctcg gaattccatc accctcacca acctcactcc 4801 aggcacagag tatgtggtca gcatcgttgc tcttaatggc agagaggaaa gtcccttatt 4861 gattggccaa caatcaacag tttctgatgt tccgagggac ctggaagttg ttgctgcgac 4921 ccccaccagc ctactgatca gctgggatgc tcctgctgtc acagtgagat attacaggat 4981 cacttacgga gagacaggag gaaatagccc tgtccaggag ttcactgtgc ctgggagcaa 5041 gtctacagct accatcagcg gccttaaacc tggagttgat tataccatca ctgtgtatgc 5101 tgtcactggc cgtggagaca gccccgcaag cagcaagcca atttccatta attaccgaac 5161 agaaattgac aaaccatccc agatgcaagt gaccgatgtt caggacaaca gcattagtgt 5221 caagtggctg ccttcaagtt cccctgttac tggttacaga gtaaccacca ctcccaaaaa 5281 tggaccagga ccaacaaaaa ctaaaactgc aggtccagat caaacagaaa tgactattga 5341 aggcttgcag cccacagtgg agtatgtggt tagtgtctat gctcagaatc caagcggaga 5401 gagtcagcct ctggttcaga ctgcagtaac caacattgat cgccctaaag gactggcatt 5461 cactgatgtg gatgtcgatt ccatcaaaat tgcttgggaa agcccacagg ggcaagtttc 5521 caggtacagg gtgacctact cgagccctga ggatggaatc catgagctat tccctgcacc 5581 tgatggtgaa gaagacactg cagagctgca aggcctcaga ccgggttctg agtacacagt 5641 cagtgtggtt gccttgcacg atgatatgga gagccagccc ctgattggaa cccagtccac 5701 agctattcct gcaccaactg acctgaagtt cactcaggtc acacccacaa gcctgagcgc 5761 ccagtggaca ccacccaatg ttcagctcac tggatatcga gtgcgggtga cccccaagga 5821 gaagaccgga ccaatgaaag aaatcaacct tgctcctgac agctcatccg tggttgtatc 5881 aggacttatg gtggccacca aatatgaagt gagtgtctat gctcttaagg acactttgac 5941 aagcagacca gctcagggag ttgtcaccac tctggagaat gtcagcccac caagaagggc 6001 tcgtgtgaca gatgctactg agaccaccat caccattagc tggagaacca agactgagac 6061 gatcactggc ttccaagttg atgccgttcc agccaatggc cagactccaa tccagagaac 6121 catcaagcca gatgtcagaa gctacaccat cacaggttta caaccaggca ctgactacaa 6181 gatctacctg tacaccttga atgacaatgc tcggagctcc cctgtggtca tcgacgcctc 6241 cactgccatt gatgcaccat ccaacctgcg tttcctggcc accacaccca attccttgct 6301 ggtatcatgg cagccgccac gtgccaggat taccggctac atcatcaagt atgagaagcc 6361 tgggtctcct cccagagaag tggtccctcg gccccgccct ggtgtcacag aggctactat 6421 tactggcctg gaaccgggaa ccgaatatac aatttatgtc attgccctga agaataatca 6481 gaagagcgag cccctgattg gaaggaaaaa gacagacgag cttccccaac tggtaaccct 6541 tccacacccc aatcttcatg gaccagagat cttggatgtt ccttccacag ttcaaaagac 6601 ccctttcgtc acccaccctg ggtatgacac tggaaatggt attcagcttc ctggcacttc 6661 tggtcagcaa cccagtgttg ggcaacaaat gatctttgag gaacatggtt ttaggcggac 6721 cacaccgccc acaacggcca cccccataag gcataggcca agaccatacc cgccgaatgt 6781 aggacaagaa gctctctctc agacaaccat ctcatgggcc ccattccagg acacttctga 6841 gtacatcatt tcatgtcatc ctgttggcac tgatgaagaa cccttacagt tcagggttcc 6901 tggaacttct accagtgcca ctctgacagg cctcaccaga ggtgccacct acaacatcat 6961 agtggaggca ctgaaagacc agcagaggca taaggttcgg gaagaggttg ttaccgtggg 7021 caactctgtc aacgaaggct tgaaccaacc tacggatgac tcgtgctttg acccctacac 7081 agtttcccat tatgccgttg gagatgagtg ggaacgaatg tctgaatcag gctttaaact 7141 gttgtgccag tgcttaggct ttggaagtgg tcatttcaga tgtgattcat ctagatggtg 7201 ccatgacaat ggtgtgaact acaagattgg agagaagtgg gaccgtcagg gagaaaatgg 7261 ccagatgatg agctgcacat gtcttgggaa cggaaaagga gaattcaagt gtgaccctca 7321 tgaggcaacg tgttatgatg atgggaagac ataccacgta ggagaacagt ggcagaagga 7381 atatctcggt gccatttgct cctgcacatg ctttggaggc cagcggggct ggcgctgtga 7441 caactgccgc agacctgggg gtgaacccag tcccgaaggc actactggcc agtcctacaa 7501 ccagtattct cagagatacc atcagagaac aaacactaat gttaattgcc caattgagtg 7561 cttcatgcct ttagatgtac aggctgacag agaagattcc cgagagtaaa tcatctttcc 7621 aatccagagg aacaagcatg tctctctgcc aagatccatc taaactggag tgatgttagc 7681 agacccagct tagagttctt ctttctttct taagcccttt gctctggagg aagttctcca 7741 gcttcagctc aactcacagc ttctccaagc atcaccctgg gagtttcctg agggttttct 7801 cataaatgag ggctgcacat tgcctgttct gcttcgaagt attcaatacc gctcagtatt 7861 ttaaatgaag tgattctaag atttggtttg ggatcaatag gaaagcatat gcagccaacc 7921 aagatgcaaa tgttttgaaa tgatatgacc aaaattttaa gtaggaaagt cacccaaaca 7981 cttctgcttt cacttaagtg tctggcccgc aatactgtag gaacaagcat gatcttgtta 8041 ctgtgatatt ttaaatatcc acagtactca ctttttccaa atgatcctag taattgccta 8101 gaaatatctt tctcttacct gttatttatc aatttttccc agtattttta tacggaaaaa

8161 attgtattga aaacacttag tatgcagttg ataagaggaa tttggtataa ttatggtggg 8221 tgattatttt ttatactgta tgtgccaaag ctttactact gtggaaagac aactgtttta 8281 ataaaagatt tacattccac aacttgaagt tcatctattt gatataagac accttcgggg 8341 gaaataattc ctgtgaatat tctttttcaa ttcagcaaac atttgaaaat ctatgatgtg 8401 caagtctaat tgttgatttc agtacaagat tttctaaatc agttgctaca aaaactgatt 8461 ggtttttgtc acttcatctc ttcactaatg gagatagctt tacactttct gctttaatag 8521 atttaagtgg accccaatat ttattaaaat tgctagttta ccgttcagaa gtataataga 8581 aataatcttt agttgctctt ttctaaccat tgtaattctt cccttcttcc ctccaccttt

8641 ccttcattga ataaacctct gttcaaagag attgcctgca agggaaataa aaatgactaa 8701 gatattaaaa gtatttgaat agtaaaaaaa aaaaaaaaaa aa

Vitronectin (NCBI Ref.: NM 000638.3; SEQ ID NO: 15)

1 gagcaaacag agcagcagaa aaggcagttc ctcttctcca gtgccctcct tccctgtctc 61 tgcctctccc tcccttcctc aggcatcaga gcggagactt cagggagacc agagcccagc 121 ttgccaggca ctgagctaga agccctgcca tggcacccct gagacccctt ctcatactgg

181 ccctgctggc atgggttgct ctggctgacc aagagtcatg caagggccgc tgcactgagg 241 gcttcaacgt ggacaagaag tgccagtgtg acgagctctg ctcttactac cagagctgct 301 gcacagacta tacggctgag tgcaagcccc aagtgactcg cggggatgtg ttcactatgc 361 cggaggatga gtacacggtc tatgacgatg gcgaggagaa aaacaatgcc actgtccatg 421 aacaggtggg gggcccctcc ctgacctctg acctccaggc ccagtccaaa gggaatcctg

481 agcagacacc tgttctgaaa cctgaggaag aggcccctgc gcctgaggtg ggcgcctcta 541 agcctgaggg gatagactca aggcctgaga cccttcatcc agggagacct cagcccccag 601 cagaggagga gctgtgcagt gggaagccct tcgacgcctt caccgacctc aagaacggtt 661 ccctctttgc cttccgaggg cagtactgct atgaactgga cgaaaaggca gtgaggcctg 721 ggtaccccaa gctcatccga gatgtctggg gcatcgaggg ccccatcgat gccgccttca

781 cccgcatcaa ctgtcagggg aagacctacc tcttcaaggg tagtcagtac tggcgctttg 841 aggatggtgt cctggaccct gattaccccc gaaatatctc tgacggcttc gatggcatcc 901 cggacaacgt ggatgcagcc ttggccctcc ctgcccatag ctacagtggc cgggagcggg 961 tctacttctt caaggggaaa cagtactggg agtaccagtt ccagcaccag cccagtcagg 1021 aggagtgtga aggcagctcc ctgtcggctg tgtttgaaca ctttgccatg atgcagcggg

1081 acagctggga ggacatcttc gagcttctct tctggggcag aacctctgct ggtaccagac 1141 agccccagtt cattagccgg gactggcacg gtgtgccagg gcaagtggac gcagccatgg 1201 ctggccgcat ctacatctca ggcatggcac cccgcccctc cttggccaag aaacaaaggt 1261 ttaggcatcg caaccgcaaa ggctaccgtt cacaacgagg ccacagccgt ggccgcaacc 1321 agaactcccg ccggccatcc cgcgccacgt ggctgtcctt gttctccagt gaggagagca

1381 acttgggagc caacaactat gatgactaca ggatggactg gcttgtgcct gccacctgtg 1441 aacccatcca gagtgtcttc ttcttctctg gagacaagta ctaccgagtc aatcttcgca 1501 cacggcgagt ggacactgtg gaccctccct acccacgctc catcgctcag tactggctgg 1561 gctgcccagc tcctggccat ctgtaggagt cagagcccac atggccgggc cctctgtagc 1621 tccctcctcc catctccttc ccccagccca ataaaggtcc cttagccccg agtttaaa

Tenascin-C (NCBI Ref.: NM 002160.3; SEQ ID NO: 16)

1 aattcgccaa ctgaaaaagt gggaaaggat gtctggaggc gaggcgtccc attacagagg

61 aaggagctcg ctatataagc cagccaaagt tggctgcacc ggccacagcc tgcctactgt 121 cacccgcctc tcccgcgcgc agatacacgc ccccgcctcc gtgggcacaa aggcagcgct 181 gctggggaac tcgggggaac gcgcacgtgg gaaccgccgc agctccacac tccaggtact 241 tcttccaagg acctaggtct ctcgcccatc ggaaagaaaa taattctttc aagaagatca 301 gggacaactg atttgaagtc tactctgtgc ttctaaatcc ccaattctgc tgaaagtgag

361 ataccctaga gccctagagc cccagcagca cccagccaaa cccacctcca ccatgggggc 421 catgactcag ctgttggcag gtgtctttct tgctttcctt gccctcgcta ccgaaggtgg 481 ggtcctcaag aaagtcatcc ggcacaagcg acagagtggg gtgaacgcca ccctgccaga 541 agagaaccag ccagtggtgt ttaaccacgt ttacaacatc aagctgccag tgggatccca 601 gtgttcggtg gatctggagt cagccagtgg ggagaaagac ctggcaccgc cttcagagcc

661 cagcgaaagc tttcaggagc acacagtgga tggggaaaac cagattgtct tcacacatcg 721 catcaacatc ccccgccggg cctgtggctg tgccgcagcc cctgatgtta aggagctgct 781 gagcagactg gaggagctgg agaacctggt gtcttccctg agggagcaat gtactgcagg 841 agcaggctgc tgtctccagc ctgccacagg ccgcttggac accaggccct tctgtagcgg 901 tcggggcaac ttcagcactg aaggatgtgg ctgtgtctgc gaacctggct ggaaaggccc

961 caactgctct gagcccgaat gtccaggcaa ctgtcacctt cgaggccggt gcattgatgg 1021 gcagtgcatc tgtgacgacg gcttcacggg cgaggactgc agccagctgg cttgccccag 1081 cgactgcaat gaccagggca agtgcgtaaa tggagtctgc atctgtttcg aaggctacgc 1141 cggggctgac tgcagccgtg aaatctgccc agtgccctgc agtgaggagc acggcacatg 1201 tgtagatggc ttgtgtgtgt gccacgatgg ctttgcaggc gatgactgca acaagcctct

1261 gtgtctcaac aattgctaca accgtggacg atgcgtggag aatgagtgcg tgtgtgatga 1321 gggtttcacg ggcgaagact gcagtgagct catctgcccc aatgactgct tcgaccgggg 1381 ccgctgcatc aatggcacct gctactgcga agaaggcttc acaggtgaag actgcgggaa 1441 acccacctgc ccacatgcct gccacaccca gggccggtgt gaggaggggc agtgtgtatg 1501 tgatgagggc tttgccggtg tggactgcag cgagaagagg tgtcctgctg actgtcacaa

1561 tcgtggccgc tgtgtagacg ggcggtgtga gtgtgatgat ggtttcactg gagctgactg 1621 tggggagctc aagtgtccca atggctgcag tggccatggc cgctgtgtca atgggcagtg 1681 tgtgtgtgat gagggctata ctggggagga ctgcagccag ctacggtgcc ccaatgactg 1741 tcacagtcgg ggccgctgtg tcgagggcaa atgtgtatgt gagcaaggct tcaagggcta 1801 tgactgcagt gacatgagct gccctaatga ctgtcaccag cacggccgct gtgtgaatgg

1861 catgtgtgtt tgtgatgacg gctacacagg ggaagactgc cgggatcgcc aatgccccag 1921 ggactgcagc aacaggggcc tctgtgtgga cggacagtgc gtctgtgagg acggcttcac 1981 cggccctgac tgtgcagaac tctcctgtcc aaatgactgc catggccagg gtcgctgtgt 2041 gaatgggcag tgcgtgtgcc atgaaggatt tatgggcaaa gactgcaagg agcaaagatg 2101 tcccagtgac tgtcatggcc agggccgctg cgtggacggc cagtgcatct gccacgaggg

2161 cttcacaggc ctggactgtg gccagcactc ctgccccagt gactgcaaca acttaggaca 2221 atgcgtctcg ggccgctgca tctgcaacga gggctacagc ggagaagact gctcagaggt 2281 gtctcctccc aaagacctcg ttgtgacaga agtgacggaa gagacggtca acctggcctg 2341 ggacaatgag atgcgggtca cagagtacct tgtcgtgtac acgcccaccc acgagggtgg 2401 tctggaaatg cagttccgtg tgcctgggga ccagacgtcc accatcatcc aggagctgga 2461 gcctggtgtg gagtacttta tccgtgtatt tgccatcctg gagaacaaga agagcattcc 2521 tgtcagcgcc agggtggcca cgtacttacc tgcacctgaa ggcctgaaat tcaagtccat 2581 caaggagaca tctgtggaag tggagtggga tcctctagac attgcttttg aaacctggga 2641 gatcatcttc cggaatatga ataaagaaga tgagggagag atcaccaaaa gcctgaggag 2701 gccagagacc tcttaccggc aaactggtct agctcctggg caagagtatg agatatctct 2761 gcacatagtg aaaaacaata cccggggccc tggcctgaag agggtgacca ccacacgctt 2821 ggatgccccc agccagatcg aggtgaaaga tgtcacagac accactgcct tgatcacctg 2881 gttcaagccc ctggctgaga tcgatggcat tgagctgacc tacggcatca aagacgtgcc 2941 aggagaccgt accaccatcg atctcacaga ggacgagaac cagtactcca tcgggaacct 3001 gaagcctgac actgagtacg aggtgtccct catctcccgc agaggtgaca tgtcaagcaa 3061 cccagccaaa gagaccttca caacaggcct cgatgctccc aggaatcttc gacgtgtttc 3121 ccagacagat aacagcatca ccctggaatg gaggaatggc aaggcagcta ttgacagtta 3181 cagaattaag tatgccccca tctctggagg ggaccacgct gaggttgatg ttccaaagag 3241 ccaacaagcc acaaccaaaa ccacactcac aggtctgagg ccgggaactg aatatgggat 3301 tggagtttct gctgtgaagg aagacaagga gagcaatcca gcgaccatca acgcagccac 3361 agagttggac acgcccaagg accttcaggt ttctgaaact gcagagacca gcctgaccct 3421 gctctggaag acaccgttgg ccaaatttga ccgctaccgc ctcaattaca gtctccccac 3481 aggccagtgg gtgggagtgc agcttccaag aaacaccact tcctatgtcc tgagaggcct 3541 ggaaccagga caggagtaca atgtcctcct gacagccgag aaaggcagac acaagagcaa 3601 gcccgcacgt gtgaaggcat ccactgaaca agcccctgag ctggaaaacc tcaccgtgac 3661 tgaggttggc tgggatggcc tcagactcaa ctggaccgca gctgaccagg cctatgagca 3721 ctttatcatt caggtgcagg aggccaacaa ggtggaggca gctcggaacc tcaccgtgcc 3781 tggcagcctt cgggctgtgg acataccggg cctcaaggct gctacgcctt atacagtctc 3841 catctatggg gtgatccagg gctatagaac accagtgctc tctgctgagg cctccacagg 3901 ggaaactccc aatttgggag aggtcgtggt ggccgaggtg ggctgggatg ccctcaaact 3961 caactggact gctccagaag gggcctatga gtactttttc attcaggtgc aggaggctga 4021 cacagtagag gcagcccaga acctcaccgt cccaggagga ctgaggtcca cagacctgcc 4081 tgggctcaaa gcagccactc attataccat caccatccgc ggggtcactc aggacttcag 4141 cacaacccct ctctctgttg aagtcttgac agaggaggtt ccagatatgg gaaacctcac 4201 agtgaccgag gttagctggg atgctctcag actgaactgg accacgccag atggaaccta 4261 tgaccagttt actattcagg tccaggaggc tgaccaggtg gaagaggctc acaatctcac 4321 ggttcctggc agcctgcgtt ccatggaaat cccaggcctc agggctggca ctccttacac 4381 agtcaccctg cacggcgagg tcaggggcca cagcactcga ccccttgctg tagaggtcgt 4441 cacagaggat ctcccacagc tgggagattt agccgtgtct gaggttggct gggatggcct 4501 cagactcaac tggaccgcag ctgacaatgc ctatgagcac tttgtcattc aggtgcagga 4561 ggtcaacaaa gtggaggcag cccagaacct cacgttgcct ggcagcctca gggctgtgga 4621 catcccgggc ctcgaggctg ccacgcctta tagagtctcc atctatgggg tgatccgggg 4681 ctatagaaca ccagtactct ctgctgaggc ctccacagcc aaagaacctg aaattggaaa 4741 cttaaatgtt tctgacataa ctcccgagag cttcaatctc tcctggatgg ctaccgatgg 4801 gatcttcgag acctttacca ttgaaattat tgattccaat aggttgctgg agactgtgga 4861 atataatatc tctggtgctg aacgaactgc ccatatctca gggctacccc ctagtactga 4921 ttttattgtc tacctctctg gacttgctcc cagcatccgg accaaaacca tcagtgccac 4981 agccacgaca gaggccctgc cccttctgga aaacctaacc atttccgaca ttaatcccta 5041 cgggttcaca gtttcctgga tggcatcgga gaatgccttt gacagctttc tagtaacggt 5101 ggtggattct gggaagctgc tggaccccca ggaattcaca ctttcaggaa cccagaggaa 5161 gctggagctt agaggcctca taactggcat tggctatgag gttatggtct ctggcttcac 5221 ccaagggcat caaaccaagc ccttgagggc tgagattgtt acagaagccg aaccggaagt 5281 tgacaacctt ctggtttcag atgccacccc agacggtttc cgtctgtcct ggacagctga 5341 tgaaggggtc ttcgacaatt ttgttctcaa aatcagagat accaaaaagc agtctgagcc 5401 actggaaata accctacttg cccccgaacg taccagggac ataacaggtc tcagagaggc 5461 tactgaatac gaaattgaac tctatggaat aagcaaagga aggcgatccc agacagtcag 5521 tgctatagca acaacagcca tgggctcccc aaaggaagtc attttctcag acatcactga 5581 aaattcggct actgtcagct ggagggcacc cacagcccaa gtggagagct tccggattac 5641 ctatgtgccc attacaggag gtacaccctc catggtaact gtggacggaa ccaagactca 5701 gaccaggctg gtgaaactca tacctggcgt ggagtacctt gtcagcatca tcgccatgaa 5761 gggctttgag gaaagtgaac ctgtctcagg gtcattcacc acagctctgg atggcccatc 5821 tggcctggtg acagccaaca tcactgactc agaagccttg gccaggtggc agccagccat 5881 tgccactgtg gacagttatg tcatctccta cacaggcgag aaagtgccag aaattacacg 5941 cacggtgtcc gggaacacag tggagtatgc tctgaccgac ctcgagcctg ccacggaata 6001 cacactgaga atctttgcag agaaagggcc ccagaagagc tcaaccatca ctgccaagtt 6061 cacaacagac ctcgattctc caagagactt gactgctact gaggttcagt cggaaactgc 6121 cctccttacc tggcgacccc cccgggcatc agtcaccggt tacctgctgg tctatgaatc 6181 agtggatggc acagtcaagg aagtcattgt gggtccagat accacctcct acagcctggc 6241 agacctgagc ccatccaccc actacacagc caagatccag gcactcaatg ggcccctgag 6301 gagcaatatg atccagacca tcttcaccac aattggactc ctgtacccct tccccaagga 6361 ctgctcccaa gcaatgctga atggagacac gacctctggc ctctacacca tttatctgaa 6421 tggtgataag gctgaggcgc tggaagtctt ctgtgacatg acctctgatg ggggtggatg 6481 gattgtgttc ctgagacgca aaaacggacg cgagaacttc taccaaaact ggaaggcata 6541 tgctgctgga tttggggacc gcagagaaga attctggctt gggctggaca acctgaacaa 6601 aatcacagcc caggggcagt acgagctccg ggtggacctg cgggaccatg gggagacagc 6661 ctttgctgtc tatgacaagt tcagcgtggg agatgccaag actcgctaca agctgaaggt 6721 ggaggggtac agtgggacag caggtgactc catggcctac cacaatggca gatccttctc 6781 cacctttgac aaggacacag attcagccat caccaactgt gctctgtcct acaaaggggc 6841 tttctggtac aggaactgtc accgtgtcaa cctgatgggg agatatgggg acaataacca 6901 cagtcagggc gttaactggt tccactggaa gggccacgaa cactcaatcc agtttgctga 6961 gatgaagctg agaccaagca acttcagaaa tcttgaaggc aggcgcaaac gggcataaat 7021 tccagggacc actgggtgag agaggaataa ggcccagagc gaggaaagga ttttaccaaa 7081 gcatcaatac aaccagccca accatcggtc cacacctggg catttggtga gagtcaaagc 7141 tgaccatgga tccctggggc caacggcaac agcatgggcc tcacctcctc tgtgatttct 7201 ttctttgcac caaagacatc agtctccaac atgtttctgt tttgttgttt gattcagcaa 7261 aaatctccca gtgacaacat cgcaatagtt ttttacttct cttaggtggc tctgggaatg 7321 ggagaggggt aggatgtaca ggggtagttt gttttagaac cagccgtatt ttacatgaag 7381 ctgtataatt aattgtcatt atttttgtta gcaaagatta aatgtgtcat tggaagccat 7441 cccttttttt acatttcata caacagaaac cagaaaagca atactgtttc cattttaagg 7501 atatgattaa tattattaat ataataatga tgatgatgat gatgaaaact aaggattttt 7561 caagagatct ttctttccaa aacatttctg gacagtacct gattgtattt tttttttaaa 7621 taaaagcaca agtacttttg agtttgttat tttgctttga attgttgagt ctgaatttca 7681 ccaaagccaa tcatttgaac aaagcgggga atgttgggat aggaaaggta agtagggata 7741 gtggtcaagt gggaggggtg gaaaggagac taaagactgg gagagaggga agcacttttt 7801 ttaaataaag ttgaacacac ttgggaaaag cttacaggcc aggcctgtaa tcccaacact 7861 ttgggaggcc aaggtgggag gatagcttaa ccccaggagt ttgagaccag cctgagcaac

7921 atagtgagaa cttgtctcta cagaaaaaaa aaaaaaaaaa aatttaatta ggcaagcgtg 7981 gtagtgcgca cctgtcgtcc cagctactca ggaggctgag gtaggaaaat cactggagcc 8041 caggagttag aggttacagt gagctatgat cacactactg cactccagcc tgggcaacag 8101 agggagaccc tgtctctaaa taaaaaaaga aaagaaaaaa aaagcttaca acttgagatt 8161 cagcatcttg ctcagtattt ccaagactaa tagattatgg tttaaaagat gcttttatac

8221 tcattttcta atgcaactcc tagaaactct atgatatagt tgaggtaagt attgttacca 8281 cacatgggct aagatcccca gaggcagact gcctgagttc aattcttggc tccaccattc 8341 ccaagttccc taacctctct atgcctcagt ttcctcttct gtaaagtagg gacactcata 8401 cttctcattt cagaacattt ttgtgaagaa taaattatgt tatccatttg aggcccttag 8461 aatggtaccc ggtgtatatt aagtgctagt acatgttagc tatcatcatt atcactttat

8521 atgagatgga ctggggttca tagaaaccca atgacttgat tgtggctact actcaataaa 8581 taatagaatt tggatttaaa aaaaa

Osteopontin (NCBI Ref.: NM 000582.2; SEQ ID NO: 17)

1 ctccctgtgt tggtggagga tgtctgcagc agcatttaaa ttctgggagg gcttggttgt

61 cagcagcagc aggaggaggc agagcacagc atcgtcggga ccagactcgt ctcaggccag 121 ttgcagcctt ctcagccaaa cgccgaccaa ggaaaactca ctaccatgag aattgcagtg 181 atttgctttt gcctcctagg catcacctgt gccataccag ttaaacaggc tgattctgga 241 agttctgagg aaaagcagct ttacaacaaa tacccagatg ctgtggccac atggctaaac 301 cctgacccat ctcagaagca gaatctccta gccccacaga cccttccaag taagtccaac

361 gaaagccatg accacatgga tgatatggat gatgaagatg atgatgacca tgtggacagc 421 caggactcca ttgactcgaa cgactctgat gatgtagatg acactgatga ttctcaccag 481 tctgatgagt ctcaccattc tgatgaatct gatgaactgg tcactgattt tcccacggac 541 ctgccagcaa ccgaagtttt cactccagtt gtccccacag tagacacata tgatggccga 601 ggtgatagtg tggtttatgg actgaggtca aaatctaaga agtttcgcag acctgacatc

661 cagtaccctg atgctacaga cgaggacatc acctcacaca tggaaagcga ggagttgaat 721 ggtgcataca aggccatccc cgttgcccag gacctgaacg cgccttctga ttgggacagc 781 cgtgggaagg acagttatga aacgagtcag ctggatgacc agagtgctga aacccacagc 841 cacaagcagt ccagattata taagcggaaa gccaatgatg agagcaatga gcattccgat 901 gtgattgata gtcaggaact ttccaaagtc agccgtgaat tccacagcca tgaatttcac

961 agccatgaag atatgctggt tgtagacccc aaaagtaagg aagaagataa acacctgaaa 1021 tttcgtattt ctcatgaatt agatagtgca tcttctgagg tcaattaaaa ggagaaaaaa 1081 tacaatttct cactttgcat ttagtcaaaa gaaaaaatgc tttatagcaa aatgaaagag 1141 aacatgaaat gcttctttct cagtttattg gttgaatgtg tatctatttg agtctggaaa 1201 taactaatgt gtttgataat tagtttagtt tgtggcttca tggaaactcc ctgtaaacta

1261 aaagcttcag ggttatgtct atgttcattc tatagaagaa atgcaaacta tcactgtatt 1321 ttaatatttg ttattctctc atgaatagaa atttatgtag aagcaaacaa aatactttta 1381 cccacttaaa aagagaatat aacattttat gtcactataa tcttttgttt tttaagttag 1441 tgtatatttt gttgtgatta tctttttgtg gtgtgaataa atcttttatc ttgaatgtaa

1501 taagaatttg gtggtgtcaa ttgcttattt gttttcccac ggttgtccag caattaataa 1561 aacataacct tttttactgc ctaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaa

Nephronectin (NCBI Ref.: NM 001033047.2; SEQ ID NO: 18)

1 tagaagggag cgggaggggg ctccgggcgc cgcgcagcag acctgctccg gccgcgcgcc 61 tcgccgctgt cctccgggag cggcagcagt agcccgggcg gcgagggctg ggggttcctc 121 gagactctca gaggggcgcc tcccatcggc gcccaccacc ccaacctgtt cctcgcgcgc 181 cactgcgctg cgccccagga cccgctgccc aacatggatt ttctcctggc gctggtgctg 241 gtatcctcgc tctacctgca ggcggccgcc gagttcgacg ggaggtggcc caggcaaata

301 gtgtcatcga ttggcctatg tcgttatggt gggaggattg actgctgctg gggctgggct 361 cgccagtctt ggggacagtg tcagcctgtg tgccaaccac gatgcaaaca tggtgaatgt 421 atcgggccaa acaagtgcaa gtgtcatcct ggttatgctg gaaaaacctg taatcaagat 481 ctaaatgagt gtggcctgaa gccccggccc tgtaagcaca ggtgcatgaa cacttacggc 541 agctacaagt gctactgtct caacggatat atgctcatgc cggatggttc ctgctcaagt

601 gccctgacct gctccatggc aaactgtcag tatggctgtg atgttgttaa aggacaaata 661 cggtgccagt gcccatcccc tggcctgcag ctggctcctg atgggaggac ctgtgtagat 721 gttgatgaat gtgctacagg aagagcctcc tgccctagat ttaggcaatg tgtcaacact 781 tttgggagct acatctgcaa gtgtcataaa ggcttcgatc tcatgtatat tggaggcaaa 841 tatcaatgtc atgacataga cgaatgctca cttggtcagt atcagtgcag cagctttgct

901 cgatgttata acatacgtgg gtcctacaag tgcaaatgta aagaaggata ccagggtgat 961 ggactgactt gtgtgtatat cccaaaagtt atgattgaac cttcaggtcc aattcatgta 1021 ccaaagggaa atggtaccat tttaaagggt gacacaggaa ataataattg gattcctgat 1081 gttggaagta cttggtggcc tccgaagaca ccatatattc ctcctatcat taccaacagg 1141 cctacttcta agccaacaac aagacctaca ccaaagccaa caccaattcc tactccacca

1201 ccaccaccac ccctgccaac agagctcaga acacctctac cacctacaac cccagaaagg 1261 ccaaccaccg gactgacaac tatagcacca gctgccagta cacctccagg agggattaca 1321 gttgacaaca gggtacagac agaccctcag aaacccagag gagatgtgtt cattccacgg 1381 caaccttcaa atgacttgtt tgaaatattt gaaatagaaa gaggagtcag tgcagacgat 1441 gaagcaaagg atgatccagg tgttctggta cacagttgta attttgacca tggactttgt

1501 ggatggatca gggagaaaga caatgacttg cactgggaac caatcaggga cccagcaggt 1561 ggacaatatc tgacagtgtc ggcagccaaa gccccagggg gaaaagctgc acgcttggtg 1621 ctacctctcg gccgcctcat gcattcaggg gacctgtgcc tgtcattcag gcacaaggtg 1681 acggggctgc actctggcac actccaggtg tttgtgagaa aacacggtgc ccacggagca 1741 gccctgtggg gaagaaatgg tggccatggc tggaggcaaa cacagatcac cttgcgaggg

1801 gctgacatca agagcgtcgt cttcaaaggt gaaaaaaggc gtggtcacac tggggagatt 1861 ggattagatg atgtgagctt gaaaaaaggc cactgctctg aagaacgcta acaactccag 1921 aactaacaat gaactcctat gttgctctat cctctttttc caattctcat cttctctcct

1981 cttctccctt ttatcaggcc taggagaaga gtgggtcagt gggtcagaag gaagtctatt 2041 tggtgaccca ggtttttctg gcctgctttt gtgcaatccc aatgaacagt gataccctcc

2101 ttgaaataca ggggcatcgc agacacatca aagccatctg tgggtgttgc cttccatcct 2161 gtgtctcttt caggaaggca ttcagcatgc gtgagccata ccatcctcca tcctgattac 2221 aaggtgctcc ttgtagcaaa ttatgagagt gagttacggg agcagttttt aaaagaaatc 2281 tttgcagatg gctatgatgt tatgtgttcg gtgttgtacc atgagtagta ttgacttccc 2341 ttgagatatg atgtacaatg tgcttgtgaa attgacttac cctcttcact taagttagtt 2401 ctggcctgac ctgaactctg acttttactg ccattcactt tataaaataa gggtgtgtaa 2461 catatcaaga tacatttatt tttatctgtt ttttttttcc tgttaaagac aattatgtag

2521 agtgggcacg taatccctcc ttagtagtat tgtgttttgt gtaaatgtgc tattgatatt

2581 aagtatttac atgttccaaa tatttacaga ctctagttgc aaggtaaagg gcagcttgtg 2641 atctcaaaaa aatacatggt gaaatgtcat ccagttccat gaccttatat tggcagcagt 2701 aggaaattgg cagaagtgtt gggttgtggt aacggagtga tgaatttttt tttaatggcc 2761 ttgagtttga tctctgcaaa ggataggaaa cctttaggaa gacaagaaac tgcagttaat 2821 ttagaactgt cactgtttca agttacactt taaaaccaca gcttttacca tcataacatg

2881 gctctggtaa tatgtaggaa gctttataaa agttttggtt gattcagaaa aaggatcctg 2941 ttgcagagtg agaggaagca tagggggaaa ctccattgga acagattttc acacaacgtt 3001 ttaaattgat ataagtttag gcagttgtag ttcataactt atgttgctca tgttgtgctg 3061 tgtcaggatg ggataggaag caagtcccat gcttagaggc atgggatgtg ttggaacggg 3121 atttacacac actggaggag cagggcaagt tggaattcta agatccatga acccccaact

3181 gtatttcctc cctgcatatt ttaccaatat attaaaaaac aatgtaactt ttaaaaggca 3241 tcattcctga ggtttgtctt aatttctgat taagtaatca gaatattttc tgctattttt 3301 gccaggaatc acaaagatga ttaaagggtt ggaaaaaaag atctatgatg gaaaattaaa 3361 ggaactggga ttattgagcc tggagaagag aagactgagg ggcaaaccat tgatggtttt 3421 caagtatatg aagggttggc acagagaggg tggcgaccag ctgttctcca tatgcactaa

3481 gaatagaaca agaggaaact ggcttagact agagtataag ggagcatttc ttggcagggg 3541 ccattgttag aatacttcat aaaaaaagaa gtgtgaaaat ctcagtatct ctctctcttt 3601 ctaaaaaatt agataaaaat ttgtctattt aagatggtta aagatgttct tacccaagga 3661 aaagtaacaa attatagaat ttcccaaaag atgttttgat cctactagta gtatgcagtg 3721 aaaatcttta gaactaaata atttggacaa ggcttaattt aggcatttcc ctcttgacct

3781 cctaatggag agggattgaa aggggaagag cccaccaaat gctgagctca ctgaaatatc 3841 tctcccttat ggcaatccta gcagtattaa agaaaaaagg aaactattta ttccaaatga 3901 gagtatgatg gacagatatt ttagtatctc agtaatgtcc tagtgtggcg gtggttttca 3961 atgtttcttc atgttaaagg tataagcctt tcatttgttc aatggatgat gtttcagatt 4021 tttttttttt taagagatcc ttcaaggaac acagttcaga gagattttca tcgggtgcat

4081 tctctctgct tcgtgtgtga caagttatct tggctgctga gaaagagtgc cctgccccac 4141 accggcagac ctttccttca cctcatcagt atgattcagt ttctcttatc aattggactc 4201 tcccaggttc cacagaacag taatattttt tgaacaatag gtacaataga aggtcttctg 4261 tcatttaacc tggtaaaggc agggctggag ggggaaaata aatcattaag cctttgagta 4321 acggcagaat atatggctgt agatccattt ttaatggttc atttccttta tggtcatata

4381 actgcacagc tgaagatgaa aggggaaaat aaatgaaaat tttacttttc gatgccaatg 4441 atacattgca ctaaactgat ggaagaagtt atccaaagta ctgtataaca tcttgtttat 4501 tatttaatgt tttctaaaat aaaaaatgtt agtggttttc caaatggcct aataaaaaca 4561 attatttgta aataaaaaca ctgttagtaa ta

Angiostatin (PLG) (NCBI Ref.: NM 000301.3; SEQ ID NO: 19)

1 gaatcattaa cttaatttga ctatctggtt tgtggatgcg tttactctca tgtaagtcaa 61 caacatcctg ggattgggac ccactttctg ggcactgctg gccagtccca aaatggaaca 121 taaggaagtg gttcttctac ttcttttatt tctgaaatca ggtcaaggag agcctctgga 181 tgactatgtg aatacccagg gggcttcact gttcagtgtc actaagaagc agctgggagc 241 aggaagtata gaagaatgtg cagcaaaatg tgaggaggac gaagaattca cctgcagggc 301 attccaatat cacagtaaag agcaacaatg tgtgataatg gctgaaaaca ggaagtcctc 361 cataatcatt aggatgagag atgtagtttt atttgaaaag aaagtgtatc tctcagagtg

421 caagactggg aatggaaaga actacagagg gacgatgtcc aaaacaaaaa atggcatcac 481 ctgtcaaaaa tggagttcca cttctcccca cagacctaga ttctcacctg ctacacaccc 541 ctcagaggga ctggaggaga actactgcag gaatccagac aacgatccgc aggggccctg 601 gtgctatact actgatccag aaaagagata tgactactgc gacattcttg agtgtgaaga 661 ggaatgtatg cattgcagtg gagaaaacta tgacggcaaa atttccaaga ccatgtctgg

721 actggaatgc caggcctggg actctcagag cccacacgct catggataca ttccttccaa 781 atttccaaac aagaacctga agaagaatta ctgtcgtaac cccgataggg agctgcggcc 841 ttggtgtttc accaccgacc ccaacaagcg ctgggaactt tgtgacatcc cccgctgcac 901 aacacctcca ccatcttctg gtcccaccta ccagtgtctg aagggaacag gtgaaaacta 961 tcgcgggaat gtggctgtta ccgtgtccgg gcacacctgt cagcactgga gtgcacagac

1021 ccctcacaca cataacagga caccagaaaa cttcccctgc aaaaatttgg atgaaaacta 1081 ctgccgcaat cctgacggaa aaagggcccc atggtgccat acaaccaaca gccaagtgcg 1141 gtgggagtac tgtaagatac cgtcctgtga ctcctcccca gtatccacgg aacaattggc 1201 tcccacagca ccacctgagc taacccctgt ggtccaggac tgctaccatg gtgatggaca 1261 gagctaccga ggcacatcct ccaccaccac cacaggaaag aagtgtcagt cttggtcatc

1321 tatgacacca caccggcacc agaagacccc agaaaactac ccaaatgctg gcctgacaat 1381 gaactactgc aggaatccag atgccgataa aggcccctgg tgttttacca cagaccccag 1441 cgtcaggtgg gagtactgca acctgaaaaa atgctcagga acagaagcga gtgttgtagc 1501 acctccgcct gttgtcctgc ttccagatgt agagactcct tccgaagaag actgtatgtt 1561 tgggaatggg aaaggatacc gaggcaagag ggcgaccact gttactggga cgccatgcca

1621 ggactgggct gcccaggagc cccatagaca cagcattttc actccagaga caaatccacg 1681 ggcgggtctg gaaaaaaatt actgccgtaa ccctgatggt gatgtaggtg gtccctggtg 1741 ctacacgaca aatccaagaa aactttacga ctactgtgat gtccctcagt gtgcggcccc 1801 ttcatttgat tgtgggaagc ctcaagtgga gccgaagaaa tgtcctggaa gggttgtagg 1861 ggggtgtgtg gcccacccac attcctggcc ctggcaagtc agtcttagaa caaggtttgg

1921 aatgcacttc tgtggaggca ccttgatatc cccagagtgg gtgttgactg ctgcccactg 1981 cttggagaag tccccaaggc cttcatccta caaggtcatc ctgggtgcac accaagaagt 2041 gaatctcgaa ccgcatgttc aggaaataga agtgtctagg ctgttcttgg agcccacacg 2101 aaaagatatt gccttgctaa agctaagcag tcctgccgtc atcactgaca aagtaatccc 2161 agcttgtctg ccatccccaa attatgtggt cgctgaccgg accgaatgtt tcatcactgg

2221 ctggggagaa acccaaggta cttttggagc tggccttctc aaggaagccc agctccctgt 2281 gattgagaat aaagtgtgca atcgctatga gtttctgaat ggaagagtcc aatccaccga 2341 actctgtgct gggcatttgg ccggaggcac tgacagttgc cagggtgaca gtggaggtcc 2401 tctggtttgc ttcgagaagg acaaatacat tttacaagga gtcacttctt ggggtcttgg 2461 ctgtgcacgc cccaataagc ctggtgtcta tgttcgtgtt tcaaggtttg ttacttggat

2521 tgagggagtg atgagaaata attaattgga cgggagacag agtgacgcac tgactcacct 2581 agaggctgga acgtgggtag ggatttagca tgctggaaat aactggcagt aatcaaacga 2641 agacactgtc cccagctacc agctacgcca aacctcggca ttttttgtgt tattttctga 2701 ctgctggatt ctgtagtaag gtgacatagc tatgacattt gttaaaaata aactctgtac 2761 ttaactttga tttgagtaaa ttttggtttt ggtcttcaac attttcatgc tctttgttca

2821 ccccaccaat ttttaaatgg gcagatgggg ggatttagct gcttttgata aggaacagct

2881 gcacaaagga ctgagcaggc tgcaaggtca cagaggggag agccaagaag ttgtccacgc

2941 atttacctca tcagctaacg agggcttgac atgcattttt actgtcttta ttcctgacac

3001 tgagatgaat gttttcaaag ctgcaacatg tatggggagt catgcaaacc gattctgtta

3061 ttgggaatga aatctgtcac cgactgcttg acttgagccc aggggacacg gagcagagag

3121 ctgtatatga tggagtgaac cggtccatgg atgtgtaaca caagaccaac tgagagtctg

3181 aatgttattc tggggcacac gtgagtctag gattggtgcc aagagcatgt aaatgaacaa

3241 caagcaaata ttgaaggtgg accacttatt tcccattgct aattgcctgc ccggttttga

3301 aacagtctgc agtacacacg gtcacaggag aatgacctgt gggagagata catgtttaga

3361 aggaagagaa aggacaaagg cacacgtttt accatttaaa atattgttac caaacaaaaa

3421 tatccattca aaatacaatt taacaatgca acagtcatct tacagcagag aaatgcagag

3481 aaaagcaaaa ctgcaagtga ctgtgaataa agggtgaatg tagtctcaaa tcctcaaa

Tissue transglutaminase factor XIII (F13A1) (NCBI Ref.: NM 000129.3; SEQ ID NO: 20)

1 atttaagagc caactgtctt gtctttcccg agtccgtttg aggaagtccc cgaggcgcac

61 agagcaagcc cacgcgaggg cacctctgga ggggagcgcc tgcaggacct tgtaaagtca

121 aaaatgtcag aaacttccag gaccgccttt ggaggcagaa gagcagttcc acccaataac

181 tctaatgcag cggaagatga cctgcccaca gtggagcttc agggcgtggt gccccggggc

241 gtcaacctgc aagagtttct taatgtcacg agcgttcacc tgttcaagga gagatgggac

301 actaacaagg tggaccacca cactgacaag tatgaaaaca acaagctgat tgtccgcaga

361 gggcagtctt tctatgtgca gattgacttc agtcgtccat atgaccccag aagggatctc

421 ttcagggtgg aatacgtcat tggtcgctac ccacaggaga acaagggaac ctacatccca

481 gtgcctatag tctcagagtt acaaagtgga aagtgggggg ccaagattgt catgagagag

541 gacaggtctg tgcggctgtc catccagtct tcccccaaat gtattgtggg gaaattccgc

601 atgtatgttg ctgtctggac tccctatggc gtacttcgaa ccagtcgaaa cccagaaaca

661 gacacgtaca ttctcttcaa tccttggtgt gaagatgatg ctgtgtatct ggacaatgag

721 aaagaaagag aagagtatgt cctgaatgac atcggggtaa ttttttatgg agaggtcaat

781 gacatcaaga ccagaagctg gagctatggt cagtttgaag atggcatcct ggacacttgc

841 ctgtatgtga tggacagagc acaaatggac ctctctggaa gagggaatcc catcaaagtc

901 agccgtgtgg ggtctgcaat ggtgaatgcc aaagatgacg aaggtgtcct cgttggatcc

961 tgggacaata tctatgccta tggcgtcccc ccatcggcct ggactggaag cgttgacatt

1021 ctattggaat accggagctc tgagaatcca gtccggtatg gccaatgctg ggtttttgct

1081 ggtgtcttta acacattttt acgatgcctt ggaataccag caagaattgt taccaattat

1141 ttctctgccc atgataatga tgccaatttg caaatggaca tcttcctgga agaagatggg

1201 aacgtgaatt ccaaactcac caaggattca gtgtggaact accactgctg gaatgaagca

1261 tggatgacaa ggcctgacct tcctgttgga tttggaggct ggcaagctgt ggacagcacc

1321 ccccaggaaa atagcgatgg catgtatcgg tgtggccccg cctcggttca agccatcaag

1381 cacggccatg tctgcttcca atttgatgca ccttttgttt ttgcagaggt caacagcgac

1441 ctcatttaca ttacagctaa gaaagatggc actcatgtgg tggaaaatgt ggatgccacc

1501 cacattggga aattaattgt gaccaaacaa attggaggag atggcatgat ggatattact

1561 gatacttaca aattccaaga aggtcaagaa gaagagagat tggccctaga aactgccctg

1621 atgtacggag ctaaaaagcc cctcaacaca gaaggtgtca tgaaatcaag gtccaacgtt 1681 gacatggact ttgaagtgga aaatgctgtg ctgggaaaag acttcaagct ctccatcacc 1741 ttccggaaca acagccacaa ccgttacacc atcacagctt atctctcagc caacatcacc 1801 ttctacaccg gggtcccgaa ggcagaattc aagaaggaga cgttcgacgt gacgctggag 1861 cccttgtcct tcaagaaaga ggcggtgctg atccaagccg gcgagtacat gggtcagctg 1921 ctggaacaag cgtccctgca cttctttgtc acagctcgca tcaatgagac cagggatgtt 1981 ctggccaagc aaaagtccac cgtgctaacc atccctgaga tcatcatcaa ggtccgtggc 2041 actcaggtag ttggttctga catgactgtg acagttgagt ttaccaatcc tttaaaagaa 2101 accctgcgaa atgtctgggt acacctggat ggtcctggag taacaagacc aatgaagaag 2161 atgttccgtg aaatccggcc caactccacc gtgcagtggg aagaagtgtg ccggccctgg 2221 gtctctgggc atcggaagct gatagccagc atgagcagtg actccctgag acatgtgtat 2281 ggcgagctgg acgtgcagat tcaaagacga ccttccatgt gaatgcacag gaagctgaga 2341 tgaaccctgg catttggcct cttgtagtct tggctaagga aattctaacg caaaaatagc 2401 tcttgctttg acttaggtgt gaagacccag acaggactgc agagggctcc agagtggaga 2461 tcccacatat ttcaaaaaca tgcttttcca aacccaggct attcggcaag gaagttagtt 2521 tttaatctct ccaccttcca aagagtgcta agcattagct ttaattaagc tctcatagct 2581 cataagagta acagtcatca tttatcatca caaatggcta catctccaaa tatcagtggg 2641 ctctcttacc agggagattt gctcaatacc tggcctcatt taaaacaaga cttcagattc 2701 cccactcagc cttttgggaa taatagcaca tgatttgggc tctagaattc cagtcccctt 2761 tctcggggtc aggttctacc ctccatgtga gaatattttt cccaggacta gagcacaaca 2821 taatttttat ttttggcaaa gccagaaaaa gatctttcat tttgcacctg cagccaagca 2881 aatgcctgcc aaattttaga tttaccttgt tagaagaggt ggccccatat taacaaattg 2941 catttgtggg aaacttaacc acctacaagg agataagaaa gcaggtgcaa cactcaagtc 3001 tattgaataa tgtagttttg tgatgcattt tatagaatgt gtcacactgt ggcctgatca 3061 gcaggagcca atatccctta ctttaaccct ttctgggatg caatactagg aagtaaagtg 3121 aagaatttat ctctttagtt agtgattata tttcacccat ctctcaggaa tcatctcctt 3181 tgcagaatga tgcaggttca ggtccccttt cagagatata ataagcccaa caagttgaag 3241 aagctggcgg atctagtgac cagatatata gaaggactgc agccactgat tctctcttgt 3301 ccttcacatc acccatgttg agacctcagc ttggcactca ggtgctgaag ggtaatatgg 3361 actcagcctt gcaaatagcc agtgctagtt ctgacccaac cacagaggat gctgacatca 3421 tttgtattat gttccaaggc tactacagag aaggctgcct gctatgtatt tgcaaggctg 3481 atttatggtc agaatttccc tctgatatgt ctagggtgtg atttaggtca gtagactgtg 3541 attcttagca aaaaatgaac agtgataagt atactggggg caaaatcaga atggaatgct 3601 ctggtctata taaccacatt tctaagcctt tgagactgtt cctgagcctt cagcactaac 3661 ctatgagggt gagctggtcc cctctatata tacatcatac ttaactttac taagtaatct 3721 cacagcattt gccaagtctc ccaatatcca attttaaaat gaaatgcatt ttgctagaca 3781 gttaaactgg cttaacttag tatattatta ttaattacaa tgtaatagaa gcttaaaata 3841 aagttaaact gattatattt gca n Willebrand Factor (NCBI Ref.: NM 000552.4; SEQ ID NO: 21)

1 gtggcagctc acagctattg tggtgggaaa gggagggtgg ttggtggatg tcacagcttg 61 ggctttatct cccccagcag tggggactcc acagcccctg ggctacataa cagcaagaca 121 gtccggagct gtagcagacc tgattgagcc tttgcagcag ctgagagcat ggcctagggt 181 gggcggcacc attgtccagc agctgagttt cccagggacc ttggagatag ccgcagccct 241 catttgcagg ggaagatgat tcctgccaga tttgccgggg tgctgcttgc tctggccctc 301 attttgccag ggaccctttg tgcagaagga actcgcggca ggtcatccac ggcccgatgc 361 agccttttcg gaagtgactt cgtcaacacc tttgatggga gcatgtacag ctttgcggga 421 tactgcagtt acctcctggc agggggctgc cagaaacgct ccttctcgat tattggggac 481 ttccagaatg gcaagagagt gagcctctcc gtgtatcttg gggaattttt tgacatccat

541 ttgtttgtca atggtaccgt gacacagggg gaccaaagag tctccatgcc ctatgcctcc 601 aaagggctgt atctagaaac tgaggctggg tactacaagc tgtccggtga ggcctatggc 661 tttgtggcca ggatcgatgg cagcggcaac tttcaagtcc tgctgtcaga cagatacttc 721 aacaagacct gcgggctgtg tggcaacttt aacatctttg ctgaagatga ctttatgacc 781 caagaaggga ccttgacctc ggacccttat gactttgcca actcatgggc tctgagcagt

841 ggagaacagt ggtgtgaacg ggcatctcct cccagcagct catgcaacat ctcctctggg 901 gaaatgcaga agggcctgtg ggagcagtgc cagcttctga agagcacctc ggtgtttgcc 961 cgctgccacc ctctggtgga ccccgagcct tttgtggccc tgtgtgagaa gactttgtgt 1021 gagtgtgctg gggggctgga gtgcgcctgc cctgccctcc tggagtacgc ccggacctgt 1081 gcccaggagg gaatggtgct gtacggctgg accgaccaca gcgcgtgcag cccagtgtgc

1141 cctgctggta tggagtatag gcagtgtgtg tccccttgcg ccaggacctg ccagagcctg 1201 cacatcaatg aaatgtgtca ggagcgatgc gtggatggct gcagctgccc tgagggacag 1261 ctcctggatg aaggcctctg cgtggagagc accgagtgtc cctgcgtgca ttccggaaag 1321 cgctaccctc ccggcacctc cctctctcga gactgcaaca cctgcatttg ccgaaacagc 1381 cagtggatct gcagcaatga agaatgtcca ggggagtgcc ttgtcacagg tcaatcacac

1441 ttcaagagct ttgacaacag atacttcacc ttcagtggga tctgccagta cctgctggcc 1501 cgggattgcc aggaccactc cttctccatt gtcattgaga ctgtccagtg tgctgatgac 1561 cgcgacgctg tgtgcacccg ctccgtcacc gtccggctgc ctggcctgca caacagcctt 1621 gtgaaactga agcatggggc aggagttgcc atggatggcc aggacgtcca gctccccctc 1681 ctgaaaggtg acctccgcat ccagcataca gtgacggcct ccgtgcgcct cagctacggg

1741 gaggacctgc agatggactg ggatggccgc gggaggctgc tggtgaagct gtcccccgtc 1801 tatgccggga agacctgcgg cctgtgtggg aattacaatg gcaaccaggg cgacgacttc 1861 cttaccccct ctgggctggc ggagccccgg gtggaggact tcgggaacgc ctggaagctg 1921 cacggggact gccaggacct gcagaagcag cacagcgatc cctgcgccct caacccgcgc 1981 atgaccaggt tctccgagga ggcgtgcgcg gtcctgacgt cccccacatt cgaggcctgc

2041 catcgtgccg tcagcccgct gccctacctg cggaactgcc gctacgacgt gtgctcctgc 2101 tcggacggcc gcgagtgcct gtgcggcgcc ctggccagct atgccgcggc ctgcgcgggg 2161 agaggcgtgc gcgtcgcgtg gcgcgagcca ggccgctgtg agctgaactg cccgaaaggc 2221 caggtgtacc tgcagtgcgg gaccccctgc aacctgacct gccgctctct ctcttacccg 2281 gatgaggaat gcaatgaggc ctgcctggag ggctgcttct gccccccagg gctctacatg

2341 gatgagaggg gggactgcgt gcccaaggcc cagtgcccct gttactatga cggtgagatc 2401 ttccagccag aagacatctt ctcagaccat cacaccatgt gctactgtga ggatggcttc 2461 atgcactgta ccatgagtgg agtccccgga agcttgctgc ctgacgctgt cctcagcagt 2521 cccctgtctc atcgcagcaa aaggagccta tcctgtcggc cccccatggt caagctggtg 2581 tgtcccgctg acaacctgcg ggctgaaggg ctcgagtgta ccaaaacgtg ccagaactat

2641 gacctggagt gcatgagcat gggctgtgtc tctggctgcc tctgcccccc gggcatggtc 2701 cggcatgaga acagatgtgt ggccctggaa aggtgtccct gcttccatca gggcaaggag 2761 tatgcccctg gagaaacagt gaagattggc tgcaacactt gtgtctgtcg ggaccggaag 2821 tggaactgca cagaccatgt gtgtgatgcc acgtgctcca cgatcggcat ggcccactac 2881 ctcaccttcg acgggctcaa atacctgttc cccggggagt gccagtacgt tctggtgcag 2941 gattactgcg gcagtaaccc tgggaccttt cggatcctag tggggaataa gggatgcagc 3001 cacccctcag tgaaatgcaa gaaacgggtc accatcctgg tggagggagg agagattgag 3061 ctgtttgacg gggaggtgaa tgtgaagagg cccatgaagg atgagactca ctttgaggtg 3121 gtggagtctg gccggtacat cattctgctg ctgggcaaag ccctctccgt ggtctgggac 3181 cgccacctga gcatctccgt ggtcctgaag cagacatacc aggagaaagt gtgtggcctg 3241 tgtgggaatt ttgatggcat ccagaacaat gacctcacca gcagcaacct ccaagtggag 3301 gaagaccctg tggactttgg gaactcctgg aaagtgagct cgcagtgtgc tgacaccaga 3361 aaagtgcctc tggactcatc ccctgccacc tgccataaca acatcatgaa gcagacgatg 3421 gtggattcct cctgtagaat ccttaccagt gacgtcttcc aggactgcaa caagctggtg 3481 gaccccgagc catatctgga tgtctgcatt tacgacacct gctcctgtga gtccattggg 3541 gactgcgcct gcttctgcga caccattgct gcctatgccc acgtgtgtgc ccagcatggc 3601 aaggtggtga cctggaggac ggccacattg tgcccccaga gctgcgagga gaggaatctc 3661 cgggagaacg ggtatgagtg tgagtggcgc tataacagct gtgcacctgc ctgtcaagtc 3721 acgtgtcagc accctgagcc actggcctgc cctgtgcagt gtgtggaggg ctgccatgcc 3781 cactgccctc cagggaaaat cctggatgag cttttgcaga cctgcgttga ccctgaagac 3841 tgtccagtgt gtgaggtggc tggccggcgt tttgcctcag gaaagaaagt caccttgaat 3901 cccagtgacc ctgagcactg ccagatttgc cactgtgatg ttgtcaacct cacctgtgaa 3961 gcctgccagg agccgggagg cctggtggtg cctcccacag atgccccggt gagccccacc 4021 actctgtatg tggaggacat ctcggaaccg ccgttgcacg atttctactg cagcaggcta 4081 ctggacctgg tcttcctgct ggatggctcc tccaggctgt ccgaggctga gtttgaagtg 4141 ctgaaggcct ttgtggtgga catgatggag cggctgcgca tctcccagaa gtgggtccgc 4201 gtggccgtgg tggagtacca cgacggctcc cacgcctaca tcgggctcaa ggaccggaag 4261 cgaccgtcag agctgcggcg cattgccagc caggtgaagt atgcgggcag ccaggtggcc 4321 tccaccagcg aggtcttgaa atacacactg ttccaaatct tcagcaagat cgaccgccct 4381 gaagcctccc gcatcaccct gctcctgatg gccagccagg agccccaacg gatgtcccgg 4441 aactttgtcc gctacgtcca gggcctgaag aagaagaagg tcattgtgat cccggtgggc 4501 attgggcccc atgccaacct caagcagatc cgcctcatcg agaagcaggc ccctgagaac 4561 aaggccttcg tgctgagcag tgtggatgag ctggagcagc aaagggacga gatcgttagc 4621 tacctctgtg accttgcccc tgaagcccct cctcctactc tgccccccga catggcacaa 4681 gtcactgtgg gcccggggct cttgggggtt tcgaccctgg ggcccaagag gaactccatg 4741 gttctggatg tggcgttcgt cctggaagga tcggacaaaa ttggtgaagc cgacttcaac 4801 aggagcaagg agttcatgga ggaggtgatt cagcggatgg atgtgggcca ggacagcatc 4861 cacgtcacgg tgctgcagta ctcctacatg gtgactgtgg agtacccctt cagcgaggca 4921 cagtccaaag gggacatcct gcagcgggtg cgagagatcc gctaccaggg cggcaacagg 4981 accaacactg ggctggccct gcggtacctc tctgaccaca gcttcttggt cagccagggt 5041 gaccgggagc aggcgcccaa cctggtctac atggtcaccg gaaatcctgc ctctgatgag 5101 atcaagaggc tgcctggaga catccaggtg gtgcccattg gagtgggccc taatgccaac 5161 gtgcaggagc tggagaggat tggctggccc aatgccccta tcctcatcca ggactttgag 5221 acgctccccc gagaggctcc tgacctggtg ctgcagaggt gctgctccgg agaggggctg 5281 cagatcccca ccctctcccc tgcacctgac tgcagccagc ccctggacgt gatccttctc 5341 ctggatggct cctccagttt cccagcttct tattttgatg aaatgaagag tttcgccaag 5401 gctttcattt caaaagccaa tatagggcct cgtctcactc aggtgtcagt gctgcagtat 5461 ggaagcatca ccaccattga cgtgccatgg aacgtggtcc cggagaaagc ccatttgctg 5521 agccttgtgg acgtcatgca gcgggaggga ggccccagcc aaatcgggga tgccttgggc 5581 tttgctgtgc gatacttgac ttcagaaatg catggtgcca ggccgggagc ctcaaaggcg 5641 gtggtcatcc tggtcacgga cgtctctgtg gattcagtgg atgcagcagc tgatgccgcc 5701 aggtccaaca gagtgacagt gttccctatt ggaattggag atcgctacga tgcagcccag 5761 ctacggatct tggcaggccc agcaggcgac tccaacgtgg tgaagctcca gcgaatcgaa 5821 gacctcccta ccatggtcac cttgggcaat tccttcctcc acaaactgtg ctctggattt 5881 gttaggattt gcatggatga ggatgggaat gagaagaggc ccggggacgt ctggaccttg 5941 ccagaccagt gccacaccgt gacttgccag ccagatggcc agaccttgct gaagagtcat 6001 cgggtcaact gtgaccgggg gctgaggcct tcgtgcccta acagccagtc ccctgttaaa 6061 gtggaagaga cctgtggctg ccgctggacc tgcccctgcg tgtgcacagg cagctccact 6121 cggcacatcg tgacctttga tgggcagaat ttcaagctga ctggcagctg ttcttatgtc 6181 ctatttcaaa acaaggagca ggacctggag gtgattctcc ataatggtgc ctgcagccct 6241 ggagcaaggc agggctgcat gaaatccatc gaggtgaagc acagtgccct ctccgtcgag 6301 ctgcacagtg acatggaggt gacggtgaat gggagactgg tctctgttcc ttacgtgggt 6361 gggaacatgg aagtcaacgt ttatggtgcc atcatgcatg aggtcagatt caatcacctt 6421 ggtcacatct tcacattcac tccacaaaac aatgagttcc aactgcagct cagccccaag 6481 acttttgctt caaagacgta tggtctgtgt gggatctgtg atgagaacgg agccaatgac 6541 ttcatgctga gggatggcac agtcaccaca gactggaaaa cacttgttca ggaatggact 6601 gtgcagcggc cagggcagac gtgccagccc atcctggagg agcagtgtct tgtccccgac 6661 agctcccact gccaggtcct cctcttacca ctgtttgctg aatgccacaa ggtcctggct 6721 ccagccacat tctatgccat ctgccagcag gacagttgcc accaggagca agtgtgtgag 6781 gtgatcgcct cttatgccca cctctgtcgg accaacgggg tctgcgttga ctggaggaca 6841 cctgatttct gtgctatgtc atgcccacca tctctggtct acaaccactg tgagcatggc 6901 tgtccccggc actgtgatgg caacgtgagc tcctgtgggg accatccctc cgaaggctgt 6961 ttctgccctc cagataaagt catgttggaa ggcagctgtg tccctgaaga ggcctgcact 7021 cagtgcattg gtgaggatgg agtccagcac cagttcctgg aagcctgggt cccggaccac 7081 cagccctgtc agatctgcac atgcctcagc gggcggaagg tcaactgcac aacgcagccc 7141 tgccccacgg ccaaagctcc cacgtgtggc ctgtgtgaag tagcccgcct ccgccagaat 7201 gcagaccagt gctgccccga gtatgagtgt gtgtgtgacc cagtgagctg tgacctgccc 7261 ccagtgcctc actgtgaacg tggcctccag cccacactga ccaaccctgg cgagtgcaga 7321 cccaacttca cctgcgcctg caggaaggag gagtgcaaaa gagtgtcccc accctcctgc 7381 cccccgcacc gtttgcccac ccttcggaag acccagtgct gtgatgagta tgagtgtgcc 7441 tgcaactgtg tcaactccac agtgagctgt ccccttgggt acttggcctc aactgccacc 7501 aatgactgtg gctgtaccac aaccacctgc cttcccgaca aggtgtgtgt ccaccgaagc 7561 accatctacc ctgtgggcca gttctgggag gagggctgcg atgtgtgcac ctgcaccgac 7621 atggaggatg ccgtgatggg cctccgcgtg gcccagtgct cccagaagcc ctgtgaggac 7681 agctgtcggt cgggcttcac ttacgttctg catgaaggcg agtgctgtgg aaggtgcctg 7741 ccatctgcct gtgaggtggt gactggctca ccgcgggggg actcccagtc ttcctggaag 7801 agtgtcggct cccagtgggc ctccccggag aacccctgcc tcatcaatga gtgtgtccga 7861 gtgaaggagg aggtctttat acaacaaagg aacgtctcct gcccccagct ggaggtccct 7921 gtctgcccct cgggctttca gctgagctgt aagacctcag cgtgctgccc aagctgtcgc 7981 tgtgagcgca tggaggcctg catgctcaat ggcactgtca ttgggcccgg gaagactgtg 8041 atgatcgatg tgtgcacgac ctgccgctgc atggtgcagg tgggggtcat ctctggattc 8101 aagctggagt gcaggaagac cacctgcaac ccctgccccc tgggttacaa ggaagaaaat 8161 aacacaggtg aatgttgtgg gagatgtttg cctacggctt gcaccattca gctaagagga 8221 ggacagatca tgacactgaa gcgtgatgag acgctccagg atggctgtga tactcacttc 8281 tgcaaggtca atgagagagg agagtacttc tgggagaaga gggtcacagg ctgcccaccc 8341 tttgatgaac acaagtgtct ggctgaggga ggtaaaatta tgaaaattcc aggcacctgc 8401 tgtgacacat gtgaggagcc tgagtgcaac gacatcactg ccaggctgca gtatgtcaag

8461 gtgggaagct gtaagtctga agtagaggtg gatatccact actgccaggg caaatgtgcc 8521 agcaaagcca tgtactccat tgacatcaac gatgtgcagg accagtgctc ctgctgctct 8581 ccgacacgga cggagcccat gcaggtggcc ctgcactgca ccaatggctc tgttgtgtac 8641 catgaggttc tcaatgccat ggagtgcaaa tgctccccca ggaagtgcag caagtgaggc 8701 tgctgcagct gcatgggtgc ctgctgctgc ctgccttggc ctgatggcca ggccagagtg

8761 ctgccagtcc tctgcatgtt ctgctcttgt gcccttctga gcccacaata aaggctgagc 8821 tcttatcttg caaaaggc

ADAM2 (NCBI Ref.: NM 001278113.1; SEQ ID NO: 22)

1 gcctacctct tccaggctgc gtggccgggg cgtcatctcg cgcttccaac tgccctgtaa

61 ccaccaactg ccattattcc ggctgggacc caggacttca agccatgtgg cgcgtcttgt 121 ttctgctcag cgggctcggc gggctgcgga tggacagtaa ttttgatagt ttacctgtgc 181 aaattacagt tccggagaaa atacggtcaa taataaagga aggaattgaa tcgcaggcat 241 cctacaaaat tgtaattgaa gggaaaccat atactgtgaa tttaatgcaa aaaaactttt 301 taccccataa ttttagagtt tacagttata gtggcacagg aattatgaaa ccacttgacc

361 aagattttca gaatttctgc cactaccaag ggtatattga aggttatcca aaatctgtgg 421 tgatggttag cacatgtact ggactcaggg gcgtactaca gtttgaaaat gttagttatg 481 gaatagaacc cctggagtct tcagttggct ttgaacatgt aatttaccaa gtaaaacata 541 agaaagcaga tgtttcctta tataatgaga aggatattga atcaagagat ctgtccttta 601 aattacaaag cgtagagtat aatcatatgg ggtctgatac aactgttgtc gctcaaaaag

661 ttttccagtt gattggattg acgaatgcta tttttgtttc atttaatatt acaattattc

721 tgtcttcatt ggagctttgg atagatgaaa ataaaattgc aaccactgga gaagctaatg 781 agttattaca cacattttta agatggaaaa catcttatct tgttttacgt cctcatgatg 841 tggcattttt acttgtttac agagaaaagt caaattatgt tggtgcaacc tttcaaggga 901 agatgtgtga tgcaaactat gcaggaggtg ttgttctgca ccccagaacc ataagtctgg

961 aatcacttgc agttatttta gctcaattat tgagccttag tatggggatc acttatgatg 1021 acattaacaa atgccagtgc tcaggagctg tctgcattat gaatccagaa gcaattcatt 1081 tcagtggtgt gaagatcttt agtaactgca gcttcgaaga ctttgcacat tttatttcaa 1141 agcagaagtc ccagtgtctt cacaatcagc ctcgcttaga tccttttttc aaacagcaag 1201 cagtgtgtgg taatgcaaag ctggaagcag gagaggagtg tgactgtggg actgaacagg

1261 attgtgccct tattggagaa acatgctgtg atattgccac atgtagattt aaagccggtt 1321 caaactgtgc tgaaggacca tgctgcgaaa actgtctatt tatgtcaaaa gaaagaatgt 1381 gtaggccttc ctttgaagaa tgcgacctcc ctgaatattg caatggatca tctgcatcat 1441 gcccagaaaa ccactatgtt cagactgggc atccgtgtgg actgaatcaa tggatctgta 1501 tagatggagt ttgtatgagt ggggataaac aatgtacaga cacatttggc aaagaagtag

1561 agtttggccc ttcagaatgt tattctcacc ttaattcaaa gactgatgta tctggaaact 1621 gtggtataag tgattcagga tacacacagt gtgaagctga caatctgcag tgcggaaaat 1681 taatatgtaa atatgtaggt aaatttttat tacaaattcc aagagccact attatttatg 1741 ccaacataag tggacatctc tgcattgctg tggaatttgc cagtgatcat gcagacagcc 1801 aaaagatgtg gataaaagat ggaacttctt gtggttcaaa taaggtttgc aggaatcaaa 1861 gatgtgtgag ttcttcatac ttgggttatg attgtactac tgacaaatgc aatgatagag 1921 gtgtatgcaa taacaaaaag cactgtcact gtagtgcttc atatttacct ccagattgct 1981 cagttcaatc agatctatgg cctggtggga gtattgacag tggcaatttt ccacctgtag

2041 ctataccagc cagactccct gaaaggcgct acattgagaa catttaccat tccaaaccaa 2101 tgagatggcc atttttctta ttcattcctt tctttattat tttctgtgta ctgattgcta

2161 taatggtgaa agttaatttc caaaggaaaa aatggagaac tgaggactat tcaagcgatg 2221 agcaacctga aagtgagagt gaacctaaag ggtagtctgg acaacagaga tgccatgata 2281 tcacttcttc tagagtaatt atctgtgatg gatggacaca aaaaaatgga aagaaaagaa

2341 tgtacattac ctggtttcct gggattcaaa cctgcatatt gtgattttaa tttgaccaga 2401 aaatatgata tatatgtata atttcacaga taatttactt atttaaaaat gcatgataat 2461 gagttttaca ttacaaattt ctgttttttt aaagttatct tacgctattt ctgttggtta

2521 gtagacacta attctgtcag taggggcatg gtataaggaa atatcataat gtaatgaggt 2581 ggtactatga ttaaaagcca ctgttacatt tcaaaaaaaa aaaaaaa

ICAM1 (NCBI Ref.: NM 000201.2; SEQ ID NO: 23)

781 gaaggagctg aaacgggagc cagctgtggg ggagcccgct gaggtcacga ccacggtgct 841 ggtgaggaga gatcaccatg gagccaattt ctcgtgccgc actgaactgg acctgcggcc 901 ccaagggctg gagctgtttg agaacacctc ggccccctac cagctccaga cctttgtcct 961 gccagcgact cccccacaac ttgtcagccc ccgggtccta gaggtggaca cgcaggggac 1021 cgtggtctgt tccctggacg ggctgttccc agtctcggag gcccaggtcc acctggcact

1081 gggggaccag aggttgaacc ccacagtcac ctatggcaac gactccttct cggccaaggc 1141 ctcagtcagt gtgaccgcag aggacgaggg cacccagcgg ctgacgtgtg cagtaatact 1201 ggggaaccag agccaggaga cactgcagac agtgaccatc tacagctttc cggcgcccaa 1261 cgtgattctg acgaagccag aggtctcaga agggaccgag gtgacagtga agtgtgaggc 1321 ccaccctaga gccaaggtga cgctgaatgg ggttccagcc cagccactgg gcccgagggc

1381 ccagctcctg ctgaaggcca ccccagagga caacgggcgc agcttctcct gctctgcaac 1441 cctggaggtg gccggccagc ttatacacaa gaaccagacc cgggagcttc gtgtcctgta 1501 tggcccccga ctggacgaga gggattgtcc gggaaactgg acgtggccag aaaattccca 1561 gcagactcca atgtgccagg cttgggggaa cccattgccc gagctcaagt gtctaaagga 1621 tggcactttc ccactgccca tcggggaatc agtgactgtc actcgagatc ttgagggcac 1681 ctacctctgt cgggccagga gcactcaagg ggaggtcacc cgcaaggtga ccgtgaatgt 1741 gctctccccc cggtatgaga ttgtcatcat cactgtggta gcagccgcag tcataatggg 1801 cactgcaggc ctcagcacgt acctctataa ccgccagcgg aagatcaaga aatacagact 1861 acaacaggcc caaaaaggga cccccatgaa accgaacaca caagccacgc ctccctgaac 1921 ctatcccggg acagggcctc ttcctcggcc ttcccatatt ggtggcagtg gtgccacact 1981 gaacagagtg gaagacatat gccatgcagc tacacctacc ggccctggga cgccggagga 2041 cagggcattg tcctcagtca gatacaacag catttggggc catggtacct gcacacctaa 2101 aacactaggc cacgcatctg atctgtagtc acatgactaa gccaagagga aggagcaaga 2161 ctcaagacat gattgatgga tgttaaagtc tagcctgatg agaggggaag tggtggggga 2221 gacatagccc caccatgagg acatacaact gggaaatact gaaacttgct gcctattggg 2281 tatgctgagg ccccacagac ttacagaaga agtggccctc catagacatg tgtagcatca 2341 aaacacaaag gcccacactt cctgacggat gccagcttgg gcactgctgt ctactgaccc 2401 caacccttga tgatatgtat ttattcattt gttattttac cagctattta ttgagtgtct

2461 tttatgtagg ctaaatgaac ataggtctct ggcctcacgg agctcccagt cctaatcaca 2521 ttcaaggtca ccaggtacag ttgtacaggt tgtacactgc aggagagtgc ctggcaaaaa 2581 gatcaaatgg ggctgggact tctcattggc caacctgcct ttccccagaa ggagtgattt 2641 ttctatcggc acaaaagcac tatatggact ggtaatggtt acaggttcag agattaccca 2701 gtgaggcctt attcctccct tccccccaaa actgacacct ttgttagcca cctccccacc 2761 cacatacatt tctgccagtg ttcacaatga cactcagcgg tcatgtctgg acatgagtgc 2821 ccagggaata tgcccaagct atgccttgtc ctcttgtcct gtttgcattt cactgggagc 2881 ttgcactatg cagctccagt ttcctgcagt gatcagggtc ctgcaagcag tggggaaggg 2941 ggccaaggta ttggaggact ccctcccagc tttggaagcc tcatccgcgt gtgtgtgtgt 3001 gtgtatgtgt agacaagctc tcgctctgtc acccaggctg gagtgcagtg gtgcaatcat 3061 ggttcactgc agtcttgacc ttttgggctc aagtgatcct cccacctcag cctcctgagt 3121 agctgggacc ataggctcac aacaccacac ctggcaaatt tgattttttt tttttttcca 3181 gagacggggt ctcgcaacat tgcccagact tcctttgtgt tagttaataa agctttctca 3241 actgccaaa

Collagen (NCBI Ref.: NM 000088.3; SEQ ID NO: 24)

1 tcgtcggagc agacgggagt ttctcctcgg ggtcggagca ggaggcacgc ggagtgtgag 61 gccacgcatg agcggacgct aaccccctcc ccagccacaa agagtctaca tgtctagggt 121 ctagacatgt tcagctttgt ggacctccgg ctcctgctcc tcttagcggc caccgccctc 181 ctgacgcacg gccaagagga aggccaagtc gagggccaag acgaagacat cccaccaatc 241 acctgcgtac agaacggcct caggtaccat gaccgagacg tgtggaaacc cgagccctgc 301 cggatctgcg tctgcgacaa cggcaaggtg ttgtgcgatg acgtgatctg tgacgagacc 361 aagaactgcc ccggcgccga agtccccgag ggcgagtgct gtcccgtctg ccccgacggc 421 tcagagtcac ccaccgacca agaaaccacc ggcgtcgagg gacccaaggg agacactggc 481 ccccgaggcc caaggggacc cgcaggcccc cctggccgag atggcatccc tggacagcct 541 ggacttcccg gaccccccgg accccccgga cctcccggac cccctggcct cggaggaaac 601 tttgctcccc agctgtctta tggctatgat gagaaatcaa ccggaggaat ttccgtgcct 661 ggccccatgg gtccctctgg tcctcgtggt ctccctggcc cccctggtgc acctggtccc 721 caaggcttcc aaggtccccc tggtgagcct ggcgagcctg gagcttcagg tcccatgggt 781 ccccgaggtc ccccaggtcc ccctggaaag aatggagatg atggggaagc tggaaaacct 841 ggtcgtcctg gtgagcgtgg gcctcctggg cctcagggtg ctcgaggatt gcccggaaca 901 gctggcctcc ctggaatgaa gggacacaga ggtttcagtg gtttggatgg tgccaaggga 961 gatgctggtc ctgctggtcc taagggtgag cctggcagcc ctggtgaaaa tggagctcct

1021 ggtcagatgg gcccccgtgg cctgcctggt gagagaggtc gccctggagc ccctggccct 1081 gctggtgctc gtggaaatga tggtgctact ggtgctgccg ggccccctgg tcccaccggc 1141 cccgctggtc ctcctggctt ccctggtgct gttggtgcta agggtgaagc tggtccccaa 1201 gggccccgag gctctgaagg tccccagggt gtgcgtggtg agcctggccc ccctggccct 1261 gctggtgctg ctggccctgc tggaaaccct ggtgctgatg gacagcctgg tgctaaaggt

1321 gccaatggtg ctcctggtat tgctggtgct cctggcttcc ctggtgcccg aggcccctct 1381 ggaccccagg gccccggcgg ccctcctggt cccaagggta acagcggtga acctggtgct 1441 cctggcagca aaggagacac tggtgctaag ggagagcctg gccctgttgg tgttcaagga 1501 ccccctggcc ctgctggaga ggaaggaaag cgaggagctc gaggtgaacc cggacccact 1561 ggcctgcccg gaccccctgg cgagcgtggt ggacctggta gccgtggttt ccctggcgca

1621 gatggtgttg ctggtcccaa gggtcccgct ggtgaacgtg gttctcctgg ccctgctggc 1681 cccaaaggat ctcctggtga agctggtcgt cccggtgaag ctggtctgcc tggtgccaag 1741 ggtctgactg gaagccctgg cagccctggt cctgatggca aaactggccc ccctggtccc 1801 gccggtcaag atggtcgccc cggaccccca ggcccacctg gtgcccgtgg tcaggctggt 1861 gtgatgggat tccctggacc taaaggtgct gctggagagc ccggcaaggc tggagagcga

1921 ggtgttcccg gaccccctgg cgctgtcggt cctgctggca aagatggaga ggctggagct 1981 cagggacccc ctggccctgc tggtcccgct ggcgagagag gtgaacaagg ccctgctggc 2041 tcccccggat tccagggtct ccctggtcct gctggtcctc caggtgaagc aggcaaacct 2101 ggtgaacagg gtgttcctgg agaccttggc gcccctggcc cctctggagc aagaggcgag 2161 agaggtttcc ctggcgagcg tggtgtgcaa ggtccccctg gtcctgctgg tccccgaggg

2221 gccaacggtg ctcccggcaa cgatggtgct aagggtgatg ctggtgcccc tggagctccc 2281 ggtagccagg gcgcccctgg ccttcaggga atgcctggtg aacgtggtgc agctggtctt 2341 ccagggccta agggtgacag aggtgatgct ggtcccaaag gtgctgatgg ctctcctggc 2401 aaagatggcg tccgtggtct gactggcccc attggtcctc ctggccctgc tggtgcccct 2461 ggtgacaagg gtgaaagtgg tcccagcggc cctgctggtc ccactggagc tcgtggtgcc

2521 cccggagacc gtggtgagcc tggtcccccc ggccctgctg gctttgctgg cccccctggt 2581 gctgacggcc aacctggtgc taaaggcgaa cctggtgatg ctggtgctaa aggcgatgct 2641 ggtccccctg gccctgccgg acccgctgga ccccctggcc ccattggtaa tgttggtgct 2701 cctggagcca aaggtgctcg cggcagcgct ggtccccctg gtgctactgg tttccctggt 2761 gctgctggcc gagtcggtcc tcctggcccc tctggaaatg ctggaccccc tggccctcct

2821 ggtcctgctg gcaaagaagg cggcaaaggt ccccgtggtg agactggccc tgctggacgt 2881 cctggtgaag ttggtccccc tggtccccct ggccctgctg gcgagaaagg atcccctggt 2941 gctgatggtc ctgctggtgc tcctggtact cccgggcctc aaggtattgc tggacagcgt 3001 ggtgtggtcg gcctgcctgg tcagagagga gagagaggct tccctggtct tcctggcccc 3061 tctggtgaac ctggcaaaca aggtccctct ggagcaagtg gtgaacgtgg tccccctggt

3121 cccatgggcc cccctggatt ggctggaccc cctggtgaat ctggacgtga gggggctcct 3181 ggtgccgaag gttcccctgg acgagacggt tctcctggcg ccaagggtga ccgtggtgag 3241 accggccccg ctggaccccc tggtgctcct ggtgctcctg gtgcccctgg ccccgttggc 3301 cctgctggca agagtggtga tcgtggtgag actggtcctg ctggtcccgc cggtcctgtc 3361 ggccctgttg gcgcccgtgg ccccgccgga ccccaaggcc cccgtggtga caagggtgag 3421 acaggcgaac agggcgacag aggcataaag ggtcaccgtg gcttctctgg cctccagggt 3481 ccccctggcc ctcctggctc tcctggtgaa caaggtccct ctggagcctc tggtcctgct 3541 ggtccccgag gtccccctgg ctctgctggt gctcctggca aagatggact caacggtctc 3601 cctggcccca ttgggccccc tggtcctcgc ggtcgcactg gtgatgctgg tcctgttggt 3661 ccccccggcc ctcctggacc tcctggtccc cctggtcctc ccagcgctgg tttcgacttc 3721 agcttcctgc cccagccacc tcaagagaag gctcacgatg gtggccgcta ctaccgggct 3781 gatgatgcca atgtggttcg tgaccgtgac ctcgaggtgg acaccaccct caagagcctg 3841 agccagcaga tcgagaacat ccggagccca gagggcagcc gcaagaaccc cgcccgcacc 3901 tgccgtgacc tcaagatgtg ccactctgac tggaagagtg gagagtactg gattgacccc 3961 aaccaaggct gcaacctgga tgccatcaaa gtcttctgca acatggagac tggtgagacc 4021 tgcgtgtacc ccactcagcc cagtgtggcc cagaagaact ggtacatcag caagaacccc 4081 aaggacaaga ggcatgtctg gttcggcgag agcatgaccg atggattcca gttcgagtat 4141 ggcggccagg gctccgaccc tgccgatgtg gccatccagc tgaccttcct gcgcctgatg 4201 tccaccgagg cctcccagaa catcacctac cactgcaaga acagcgtggc ctacatggac 4261 cagcagactg gcaacctcaa gaaggccctg ctcctccagg gctccaacga gatcgagatc 4321 cgcgccgagg gcaacagccg cttcacctac agcgtcactg tcgatggctg cacgagtcac 4381 accggagcct ggggcaagac agtgattgaa tacaaaacca ccaagacctc ccgcctgccc 4441 atcatcgatg tggccccctt ggacgttggt gccccagacc aggaattcgg cttcgacgtt 4501 ggccctgtct gcttcctgta aactccctcc atcccaacct ggctccctcc cacccaacca 4561 actttccccc caacccggaa acagacaagc aacccaaact gaaccccctc aaaagccaaa 4621 aaatgggaga caatttcaca tggactttgg aaaatatttt tttcctttgc attcatctct

4681 caaacttagt ttttatcttt gaccaaccga acatgaccaa aaaccaaaag tgcattcaac 4741 cttaccaaaa aaaaaaaaaa aaaaagaata aataaataac tttttaaaaa aggaagcttg 4801 gtccacttgc ttgaagaccc atgcgggggt aagtcccttt ctgcccgttg ggcttatgaa 4861 accccaatgc tgccctttct gctcctttct ccacaccccc cttggggcct cccctccact 4921 ccttcccaaa tctgtctccc cagaagacac aggaaacaat gtattgtctg cccagcaatc 4981 aaaggcaatg ctcaaacacc caagtggccc ccaccctcag cccgctcctg cccgcccagc 5041 acccccaggc cctgggggac ctggggttct cagactgcca aagaagcctt gccatctggc 5101 gctcccatgg ctcttgcaac atctcccctt cgtttttgag ggggtcatgc cgggggagcc 5161 accagcccct cactgggttc ggaggagagt caggaagggc cacgacaaag cagaaacatc 5221 ggatttgggg aacgcgtgtc aatcccttgt gccgcagggc tgggcgggag agactgttct 5281 gttccttgtg taactgtgtt gctgaaagac tacctcgttc ttgtcttgat gtgtcaccgg 5341 ggcaactgcc tgggggcggg gatgggggca gggtggaagc ggctccccat tttataccaa 5401 aggtgctaca tctatgtgat gggtggggtg gggagggaat cactggtgct atagaaattg 5461 agatgccccc ccaggccagc aaatgttcct ttttgttcaa agtctatttt tattccttga 5521 tatttttctt tttttttttt tttttttgtg gatggggact tgtgaatttt tctaaaggtg

5581 ctatttaaca tgggaggaga gcgtgtgcgg ctccagccca gcccgctgct cactttccac 5641 cctctctcca cctgcctctg gcttctcagg cctctgctct ccgacctctc tcctctgaaa 5701 ccctcctcca cagctgcagc ccatcctccc ggctccctcc tagtctgtcc tgcgtcctct 5761 gtccccgggt ttcagagaca acttcccaaa gcacaaagca gtttttcccc ctaggggtgg 5821 gaggaagcaa aagactctgt acctattttg tatgtgtata ataatttgag atgtttttaa 5881 ttattttgat tgctggaata aagcatgtgg aaatgaccca aacataa E-cadherin (NCBI Ref.: NM 001317184.1; SEQ ID NO: 25)

1 tcagtggcgt cggaactgca aagcacctgt gagcttgcgg aagtcagttc agactccagc 61 ccgctccagc ccggcccgac ccgaccgcac ccggcgcctg ccctcgctcg gcgtccccgg 121 ccagccatgg gcccttggag ccgcagcctc tcggcgctgc tgctgctgct gcaggtctcc 181 tcttggctct gccaggagcc ggagccctgc caccctggct ttgacgccga gagctacacg

241 ttcacggtgc cccggcgcca cctggagaga ggccgcgtcc tgggcagagt gaattttgaa 301 gattgcaccg gtcgacaaag gacagcctat ttttccctcg acacccgatt caaagtgggc 361 acagatggtg tgattacagt caaaaggcct ctacggtttc ataacccaca gatccatttc 421 ttggtctacg cctgggactc cacctacaga aagttttcca ccaaagtcac gctgaataca 481 gtggggcacc accaccgccc cccgccccat caggcctccg tttctggaat ccaagcagaa

541 ttgctcacat ttcccaactc ctctcctggc ctcagaagac agaagagaga ctgggttatt 601 cctcccatca gctgcccaga aaatgaaaaa ggcccatttc ctaaaaacct ggttcagatc 661 aaatccaaca aagacaaaga aggcaaggtt ttctacagca tcactggcca aggagctgac 721 acaccccctg ttggtgtctt tattattgaa agagaaacag gatggctgaa ggtgacagag 781 cctctggata gagaacgcat tgccacatac actctcttct ctcacgctgt gtcatccaac

841 gggaatgcag ttgaggatcc aatggagatt ttgatcacgg taaccgatca gaatgacaac 901 aagcccgaat tcacccagga ggtctttaag gggtctgtca tggaaggtgc tcttccagga 961 acctctgtga tggaggtcac agccacagac gcggacgatg atgtgaacac ctacaatgcc 1021 gccatcgctt acaccatcct cagccaagat cctgagctcc ctgacaaaaa tatgttcacc 1081 attaacagga acacaggagt catcagtgtg gtcaccactg ggctggaccg agagagtttc

1141 cctacgtata ccctggtggt tcaagctgct gaccttcaag gtgaggggtt aagcacaaca 1201 gcaacagctg tgatcacagt cactgacacc aacgataatc ctccgatctt caatcccacc 1261 acgggcttgg attttgaggc caagcagcag tacattctac acgtagcagt gacgaatgtg 1321 gtaccttttg aggtctctct caccacctcc acagccaccg tcaccgtgga tgtgctggat 1381 gtgaatgaag cccccatctt tgtgcctcct gaaaagagag tggaagtgtc cgaggacttt

1441 ggcgtgggcc aggaaatcac atcctacact gcccaggagc cagacacatt tatggaacag 1501 aaaataacat atcggatttg gagagacact gccaactggc tggagattaa tccggacact 1561 ggtgccattt ccactcgggc tgagctggac agggaggatt ttgagcacgt gaagaacagc 1621 acgtacacag ccctaatcat agctacagac aatggttctc cagttgctac tggaacaggg 1681 acacttctgc tgatcctgtc tgatgtgaat gacaacgccc ccataccaga acctcgaact

1741 atattcttct gtgagaggaa tccaaagcct caggtcataa acatcattga tgcagacctt 1801 cctcccaata catctccctt cacagcagaa ctaacacacg gggcgagtgc caactggacc 1861 attcagtaca acgacccaac ccaagaatct atcattttga agccaaagat ggccttagag 1921 gtgggtgact acaaaatcaa tctcaagctc atggataacc agaataaaga ccaagtgacc 1981 accttagagg tcagcgtgtg tgactgtgaa ggggccgctg gcgtctgtag gaaggcacag

2041 cctgtcgaag caggattgca aattcctgcc attctgggga ttcttggagg aattcttgct 2101 ttgctaattc tgattctgct gctcttgctg tttcttcgga ggagagcggt ggtcaaagag 2161 cccttactgc ccccagagga tgacacccgg gacaacgttt attactatga tgaagaagga 2221 ggcggagaag aggaccagga ctttgacttg agccagctgc acaggggcct ggacgctcgg 2281 cctgaagtga ctcgtaacga cgttgcacca accctcatga gtgtcccccg gtatcttccc

2341 cgccctgcca atcccgatga aattggaaat tttattgatg aaaatctgaa agcggctgat 2401 actgacccca cagccccgcc ttatgattct ctgctcgtgt ttgactatga aggaagcggt 2461 tccgaagctg ctagtctgag ctccctgaac tcctcagagt cagacaaaga ccaggactat 2521 gactacttga acgaatgggg caatcgcttc aagaagctgg ctgacatgta cggaggcggc 2581 gaggacgact aggggactcg agagaggcgg gccccagacc catgtgctgg gaaatgcaga 2641 aatcacgttg ctggtggttt ttcagctccc ttcccttgag atgagtttct gggg aaaaaa 2701 aagagactgg ttagtgatgc agttagtata gctttatact ctctccactt tatagctcta 2761 ataagtttgt gttagaaaag tttcgactta tttcttaaag cttttttttt tttcccatca

2821 ctctttacat ggtggtgatg tccaaaagat acccaaattt taatattcca gaagaacaac 2881 tttagcatca gaaggttcac ccagcacctt gcagattttc ttaaggaatt ttgtctcact 2941 tttaaaaaga aggggagaag tcagctactc tagttctgtt gttttgtgta tataattttt 3001 taaaaaaaat ttgtgtgctt ctgctcatta ctacactggt gtgtccctct gccttttttt

3061 tttttttaag acagggtctc attctatcgg ccaggctgga gtgcagtggt gcaatcacag 3121 ctcactgcag ccttgtcctc ccaggctcaa gctatccttg cacctcagcc tcccaagtag 3181 ctgggaccac aggcatgcac cactacgcat gactaatttt ttaaatattt gagacggggt 3241 ctccctgtgt tacccaggct ggtctcaaac tcctgggctc aagtgatcct cccatcttgg 3301 cctcccagag tattgggatt acagacatga gccactgcac ctgcccagct ccccaactcc 3361 ctgccatttt ttaagagaca gtttcgctcc atcgcccagg cctgggatgc agtgatgtga 3421 tcatagctca ctgtaacctc aaactctggg gctcaagcag ttctcccacc agcctccttt 3481 ttattttttt gtacagatgg ggtcttgcta tgttgcccaa gctggtctta aactcctggc 3541 ctcaagcaat ccttctgcct tggcccccca aagtgctggg attgtgggca tgagctgctg 3601 tgcccagcct ccatgtttta atatcaactc tcactcctga attcagttgc tttgcccaag 3661 ataggagttc tctgatgcag aaattattgg gctcttttag ggtaagaagt ttgtgtcttt 3721 gtctggccac atcttgacta ggtattgtct actctgaaga cctttaatgg cttccctctt 3781 tcatctcctg agtatgtaac ttgcaatggg cagctatcca gtgacttgtt ctgagtaagt 3841 gtgttcatta atgtttattt agctctgaag caagagtgat atactccagg acttagaata 3901 gtgcctaaag tgctgcagcc aaagacagag cggaactatg aaaagtgggc ttggagatgg 3961 caggagagct tgtcattgag cctggcaatt tagcaaactg atgctgagga tgattgaggt 4021 gggtctacct catctctgaa aattctggaa ggaatggagg agtctcaaca tgtgtttctg 4081 acacaagatc cgtggtttgt actcaaagcc cagaatcccc aagtgcctgc ttttgatgat 4141 gtctacagaa aatgctggct gagctgaaca catttgccca attccaggtg tgcacagaaa 4201 accgagaata ttcaaaattc caaatttttt tcttaggagc aagaagaaaa tgtggcccta 4261 aagggggtta gttgaggggt agggggtagt gaggatcttg atttggatct ctttttattt 4321 aaatgtgaat ttcaactttt gacaatcaaa gaaaagactt ttgttgaaat agctttactg 4381 tttctcaagt gttttggaga aaaaaatcaa ccctgcaatc actttttgga attgtcttga 4441 tttttcggca gttcaagcta tatcgaatat agttctgtgt agagaatgtc actgtagttt 4501 tgagtgtata catgtgtggg tgctgataat tgtgtatttt ctttgggggt ggaaaaggaa 4561 aacaattcaa gctgagaaaa gtattctcaa agatgcattt ttataaattt tattaaacaa 4621 ttttgttaaa ccattaaaaa aaaaaaaaaa aaaaaaaaaa aa

Laminin (LAMAl) (NCBI Ref.: NM 005559.3; SEQ ID NO: 26)

1 cggggccagg gcagcgcgga ctcgcgtccc gtggagcgtt ccaggcgggc gcgcggcttt 61 ctccccagac ccaccgagtg gcggcggagg cgagatgcgc gggggcgtgc tcctggtctt 121 gctgctgtgt gtcgccgcgc agtgccggca gagaggcctg tttcctgcca ttctcaatct 181 tgccagcaat gctcacatca gcaccaatgc cacctgtggc gagaaggggc cggagatgtt 241 ctgcaaactt gtggagcatg tgccaggtcg gcccgtccga aacccacagt gccggatctg 301 tgatggcaac agcgcaaacc ccagagaacg ccatccaata tcacatgcca tagatggcac 361 caataactgg tggcaaagtc ccagcattca gaatgggaga gaatatcact gggtcacaat 421 cactctggac ttaagacagg tctttcaagt tgcatatgtc atcattaaag ctgccaatgc 481 ccctcgacct ggaaactgga ttttggagcg ttctctggat ggcaccacgt tcagcccctg 541 gcagtattat gcagtcagcg actcagagtg tttgtctcgt tacaatataa ctccaagacg 601 agggccaccc acctacaggg ctgatgatga agtgatctgc acctcctatt attccagatt

661 ggtgccactt gagcatggag agattcatac atcactcatc aatggcagac caagcgctga 721 cgatctttca cccaagttgt tggaattcac ttctgcacga tatattcgcc ttcgcttgca 781 acgcattaga acgctcaatg cagatctcat gacccttagc caccgggaac ctaaagaact 841 ggatcctatt gttaccagac gctattatta ttcaataaag gacatttctg ttggaggcat 901 gtgtatctgc tatggccatg ctagtagctg cccatgggat gaaactacaa agaaactgca

961 gtgtcaatgt gagcataata cttgcgggga gagctgtaac aggtgctgtc ctgggtacca 1021 tcagcagccc tggaggccgg gaaccgtgtc ctccggcaat acatgtgaag catgtaattg 1081 tcacaataaa gccaaagact gttactatga tgaaagtgtt gcaaagcaga agaaaagttt 1141 gaatactgct ggacagttca gaggaggagg ggtttgcata aattgcttgc agaacaccat 1201 gggaatcaac tgtgaaacct gtattgatgg atattataga ccacacaaag tgtctcctta

1261 tgaggatgag ccttgccgcc cctgtaattg tgaccctgtg gggtccctca gttctgtctg 1321 tattaaggat gacctccatt ctgacttaca caatgggaag cagccaggtc agtgcccatg 1381 taaggaaggt tatacaggag aaaaatgtga tcgctgccaa cttggctata aggattaccc 1441 gacctgtgtc tcctgtgggt gcaacccagt gggcagtgcc agtgatgagc cctgcacagg 1501 gccctgtgtt tgtaaggaaa acgttgaggg gaaggcctgt gatcgctgca agccaggatt

1561 ctataacttg aaggaaaaaa acccccgggg ctgctccgag tgcttctgct ttggcgtttc 1621 tgatgtctgc agcagcctct cttggcctgt tggtcaggta aacagtatgt ccgggtggct 1681 ggtcaccgac ttgatcagtc ccaggaagat cccgtctcag caagatgcac taggcgggcg 1741 ccatcaggtc agcatcaaca acaccgcggt catgcagaga ctggctccca agtactactg 1801 ggcagccccc gaggcctacc ttggaaataa gctgactgcg tttggcggat tcctgaaata

1861 cacggtgtcc tacgatattc cggtagagac ggtagacagt aacctcatgt cgcatgctga 1921 cgtcatcatt aagggaaacg gactcacttt aagcacacag gctgagggtc tgtcattgca 1981 gccttatgaa gagtacctaa acgtggttag acttgtgcct gaaaacttcc aagattttca 2041 cagcaaaagg cagattgatc gtgaccagct gatgactgtc cttgccaatg tgacacatct 2101 tttgatcaga gccaactaca attctgcaaa aatggctctt tacaggttgg agtccgtctc

2161 tctggacata gccagctcta atgccatcga cctggtggtg gccgctgatg tggagcactg 2221 tgaatgtccg caaggctaca cagggacctc ctgtgagtcg tgcctctctg gctattaccg 2281 cgtggatgga atactctttg gaggaatttg tcaaccctgt gaatgccacg gccatgcagc 2341 tgagtgtaat gttcacggcg tttgcattgc gtgtgcgcac aacaccaccg gcgtccactg 2401 tgagcagtgc ttgcccggct tctacgggga gccttcccga gggacacctg gggactgcca

2461 gccctgcgcc tgccctctca ccatagcctc caacaatttc agccccacct gccacctcaa 2521 tgatggagat gaagtggtct gtgactggtg tgccccgggc tactcaggag cttggtgtga 2581 gagatgtgca gatggttact atggaaaccc aacagtgcct ggcgaatctt gtgttccctg 2641 tgactgcagc ggcaacgtgg acccctcgga ggctggtcac tgtgactcag tcaccgggga 2701 gtgcctgaag tgcctgggga acacagatgg cgcccactgt gaaaggtgtg ctgacgggtt

2761 ctatggggac gctgtgacag ccaagaactg ccgcgcctgt gaatgccatg tgaaaggctc 2821 ccattctgcc gtgtgccatc ttgagaccgg gctctgtgac tgcaaaccaa acgtgactgg 2881 acagcagtgt gaccagtgct tgcatggcta ttatgggctg gactcaggcc atggctgccg 2941 gccctgcaac tgcagcgtgg caggctccgt gtcagatggc tgcacggatg aaggccagtg 3001 tcactgtgtc ccaggtgtgg cagggaaaag gtgtgacagg tgtgcccatg gcttctacgc 3061 ctaccaggat ggtagctgta caccctgtga ctgcccacac actcagaata cctgcgaccc 3121 agaaactgga gagtgtgtct gcccccctca cacacagggt gtgaagtgtg aagaatgtga 3181 ggatgggcac tggggctacg atgcggaggt ggggtgccag gcctgcaatt gcagtctcgt 3241 ggggtcgact catcatcggt gcgatgtggt caccggccat tgccagtgca agtcaaaatt 3301 tggtggccgg gcctgcgatc agtgttcctt gggttacaga gactttcccg actgtgttcc 3361 ctgtgactgt gacctgaggg ggacgtcggg ggacgcctgc aacctggagc agggtctctg 3421 cggctgtgtg gaggaaaccg gggcctgccc ttgcaaggaa aatgtctttg gtcctcagtg 3481 caacgaatgt cgagagggca ccttcgctct ccgcgcagac aaccccctgg gctgcagccc 3541 gtgcttctgc tccgggctgt cccacctctg ctcagagctg gaggactacg tgaggacccc 3601 agtaacgctg ggctccgatc agcctcttct gcgtgtggtt tctcagagta acttgagggg 3661 cacgaccgag ggggtttact accaggcccc cgacttcctg ctggatgccg ccaccgtccg 3721 gcagcacatc cgtgcagagc cgttttactg gcggctgccg cagcagttcc aaggagacca 3781 gctcatggcc tatggtggca aactgaagta cagcgtggcc ttctattctt tggatggcgt 3841 cggcacctcc aattttgagc ctcaagttct catcaaaggt ggtcggatca gaaagcaagt 3901 catttacatg gatgcaccag ccccagagaa tggagtgaga caggaacaag aagtagcaat 3961 gagagagaat ttttggaaat attttaactc tgtttctgaa aaacctgtca cgcgagagga 4021 ttttatgtct gtcctcagcg atattgagta catcctcatc aaggcatcgt atggtcaagg 4081 attacagcag agcagaatct cagacatttc aatggaggtt ggcagaaagg ctgaaaagct 4141 gcacccagaa gaagaggttg catctctttt agagaattgt gtctgtcctc ctggcactgt 4201 gggattctca tgtcaggact gcgcccctgg gtaccacaga gggaagctcc cagcagggag 4261 tgacagggga ccacgccctc tggttgctcc ttgtgttccc tgcagttgca acaaccacag 4321 tgacacctgt gaccccaaca ccgggaagtg tctgaactgt ggcgataaca cagcaggtga 4381 ccattgtgat gtgtgtactt ctggctacta cgggaaggtg actggctcag caagtgactg 4441 tgctctgtgt gcctgtcctc acagccctcc tgccagtttt agtcccactt gtgtcttgga 4501 aggggaccac gatttccgtt gtgacgcctg tctcctgggc tatgaaggaa aacactgtga 4561 aaggtgctcc tcaagctatt atgggaaccc tcaaacacca ggtggcagtt gccagaagtg 4621 tgactgcaac ccgcacggct ctgtccacgg tgactgtgac cgcacatctg ggcagtgcgt 4681 ttgcaggctg ggggcctcgg ggctccggtg cgatgagtgt gaaccgaggc acattctgat 4741 ggaaacagat tgtgtttcct gtgatgatga gtgtgtaggt gtgctgctga atgacttgga 4801 tgagattggt gatgccgttc tttctctgaa cctcactggc attatccctg tcccatatgg 4861 aattttgtca aacctggaaa atacaactaa atatctccag gaatctttat taaaagaaaa 4921 tatgcaaaag gacctgggaa aaattaagct tgaaggtgtt gcagaagaaa cggacaacct 4981 gcaaaagaag ctcactagga tgttagcgag tacccaaaag gtgaataggg caactgagag 5041 aatcttcaag gagagtcaag acctggccat agccattgag aggctgcaga tgagcatcac 5101 agaaattatg gaaaagacaa ctttaaatca gactttggat gaagatttcc tactacccaa 5161 ttctactctt cagaacatgc aacagaatgg tacatctttg ctagaaatca tgcagataag 5221 agacttcaca cagttgcacc aaaatgccac ccttgaactc aaggctgctg aagatttatt 5281 gtcacaaatt caggaaaatt accagaagcc gctggaagaa ttggaggtat tgaaagaagc 5341 agcaagccac gtcctttcaa agcacaacaa tgaactaaag gcggctgagg cgctcgtgag 5401 ggaagctgag gcaaagatgc aggaaagcaa ccacctgctg ctcatggtca atgctaatct 5461 gagagaattc agtgataaaa agctgcatgt tcaagaagaa caaaatctga cctcagagct 5521 cattgtccaa ggaagaggat tgatagatgc tgctgctgca caaacagatg ctgtacaaga 5581 tgctctagag cacttagagg atcaccagga taagctactt ttatggtctg ccaaaatcag 5641 gcaccacata gatgacctgg tcatgcacat gtcccaaagg aacgcagtcg acctggtcta 5701 cagagctgag gaccatgccg ctgagttcca gagactagca gatgttctgt acagtggcct 5761 tgaaaacatc agaaatgtgt ccctgaatgc caccagtgca gcctatgtcc attacaacat 5821 ccagagcctg attgaagaat cggaggaact ggccagagat gctcacagga ctgtgactga 5881 gacgagcctg ctctcagaat cccttgtttc taacgggaaa gcggccgtgc agcgcagctc 5941 cagatttcta aaagaaggca acaacctcag caggaagctt ccaggtattg cattggaact 6001 gagtgaattg agaaataaga caaacagatt tcaagagaat gctgttgaaa ttaccaggca 6061 aaccaatgaa tcactcttga tacttagagc aattcctaaa ggtataagag acaagggagc 6121 caaaaccaaa gagctggcca cgtctgcaag ccagagcgcg gtgagcacgc tgagggacgt 6181 ggcggggctg agccaggagc tgctgaacac atctgccagc ctgtccaggg tcaacaccac 6241 attacgagag acacaccagc ttctgcagga ctccaccatg gccactctgt tggctggaag 6301 aaaagtcaaa gacgtggaaa ttcaagccaa ccttttgttt gatcggttga agcctttgaa 6361 gatgttagag gagaatctga gcagaaacct atcagaaatt aaactgttga tcagccaggc 6421 ccgcaaacaa gcagcttcta ttaaagtcgc cgtgtctgca gacagagatt gcatccgggc 6481 ctaccagcct cagatttcct ctaccaacta caatacctta acactaaatg ttaagacaca 6541 ggaacccgat aatcttctct tctacctcgg tagcagcacc gcttctgatt tccttgcagt 6601 ggagatgcgg cgagggagag tggccttcct gtgggacctg ggctccgggt ccacacgctt 6661 ggagtttcca gactttccca ttgatgacaa cagatggcac agtatccatg tagccagatt 6721 tggaaacatt ggttcactga gtgtaaagga aatgagctca aatcaaaagt caccaacaaa 6781 aacaagtaaa tcccctggga cagctaatgt tctggatgta aacaattcaa cactcatgtt 6841 tgttggaggt cttggaggac aaatcaagaa atctcctgct gtgaaggtta ctcattttaa 6901 aggctgcttg ggggaggcct tcctgaatgg aaaatccata ggcctatgga actatattga 6961 aagggaaggc aagtgccgtg ggtgcttcgg aagctcccag aatgaagacc cttccttcca 7021 ttttgacggg agtgggtact ctgtcgtgga gaagtcactt ccggctaccg tgacccagat 7081 aatcatgctt tttaatacct tttcacctaa tggacttctt ctctacctgg gttcatacgg

7141 cacaaaagac tttttatcca tcgagctgtt tcgtggcaga gtgaaggtta tgactgacct 7201 gggttcagga cccattaccc ttttgacaga cagacgttat aacaatggaa cctggtacaa 7261 aattgccttc cagcgaaacc ggaagcaagg agtgctagca gttatcgatg cctataacac 7321 cagtaataaa gaaaccaagc agggcgagac tccgggagca tcttctgacc tcaaccgcct 7381 agacaaggac ccgatttatg tgggtggatt accaaggtca agagttgtaa ggagaggtgt 7441 caccaccaaa agctttgtgg gctgcatcaa gaacctggaa atatccagat caacctttga 7501 cttactcaga aattcctatg gagtgagaaa aggctgttta ctggagccca tccggagtgt 7561 tagcttcctg aaaggcggct acattgaatt gccacccaaa tctttgtcac cagaatcaga 7621 atggctggta acatttgcca ccacgaacag cagtggcatc atcctggctg ccctcggcgg 7681 ggatgtggag aagcggggtg atcgtgagga agcacacgtg cccttctttt ccgtcatgct 7741 gatcggaggc aacattgagg tacatgtcaa tcctggggat gggacaggcc tgagaaaagc 7801 tctcctgcac gctcccacgg gtacctgcag tgatggacaa gcgcattcca tctccttggt 7861 caggaatcgg agaattatca ctgtccaatt ggatgagaac aatcctgtgg aaatgaagtt 7921 gggcacatta gtagaaagca ggacgataaa tgtgtccaat ctgtacgtcg ggggaattcc 7981 agagggagag gggacgtcac tgctcacaat gagaagatcg ttccatggct gtatcaaaaa 8041 cctgatcttc aatttggaac ttttggattt caacagtgca gttggccatg agcaagtcga 8101 cctggacacc tgctggctgt cagaaaggcc taagctggct cccgatgcag aggacagcaa 8161 gctcttgcca gagccccggg cttttccaga acagtgtgtg gtggatgcag ctctggagta 8221 cgttcccggc gctcaccagt ttggtctcac acaaaacagc catttcatct tgccttttaa 8281 tcagtcggct gtcagaaaga agctctcggt tgagctaagc atccgcacgt tcgcctccag 8341 cggcctgatt tactacatgg ctcatcagaa ccaagcagac tacgctgtgc tccagctgca 8401 cgggggccgc ctccacttca tgtttgacct tggcaaaggc agaacaaagg tctctcaccc 8461 tgcactgctc agtgatggca agtggcacac ggtcaagaca gactatgtta aaagaaaagg 8521 cttcataact gtcgacggcc gagagtctcc catggtgact gtggtgggag atggaaccat

8581 gctggatgtg gagggtttgt tctacctagg aggcctgccc tcccagtacc aggccaggaa 8641 aattggaaat atcacccaca gcatccctgc ctgcattggg gatgtgacgg ttaacagcaa 8701 acagctggac aaggacagcc cggtgtctgc cttcacggtg aacaggtgct acgcagtggc 8761 ccaggaagga acatactttg acggaagcgg atatgcagct cttgtcaaag agggctacaa 8821 agtccagtca gatgtgaaca tcacactgga gtttcgaacc tcctcgcaga atggcgtcct

8881 cctggggatc agcactgcca aagtggatgc cattggacta gagcttgtgg acggcaaggt 8941 cttgttccat gtcaacaatg gtgctggcag gataacagct gcatatgagc ccaaaaccgc 9001 cactgtgctc tgtgatggaa aatggcacac tcttcaagct aacaaaagca aacaccgtat 9061 cactctgatt gttgacggga acgcagttgg cgctgaaagt ccacacaccc agtctacctc 9121 agtggacacc aacaatccca tttatgttgg tggctatcct gctggtgtga agcaaaaatg

9181 cctgcgcagc cagacctcgt tccgcgggtg tttgaggaag ctagctctga ttaagagccc 9241 gcaggtgcag tcctttgact tcagcagagc gttcgaactg cacggagttt tccttcattc 9301 ctgtcctggg accgagtcct gaacttcaag cagaatcctc agttggaatc attgctaata 9361 ttttgaggag aagtgtatgt gtgaattaag aatctcttca gttcatattt catttccaac 9421 tcaggttaag tgtttctggg gagagatgtt gtgtttacgt tacactaaaa ccacatgtgc

9481 aacaaatacc tccattaaat ggtctaaaat gtaaattgaa ttccctggct ctctttttaa 9541 acgtattttt aaaaaaatct ttatacacat tgaatgttct gttgattact tgatagtatt

9601 ttatgttttt cattttgagc tttttaaaaa agtatcaata cagatgataa cagatca Fibulin-5 (NCBI Ref.: NM 006329.3; SEQ ID NO: 27)

1 cgcccctcgc cttctgcccg ggcgctcgca gccgagcgcg gccggggaag ggctctcctc 61 ccagcgccga gcactgggcc ctggcagacg ccccaagatt gttgtgagga gtctagccag 121 ttggtgagcg ctgtaatctg aaccagctgt gtccagactg aggccccatt tgcattgttt 181 aacatactta gaaaatgaag tgttcatttt taacattcct cctccaattg gtttaatgct

241 gaattactga agagggctaa gcaaaaccag gtgcttgcgc tgagggctct gcagtggctg

301 ggaggacccc ggcgctctcc ccgtgtcctc tccacgactc gctcggcccc tctggaataa 361 aacacccgcg agccccgagg gcccagagga ggccgacgtg cccgagctcc tccgggggtc 421 ccgcccgcga gctttcttct cgccttcgca tctcctcctc gcgcgtcttg gacatgccag 481 gaataaaaag gatactcact gttaccattc tggctctctg tcttccaagc cctgggaatg 541 cacaggcaca gtgcacgaat ggctttgacc tggatcgcca gtcaggacag tgtttagata

601 ttgatgaatg ccgaaccatc cccgaggcct gccgaggaga catgatgtgt gttaaccaaa 661 atggcgggta tttatgcatt ccccggacaa accctgtgta tcgagggccc tactcgaacc 721 cctactcgac cccctactca ggtccgtacc cagcagctgc cccaccactc tcagctccaa 781 actatcccac gatctccagg cctcttatat gccgctttgg ataccagatg gatgaaagca 841 accaatgtgt ggatgtggac gagtgtgcaa cagattccca ccagtgcaac cccacccaga

901 tctgcatcaa tactgaaggc gggtacacct gctcctgcac cgacggatat tggcttctgg 961 aaggccagtg cttagacatt gatgaatgtc gctatggtta ctgccagcag ctctgtgcga 1021 atgttcctgg atcctattct tgtacatgca accctggttt taccctcaat gaggatggaa 1081 ggtcttgcca agatgtgaac gagtgtgcca ccgagaaccc ctgcgtgcaa acctgcgtca 1141 acacctacgg ctctttcatc tgccgctgtg acccaggata tgaacttgag gaagatggcg

1201 ttcattgcag tgatatggac gagtgcagct tctctgagtt cctctgccaa catgagtgtg

1261 tgaaccagcc cggcacatac ttctgctcct gccctccagg ctacatcctg ctggatgaca

1321 accgaagctg ccaagacatc aacgaatgtg agcacaggaa ccacacgtgc aacctgcagc

1381 agacgtgcta caatttacaa gggggcttca aatgcattga ccccatccgc tgtgaggagc

1441 cttatctgag gatcagtgat aaccgctgta tgtgtcctgc tgagaaccct ggctgcagag

1501 accagccctt taccatcttg taccgggaca tggacgtggt gtcaggacgc tccgttcccg

1561 ctgacatctt ccaaatgcaa gccacgaccc gctaccctgg ggcctattac attttccaga

1621 tcaaatctgg gaatgagggc agagaatttt acatgcggca aacgggcccc atcagtgcca

1681 ccctggtgat gacacgcccc atcaaagggc cccgggaaat ccagctggac ttggaaatga

1741 tcactgtcaa cactgtcatc aacttcagag gcagctccgt gatccgactg cggatatatg

1801 tgtcgcagta cccattctga gcctcgggct ggagcctccg acgctgcctc tcattggcac

1861 caagggacag gagaagagag gaaataacag agagaatgag agcgacacag acgttaggca

1921 tttcctgctg aacgtttccc cgaagagtca gccccgactt cctgactctc acctgtacta

1981 ttgcagacct gtcaccctgc aggacttgcc acccccagtt cctatgacac agttatcaaa

2041 aagtattatc attgctcccc tgatagaaga ttgttggtga attttcaagg ccttcagttt

2101 atttccacta ttttcaaaga aaatagatta ggtttgcggg ggtctgagtc tatgttcaaa

2161 gactgtgaac agcttgctgt cacttcttca cctcttccac tccttctctc actgtgttac

2221 tgctttgcaa agacccggga gctggcgggg aaccctggga gtagctagtt tgctttttgc

2281 gtacacagag aaggctatgt aaacaaacca cagcaggatc gaagggtttt tagagaatgt

2341 gtttcaaaac catgcctggt attttcaacc ataaaagaag tttcagttgt ccttaaattt

2401 gtataacggt ttaattctgt cttgttcatt ttgagtattt ttaaaaaata tgtcgtagaa

2461 ttccttcgaa aggccttcag acacatgcta tgttctgtct tcccaaaccc agtctcctct

2521 ccattttagc ccagtgtttt ctttgaggac cccttaatct tgctttcttt agaattttta

2581 cccaattgga ttggaatgca gaggtctcca aactgattaa atatttgaag agaaaaa

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 a target integrin or a target integrin ligand (e.g., any of the exemplary target integrins or any of the exemplary integrin ligands described herein). 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 a target integrin (e.g., any of the exemplary target integrins described herein) or a nucleic acid encoding an integrin ligands (e.g., any of the exemplary integrin ligands described herein). Antisense nucleic acids targeting a nucleic acid encoding a target integrin (e.g., any of the exemplary integrins described herein) or a nucleic acid encoding an integrin ligand (e.g., any of the exemplary integrin ligands described herein) 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 a target integrin (e.g., any of the exemplary target integrins described herein) or encoding a integrin ligand (e.g., any of the exemplary integrin ligands described herein) 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 integrin inhibitors that are antisense nucleic acids include ATL1102 (e.g.,

Limmroth et al, Neurology 83(20): 1780-1788, 2014; Li et al, Dig. Liver Dis. 39(6):557-565, 2007; Goto et al., Inflamm. Bowel Dis. 12(8):758-765, 2006).

Another example of an inhibitory nucleic acid is a ribozyme that has specificity for a nucleic acid encoding a target integrin (e.g., any of the exemplary target integrins described herein) or an integrin ligand (e.g., any of the exemplary integrin ligands described herein). 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 a target integrin (e.g., any of the exemplary target integrins described herein) or an integrin ligand (e.g., any of the exemplary integrin ligands described herein) can be designed based upon the nucleotide sequence of any of the integrin mRNA sequences or integrin ligand mRNA sequences disclosed herein or known in the art. For example, a derivative of a Tetrahymena L-19 IV S RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a target integrin mRNA or an integrin ligand mRNA (see, e.g., U. S. Patent. Nos. 4,987,071 and 5, 1 16,742). Alternatively, an integrin mRNA (e.g., any of the exemplary integrin mRNAs described herein) or an integrin ligand mRNA (e.g., any of the exemplary integrin ligand mRNAs described herein) 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 a target integrin (e.g., any of the exemplary target integrins described herein) or an integrin ligand (e.g., any of the exemplary integrin ligands described herein) can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the gene encoding the target integrin (e.g., any of the exemplary target integrins described herein) or the integrin ligand (e.g., any of the exemplary integrin ligands described herein) (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 ; dene, 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-methoxytrit l)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 : 11 19-1 1 124, 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 a target integrin (e.g., any of the exemplary target integrins described herein) mRNA or an integrin ligand (e.g., any of the exemplary integrin ligands described herein) 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 a target integrin (e.g., any of the exemplary target integrins described herein) or a integrin ligand (e.g., any of the exemplary integrin ligands described herein)) is introduced into a mammalian cell. The dsRNA is digested into 21 -23 nucleotide- 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 al, Nature Rev. Gen. 2: 1 10-119, 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 a target integrin (e.g., any of the exemplary target integrins described herein) mRNA or an integrin ligand (e.g., any of the exemplary integrin ligands described herein) 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 a target integrin (e.g., any of the exemplary target integrins described herein) mRNA or an integrin ligand (e.g., any of the exemplary integrin ligands described herein) mRNA, provided it has sufficient homology to the target of interest (e.g., a sequence present in any one of SEQ ID NOs: 1-27, 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).

As described herein, inhibitory nucleic acids preferentially bind (e.g., hybridize) to a nucleic acid encoding a target integrin (e.g., any of the exemplary target integrins described herein) or an integrin ligand (e.g., any of the exemplary integrin ligands described herein).

Non-limiting examples of integrin inhibitors that are short interfering RNAs (siRNAs) are described in Wang et al, Cancer Cell Int. 16:90, 2016). In some embodiments, the integrin inhibitor is a short hairpin RNA (shRNA).

Non-limiting examples of integrin inhibitors that are microRNA include miR-124 (Cai et al, Sci. Rep. 7:40733, 2017), miR-134 (Qin et al, Oncol. Rep. 37(2): 823-830, 2017), miR-92b (Ma et al, Oncotarget 8(4):6681 -6690, 2007), miR-17 (Gong et al, Oncol. Rep. 36(4), 2016), miR-338 (Chen et al, Oncol. Rep. 36(3): 1467-74, 2016), and miR-30a-5p (Li et &\., Int. J. Oncol. 48(3): 1155-1164, 2016).

In some embodiments, the integrin inhibitor can include modified bases/locked nucleic acids (LNAs). In some embodiments, the integrin inhibitor is an aptamer (e.g., Berg et al, Mol. Ther. Nucl. Acids 5: e294, 2016; and Hussain et al, Nucleic Acid Ther. 23(3):203- 212, 2013). Additional examples of integrin inhibitors that are inhibitory nucleic acids are described in Juliano et al., Theranostics 1 :211 -219, 2011 ; Millard et al, Theranostics 1 : 154- 188, 201 1 ; and Teoh et al., Curr. Mol. Med. 15 :714-734, 2015. In some embodiments, the integrin inhibitor is an antisense nucleic acid, e.g., alicaforsen (Yacyshyn et al., Clin.

Gastroenterol. Hepatol. 5(2):215-220, 2007).

In certain embodiments, a therapeutically effective amount of an inhibitory nucleic acid targeting a nucleic acid encoding a target integrin (e.g., any of the exemplary target integrins described herein) or an integrin ligand (e.g., any of the exemplary integrin ligands described herein) 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, 1 1 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 a target integrin, e.g., any of the exemplary target integrins described herein, or a nucleic acid encoding an integrin ligand, e.g., any of the exemplary integrin ligands described herein) 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 a target integrin, e.g., any of the exemplary target integrins described herein, or a nucleic acid encoding an integrin ligand, e.g., any of the exemplary integrin ligands described herein) with a Tm 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 ?&., 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. Drug Deliv. 17: 1-14, 2017), a micelle (e.g., a mixed micelle) (Tangs angasaksri et al,

BioMacromolecules 17:246-255, 2016; Wu et &\., 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.

In certain embodiments, a therapeutically effective amount of an inhibitory nucleic acid targeting an integrin can be administered to a subject (e.g., a human subject) in need of thereof.

In certain embodiments, the inhibitory nucleic acids are 10 to 40 (e.g., 10 to 30, 10 to 25, 10 to 20, 10 to 15, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 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 the DNA or RNA.

Antibodies

In some embodiments, the integrin inhibitor is an antibody or an antigen-binding fragment thereof (e.g., a Fab or a scFv). 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 IgG, a 2-in-l-IgG, IgG-ScFv, scFv2-Fc, a bi-nanobody, tanden antibody, a DART- Fc, a scFv-HAS-scFv, DNL-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-IgG, 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-IgG, 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 IgG, 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).

Any of the antibodies or antigen-binding fragments thereof described herein can bind to any of the integrins described herein or any of the integrin ligands described herein.

In some embodiments, the antibody is a pan-βΐ antibody (e.g., OS2966 (Carbonell et al, Cancer Res. 73(10):3145-3154, 2013). In some embodiments, the integrin antibody is a monoclonal antibody (e.g., 17E6 (Castel et al, Eur. J. Cell. Biol. 79(7):502-512, 2000); Mitjans et al, Int. J. Cancer 87(5):716-723, 2000)). In some embodiments, the monoclonal antibody is vedolizumab (e.g., Entyvio®) or a variant thereof (Feagan et al, N. Engl. J. Med 369:699-710, 2013; Sandborn et al., N. Engl. J. Med. 369:711-721, 2013; Sands et al, Gastroenterology 147:618-627, 2014; and Milch et al, Neuroimmunol. 264: 123-126, 2013; Wyant et al, J. Crohns Colitis 10(12): 1437-1444, 2016; and Feagan et al, Gastroenterology 142(5):S 160-S161, 2012).

In some embodiments, the antibody can be a Fab fragment of a monoclonal chimeric mouse-human antibody (e.g., abciximab (ReoPro, c7E3), Kononczuk et al, Curr. Drug Targets 16(13): 1429-1437, 2015; Jiang et al, Appl. Microbiol. Biotechnol. 98(1): 105-114, 2014), or a variant thereof. In some embodiments, the integrin antibody is a humanized monoclonal antibody. In some embodiments, the humanized monoclonal antibody is natalizumab (Tysabri®) (Targan et al, Gastroenterology 132(5): 1672-1683, 2007; Sandborn et al, N. Engl. J. Med. 353(18): 1912-1925, 2005; Nakamura et al, Intern Med. 56(2):211- 214, 2017; Singh et al, J. Pediatr. Gastroenterol. Nutr. 62(6): 863-866, 2016). In some embodiments, the humanized monoclonal antibody is vitaxin (MEDI-523) or a variant thereof (Huveneers et εά., Ιηί, J. Radiat. Biol. 81(11-12):743-751, 2007; Coleman et al, Circ. Res. 84(11): 1268-1276, 1999). In some embodiments, the humanized monoclonal antibody is etaracizumab (Abegrin®, MEDI-522, LM609) or a variant thereof (Hersey et al, Cancer 116(6): 1526-1534, 2010; Delbaldo et al, Invest New Drugs 26(l):35-43, 2008). In some embodiments, the humanized monoclonal antibody is CNT095 (Intetumumab®) or a variant thereof (Jia et al, Anticancer Drugs 24(3):237-250, 2013; Heidenreich et al, Ann. Oncol. 24(2):329-336, 2013; Wu et al, J. Neurooncol. 110(l):27-36, 2012). In some embodiments, the humanized monoclonal antibody is efalizumab (Raptiva®) or a variant thereof (Krueger et al, J. Invest. Dermatol. 128(11):2615-2624, 2008; Li et al., PNAS 106(11)_:4349-4354, 2009; Woolacott et al, Health Technol. Assess 10: 1-233, 2006). In some embodiments, the humanized monoclonal antibody is STX-100 (Stromedix®) or a variant thereof (van Aarsen et al, Cancer Res. 68:561-570, 2008; Lo et al, Am. J. Transplant. 13(12):3085-3093, 2013). In some embodiments, the humanized monoclonal antibody is 264RAD or a variant thereof (Eberlein et al., Oncogene 32(37):4406-4417, 2013).

In some embodiments, the humanized monoclonal antibody is rovelizumab or a variant thereof (Goodman et al, Trends Pharmacol. Sci 33:405-412, 2012). In some embodiments, the humanized monoclonal antibody is Cytolin® or a variant thereof (Ry chert et al, Virology J. 10: 120, 2013). In some embodiments, the humanized monoclonal antibody is etrolizumab or a variant thereof (Vermeire et al, Lancet 384:309-318, 2014; Rutgeerts et al, Gut 62: 1122-1130, 2013; Lin et al, Gastroenterology 146:307-309, 2014; Ludviksson et al., J. Immunol. 162(8):4975-4982, 1999; Stefanich et al., 5r. J. Pharmacol. 162(8): 1855- 1870, 2011). In some embodiments, the humanized monoclonal antibody is abrilumab (AMG 181 ; MEDI-7183) or a variant thereof (Pan et al, Br. J. Pharmacol. 169(l):51-68, 2013; Pan et al., Br. J. Clin. Pharmacol. 78(6): 1315-1333, 2014). In some embodiments, the humanized monoclonal antibody is PF-00547659 (SHP647) or a variant thereof (Vermeire et al, Gut 60(8): 1068-1075, 2011 ; Sandborn et al, Gastroenterology 1448(4):S-162, 2015). In some embodiments, the humanized monoclonal antibody is SAN-300 (hAQC2) or a variant thereof (Karpusas et al, J. Mol. Biol. 327: 1031-1041, 2003). In some embodiments, the humanized monoclonal antibody is DI176E6 (EMD 5257) or a variant thereof (Goodman et al, Trends Pharmacol. Sci 33:405-412, 2012; and Sheridan et al, Nat. Biotech. 32:205-207, 2014).

In some embodiments, the integrin antibody is a chimeric monoclonal antibody. In some embodiments, the chimeric monoclonal antibody is volociximab or a variant thereof (Kuwada et al., Curr. Opin. Mol. Ther. 9(l):92-98, 2007; Ricart et al, Clin. Cancer Res. 14(23):7924-7929, 2008; Ramakrishnan et al., J. Exp. Ther. Oncol. 5(4):273-86, 2006; Bell- McGuinn et al, Gynecol. Oncol. 121 :273-279, 2011 ; Almokadem et al., Exp. Opin. Biol. Ther. 12:251-7, 2012). In some embodiments, the antibody specifically binds one or more (e.g., 1, 2, 3, 4, or 5) integrin. In some embodiments, the antibody specifically binds an integrin dimer (e.g., MLN-00002, MLN02 (Feagan et al, Clin. Gastroenterol. Hepatol. 6(12): 1370-1377, 2008; Feagan et al, N. Engl. J. Med. 352(24):2499-2507, 2005). In certain embodiments, the antibody comprises or consists of an antigen-binding fragment of abciximab (Reopro™) (Straub et al, Eur. J. Cardiothorac Surg. 27(4):617-621, 2005; Kim et al, Korean J. Intern. Med. 19(4): 220-229, 2004). In some embodiments, the integrin inhibitor is an antibody-drug conjugate (e.g., IMGN388 (Bendell et al, EJC Suppl 8(7): 152, 2010).

Further examples of antibodies and antigen-binding fragments thereof are described in U.S. Patent Nos. 5,919,792; 6,214,834; 7,074,408; 6,833,373;; 7,655,624; 7,465,449;

9,558,899; 7,659,374; 8,562,986; 8,398,975; and 8,853,149; US 2007/0117849; US

2009/0180951; US 2014/0349944; US 2004/0018192; WO 11/137418; and WO 01/068586; each of which is incorporated by reference in its entirety.

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^"η Μ, 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 Μ, about 0.5 x 10^"10 Μ, 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 Koff 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^" ¹, 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 K_<,n of about 1 x 10² M^{' 1} to about 1 x 10⁶ M^'V¹, about 0.5 x 10⁶ M^'V¹, about 1 x 10⁵ M-y¹, about 0.5 x 10⁵ M^'V¹, about 1 x 10⁴ M^'V¹, about 0.5 x 10⁴ M^'V¹, about 1 x 10³ M^s^"1, or about 0.5 x 10³ M^s^"1 (inclusive); about 0.5 x 10³ M^'V¹ to about 1 x l O^V¹, about 0.5 x 10⁶ M^s^"1, about 1 x 10⁵ M^s^"1, about 0.5 x 10⁵ M^s^"1, about 1 x 10⁴ M^'V¹, about 0.5 x 10⁴ M-^ls- or about 1 x 10³ M^s^"1 (inclusive); about 1 x 10³ M^s^ to about 1 x l O^V about 0.5 x 10⁶ M^s^"1, about 1 x 10^s M^s^"1, about 0.5 x 10⁵ M^s^"1, about 1 x 10⁴ M^s^"1, or about 0.5 x 10⁴ M^s^"1 (inclusive); about 0.5 x 10⁴ M^s^ to about 1 x lO⁶ ]^^"^^"1, about 0.5 x 10⁶ M-y¹, about 1 x 10⁵ 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 K^JVr ¹, about 0.5 x 10⁶ M^'V¹, about 1 x 10⁵ M^'V¹, or about 0.5 x 10⁵ M^{' 1} (inclusive); about 0.5 x 10⁵ M^{' 1} to about 1 x 10⁶ M^'V¹, about 0.5 x 10⁶ M^As- or about 1 x 10⁵ M' ¹ (inclusive); about 1 x 10^s M- ¹ to about 1 x lO^ ¹, or about 0.5 x 10⁶ M'V¹ (inclusive); or about 0.5 x 10⁶ M'V¹ to about 1 x lO^' ¹ (inclusive), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).

Fusion Proteins

In some embodiments, the integrin inhibitor is a fusion protein (e.g., an Fc fusion protein of an extracellular domain of an integrin or an integrin receptor), a soluble receptor (e.g., the extracellular domain of an integrin or an integrin receptor), or a recombinant integrin binding protein (e.g., an integrin ligand). See, e.g., Lode et al., PNAS 96(4): 1591- 1596, 1999; Stephens et al, Cell Adhesion Comm. 7:377-390, 2000; and US 2008/0739003; incorporated by reference herein). Non-limiting examples of fusion proteins that are integrin inhibitors include Ag25426 (Proteintech).

Small Molecules Antagonists

In some embodiments, the integrin inhibitor is a small molecule. In some

embodiments, the small molecule is a non-peptide small molecule. In some embodiments, the non-peptide small molecule is a RGD (ArgGlyAsp)-mimetic antagonist (e.g., tirofiban (Aggrastat®); Pierro et al, Eur. J. Ophthalmol. 26(4):e74-76, 2016; Guan et al, Eur. J. Pharmacol 761 : 144-152, 2015. In some embodiments, the small molecule is a4 antagonist (e.g., firategrast (Miller et al, Lancet Neurol. 11(2): 131-139, 2012) AJM300 (Yoshimura et al, Gastroenterology 149(7): 1775-1783, 2015; Takazoe et al, Gastroenterology 136(5):A- 181, 2009; Sugiura et al, J. Crohns Colitis 7(1 l):e533-542, 2013)). In some embodiments, the small molecule is α4β1 antagonist (e.g., IVL745 (Norris et al, J. Allergy Clin. Immunol. 116(4):761-767, 2005; Cox et ., Ναί. Rev. Drug Discov. 9(10):804-820, 2010)), BIO-1211 (Abraham et ?&., Am. J. Respir. Crit. Care Med. 162:603-611, 2000; Ramroodi et al, Immunol. Invest. 44(7): 694-712, 2015; Lin et al, J. Med. Chem. 42(5):920-934, 1999), HMR 1031 (Diamant et al, Clin. Exp. Allergy 35(8): 1080-1087, 2005); valategrast (R411) (Cox et al, Nat. Rev. Drug Discov. 9(10):804-820, 2010), GW559090X (Ravensberg et al, Allergy 61(9): 1097-1103, 2006), TR14035 (Sircar et al, Bioorg. Med. Chem. 10(6):2051-2066, 2002; Cortijo et al, Br. J. Pharmacol. 147(6):661-670, 2006)). In some embodiments, the small molecule is ανβ3 antagonist (e.g., L0000845704, SB273005). In some embodiments, the small molecule is α5β1 antagonist (e.g., JSM6427). In some embodiments, the small molecule is GLPG0974 (Vermeire et al, J. Crohns Colitis Suppl. 1 :S39, 2015). In some embodiments, the small molecule is MK-0429 (Pickarksi et al, Oncol. Rep. 33(6):2737-45, 2015; Rosenthal et si., Asia Pac J. Clin. Oncol. 6:42-8, 2010). In some embodiments, the small molecule is JSM-6427 or a variant thereof (Zahn et al, Arch.

0/j> ∞/mo/.127(10): 1329-1335, 2009; Stragies et al., J Med. Chem. 50:3786-94, 2007).

In some embodiments, the small molecule targets a β2 integrin. In some

embodiments, the small molecule is SAR-118 (SARI 118) or a variant thereof (Zhong et al, ACSMed. Chem. Lett. 3(3):203-206, 2012; Suchard et al., J. Immunol. 184:3917-3926, 2010; Yandrapu et al, J. Ocul. Pharmacol. Ther. 29(2):236-248, 2013; Semba et &\., Am. J.

Ophthalmol. 153: 1050-60, 2012). In some embodiments, the small molecule is BMS-587101 or a variant thereof (Suchard et al, J. Immunol. 184(7):3917-3926, 2010; Potin et al, J. Med. Chem. 49:6946-6949, 2006). See e.g., Shimaoka et al., Immunity 19(3):391-402, 2003; U.S. Patent Nos. 7,138,417; 7,928,113; 7,943,660; and 9,216,174; US 2008/0242710; and US 2008/0300237.

Cyclic Peptides

In some embodiments, the integrin inhibitor is a cyclic peptide. In some

embodiments, the cyclic peptide comprises or consists of an amino acid sequence as set forth in the amino acid sequence of a ligand recognition sequence of an endogenous integrin ligand. In some embodiments, the cyclic peptide competes for a target integrin ligand binding site with an endogenous integrin ligand. In some embodiments, the cyclic peptide includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8) D-amino acids. In some embodiments, the cyclic peptide is a synthetic cyclic peptide. In some embodiments, the synthetic cyclic peptide is a heptapeptide. In some embodiments, the synthetic cyclic peptide is eptifabitide (Integrilin™), or a variant thereof. In some embodiments, the cyclic peptide comprises a heterocyclic nucleic (e.g., a benzodiazepinone, a piperazine, a benzoazepinone, a nitroaryl, an isoxazoline, an indazole, or a phenol; Spalluto et al, Curr. Med. Chem. 12:51-70, 2005). In some embodiments, the cyclic peptide is a macrocycle (see, e.g., Halland et al, ACSMed. Chem. Lett. 5(2): 193-198, 2014). In some embodiments, the peptide is ALG-1001 or a variant thereof (Mathis et al, Retin. Phys. 9:70, 2012). In some embodiments, the cyclic peptide is an imidazolone-phenylalanine derivative, a heteroaryl, hetrocyclic, and aryl derivative, a bicyclic-aromatic amino acid derivative, a cyclohexane-carboxylic acid derivative, a di-aryl substituted urea derivative, a multimeric L-alanine derivative, a L-alanine derivative, or a pyrimidyl-sulfonamide derivative (see, e.g., U.S. Patent Nos. 6,630,492; 6,794,506; 7,049,306; 7,371,854; 7,759,387; 8,030,328; 8,129,366; 7,820,687; 8,350,010; and 9,345,793).

Peptidomimetics

In some embodiments, the integrin inhibitor is a peptidomimetic. In some embodiments, the peptidomimetic has an integrin-ligand recognition motif (e.g., RGD, KTS, or MLD). See, e.g., Carron et al, Cancer Research 58: 1930-1935, 1998; Fanelli et al.,

Vascular Cell 6: 11, 2014; and De Marco et al, Curr. Top. Med. Chem. 16(3):343-359, 2016.

In some embodiments, the peptidomimetic is an RGD(ArgGlyAsp)-based peptide (US Patent No. 8,809,338, incorporated by reference in its entirety herein). In some

embodiments, the RGD-based peptide can be cilengitide or a variant thereof (EMD 12974) (Mas-Moruno et al, Anticancer Agents Med. Chem. 10:753-768, 2010; Reardon et al, Future Oncol. 7(3):339-354, 2011; Beekman et al, Clin. Genitourin Cancer 4(4):299-302, 2006; SC56631 (e.g., Engleman et al, Am Soc. Clin. Invest. 99(9):2284-2292, 1997; Peng et al., Nature Chem Biol. 2:381-389, 2006). In some embodiments, the peptidomimetic can be a Lys-Gly-Asp (KGD)-based peptide. In some embodiments, the peptidomimetic can be vipegitide or a variant thereof (Momic et al., Drug Design Devel. Therapy 9:291-304, 2015). In some embodiments, the peptidomimetic can be a peptide conjugated with an antimicrobial synthetic peptide, (e.g., ACDCRGDCFC conjugated with (KLAKLAK)₂ (Ellerby et al, Nat. Med. 5(9): 1032-1038, 1999). See, e.g., U.S. Patent No. 8,636,977. Disintegrins

In some embodiments, the integrin inhibitor can be a disintegrin. The term

"disintegrin" as used herein refers to a low molecular weight peptide integrin inhibitor derived from a snake venom (e.g., pit viper venom). In some embodiments, the disintegrin is a RGD(ArgGlyAsp)-, a KTS- or an MLD-based disintegrin.

Non-limiting examples of disintegrins include accutin, accurhagin-C, albolabrin, alternagin-c, barbourin, basilicin, bitisgabonin-1, bitisgabonin-2, bitistatin, cerastin, cereberin, cumanastatin 1, contortrostatin, cotiarin, crotatroxin, dendroaspin, disba-01, durissin, echistatin, EC3, elegantin, eristicophin, eristostatin, EMS11, E04, E05, fiavoridin, flavostatin, insularin, jarastatin, jerdonin, jerdostatin, lachesin, lebein (e.g., lebein-1, lebein- 2), leberagin-C, lebestatin, lutosin, molossin, obtustatin, ocellatusin, rhodocetin, rhodostomin, R-mojastin 1, salmosin, saxatilin, schistatin, tablysin-15, tergeminin, triflavin, trigramin, trimestatin, VA6, vicrostatin, viridin, viperstatin, VB7, VL04, and VL05, or a variant thereof. See, e.g., Arruda Macedo et al, Curr. Protein. Pept. Sci. 16(6):532-548, 2015; Hsu et al, Sci. Rep. 6:23387, 2016; Kele et al. Curr. Protein Pept. Sci. 6:532-548, 2015; Koh et al, Toxicon 59(4):497-506, 2012; Scarborough et al., J. Biol. Chem. 268: 1058-1065, 1993; Kisiel et al, FEES Lett. 577:478-482, 2004; Souza et al, Arch. Biochem. Biophys. 384:341- 350, 2000; Eble et al, J. Biol. Chem. 278:26488-26496, 2003; Marcinkiewicz et al, J. Biol. Chem. 274: 12468-12473, 1999; Calvete et al., J. Proteome Res. 6:326-336, 2007; Scibelli et al, FEMS Microbiol. Lett. 247:51-57, 2005; Oliva et al, Toxicon 50: 1053-1063, 2007; Minea et al, Toxicon 59:472-486, 2012; Smith et al, FEBS Lett. 512: 111-115, 2002; Tselepis et al, J. Biol. Chem. 272:21341-21348, 1997; Da Silva et al, Tromb. Res. 123:731-739, 2009; Thibault et al, Mol. Pharmacol. 58: 1137-1145, 2000; Lu et al, Biochem. J. 304:818-825, 1994; Yeh et al, Biochim. Biophys. Acta. 1425:493-504, 1998; Huang et al, Exp. Hematol. 36: 1704-1713, 2008; Shih et al, Matrix Biol. 32: 152-159, 2013; Wang et al, Br. J.

Pharmacol. 160: 1338-1351, 2010; Della-Casa et al., Toxicon 57: 125-133, 2011 ; Sheu et al, Biochim. Biophys. Acta. 1336:445-454, 1997; Fujii et al, J. Mol. Biol. 332: 115-122, 2003; Bilgrami et al., J. Mol. Biol. 341 :829-837, 2004; Zhou et al, Toxicon 43:69-75, 2004;

Scarborough et al, J. Biol. Chem. 268: 1066-1073, 1993; Shebuski et al., J. Biol. Chem.

264:21550-21556, 1989; Lu et al, Biochem. J. 304:929-936, 1994; McLane et al, Biochem. J. 301 :429-436, 1994; Juarez et al, Toxicon 56: 1052-1058, 2010; Olfa et al, Lab. Invest. 85: 1507-1516, 2005; Elbe et al, Matrix Biol. 21 :547-558, 2002; Bazan-Socha et al,

Biochemistry 43: 1639-1647, 2004; Danen et al, Exp. Cell. Res. 238: 188-196, 1998;

Marcinkiewicz et al., Biochemistry 38(40): 13302-13309, 1999; Calvete et al, Biochem. J. 372:725-734, 2003; Swenson et al, Pathophysiol. Haemost. Thromb. 34: 169-176, 2005; Kwon et al, PLoS One 8; e81165, 2013; Yang et al, Toxicon 45:661-669, 2005; Limam et al, Matrix Biol. 29: 117-126, 2010; Gan et al, J. Biol. Chem. 263: 19827-19832, 1988; Ma et al, Thromb. Haemost. 105(6): 1032-1045, 2011; and U.S. Patent No. 7,074,408, incorporated in their entirety herein. Exemplary embodiments:

The following embodiments 1) - 94) are exemplary embodiments provided herein:

1) A method of treating a disease of the gastro-intestinal tract in a subject, comprising: delivering an integrin 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 integrin inhibitor.

2) The method of exemplary embodiment 1 , wherein the disease of the GI tract is an inflammatory bowel disease.

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

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

5) The method of any one of exemplary embodiments 1 , 2, or 3, 4, wherein the integrin inhibitor is delivered at a location in the large intestine of the subject.

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

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

8) The method of any one of exemplary embodiments 1 , 2, or 3, 4, wherein the integrin inhibitor is delivered at a location in the ascending colon of the subject.

9) The method of exemplary embodiment 8, wherein the location is in the proximal portion of the ascending colon. 10) The method of exemplary embodiment 8, wherein the location is in the distal portion of the ascending colon. 11) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the integrin inhibitor is delivered at a location in the cecum of the subject.

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

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

14) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the integrin inhibitor is delivered at a location in the sigmoid colon of the subject.

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

17) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the integrin inhibitor is delivered at a location in the transverse colon of the subject.

18) The method of exemplary embodiment 17, wherein the location is in the proximal portion of the transverse colon.

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

20) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the integrin inhibitor is delivered at a location in the descending colon of the subject. ) The method of exemplary embodiment 20, wherein the location is in the proximal portion of the descending colon. ) The method of exemplary embodiment 20, wherein the location is in the distal portion of the descending colon. ) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the integrin inhibitor is delivered at a location in the small intestine of the subject. ) The method of exemplary embodiment 23, wherein the location is in the proximal portion of the small intestine. ) The method of exemplary embodiment 23, wherein the location is in the distal portion of the small intestine. ) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the integrin inhibitor is delivered at a location in the duodenum of the subject. ) The method of exemplary embodiment 26, wherein the location is in the proximal portion of the duodenum. ) The method of exemplary embodiment 26, wherein the location is in the distal portion of the duodenum. ) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the integrin inhibitor is delivered at a location in the jejunum of the subject. ) The method of exemplary embodiment 29, wherein the location is in the proximal portion of the jejunum. ) The method of exemplary embodiment 29, wherein the location is in the distal portion of the jejunum. ) The method of any one of exemplary embodiments 1 , 2, or 3, 4, wherein the integrin inhibitor is delivered at a location in the ileum of the subj ect. ) The method of exemplary embodiment 32, wherein the location is in the proximal portion of the ileum. ) The method of exemplary embodiment 32, wherein the location is in the distal portion of the ileum. ) The method of any one of the preceding exemplary embodiments, wherein the location is proximate to one or more sites of disease. ) 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. ) The method of any one of the preceding exemplary embodiments, wherein the integrin inhibitor is delivered to the location by mucosal contact. ) The method of any one of the preceding exemplary embodiments, wherein the integrin inhibitor is delivered to the location by a process that does not comprise systemic transport of the integrin inhibitor. ) The method of any one of the preceding exemplary embodiments, wherein the amount of the integrin inhibitor that is administered is from about 1 mg to about 300 mg. ) The method of exemplary embodiment 39, wherein the amount of the integrin inhibitor that is administered is from about 1 mg to about 100 mg. ) The method of exemplary embodiment 40, wherein the amount of the integrin inhibitor that is administered is from about 5 mg to about 40 mg. 42) The method of any one of exemplary embodiments 1 to 41, wherein the amount of the integrin inhibitor is less than an amount that is effective when the integrin inhibitor is administered systemically. 43) The method of any one of the preceding exemplary embodiments, comprising

administering (i) an amount of the integrin inhibitor that is an induction dose.

44) The method of exemplary embodiment 43, further comprising (ii) administering an amount of the integrin inhibitor that is a maintenance dose following the

administration of the induction dose.

45) The method of exemplary embodiment 43 or 44, wherein the induction dose is

administered once a day. 46) The method of exemplary embodiment 43 or 44, wherein the induction dose is

administered once every three days.

47) The method of exemplary embodiment 43 or 44, wherein the induction dose is

administered once a week.

48) The method of exemplary embodiment 44, wherein step (ii) is repeated one or more times.

49) The method of exemplary embodiment 44, wherein the induction dose is equal to the maintenance dose.

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

52) The method of exemplary embodiment 44, wherein the induction dose is 2 greater than the maintenance dose. ) The method of any one of the preceding exemplary embodiments, wherein the method comprises delivering the integrin inhibitor at the location in the gastrointestinal tract as a single bolus. ) The method of any one of exemplary embodiments 1 to 52, wherein the method comprises delivering the integrin inhibitor at the location in the gastrointestinal tract as more than one bolus. ) The method of any one of exemplary embodiments 1 to 52, wherein the method comprises delivering the integrin inhibitor at the location in the gastrointestinal tract in a continuous manner. ) The method of exemplary embodiment 55, wherein the method comprises delivering the integrin inhibitor at the location in the gastrointestinal tract over a time period of 20 or more minutes. ) The method of any one of the preceding exemplary embodiments, wherein the method provides a concentration of the integrin inhibitor in the plasma of the subject that is less than 3 μg/ml. ) The method of exemplary embodiment 57, wherein the method provides a concentration of the integrin inhibitor in the plasma of the subject that is less than 0.3 ) The method of exemplary embodiment 58, wherein the method provides a concentration of the integrin inhibitor in the plasma of the subject that is less than 0.01 μg/ml. ) The method of any one of exemplary embodiments 1 to 59, wherein the method does not comprise delivering an integrin inhibitor rectally to the subject. ) The method of any one of exemplary embodiments 1 to 59, wherein the method does not comprise delivering an integrin inhibitor via an enema to the subject. 62) The method of any one of exemplary embodiments 1 to 59, wherein the method does not comprise delivering an integrin inhibitor via suppository to the subject.

63) The method of any one of exemplary embodiments 1 to 59, wherein the method does not comprise delivering an integrin inhibitor via instillation to the rectum of the subject.

64) The method of exemplary embodiment 63, wherein the integrin inhibitor is selected from vedolizumab (Entyvio®, Millennium Pharmaceuticals), natalizumab (Tysabri®), etrolizumab (Genentech/Roche), and AJM300 (Ajinomoto Pharmaceuticals); 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.

65) The method of exemplary embodiment 63, wherein the integrin inhibitor is

PF00547659 (Shire Pharmaceuticals/Roche), or a generic equivalent thereof.

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 integrin inhibitor, wherein a first end of the storage reservoir is connected to the first end of the housing; a mechanism for releasing the integrin inhibitor from the storage reservoir; and; an exit valve configured to allow the integrin inhibitor to be released out of the housing from the storage reservoir. 67) The method of exemplary embodiment 66, wherein the ingestible 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.

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.

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,

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

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

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 injection device located at the first end of the housing,

wherein the jet inj ection device is configured to inject 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. 71) 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 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 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 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.

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. 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.

74) The method of any one of exemplary embodiments 1-73, wherein the pharmaceutical composition is not a dart-like dosage form. 75) A method of treating a disease of the large intestine of a subject, comprising: delivering of an integrin 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 integrin inhibitor.

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

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

78) The method of exemplary embodiment 75, wherein the disease the large intestine is Crohn's disease.

79) The method of any one of exemplary embodiments 75 to 78, wherein the integrin inhibitor is delivered at a location in the proximal portion of the ascending colon. 80) The method of any one of exemplary embodiments 75 to 78, wherein the integrin inhibitor is delivered at a location in the proximal portion of the cecum.

81) The method of any one of exemplary embodiments 75 to 78, wherein the integrin inhibitor is delivered at a location in the proximal portion of the sigmoid colon. 82) The method of any one of exemplary embodiments 75 to 78, wherein the integrin inhibitor is delivered at a location in the proximal portion of the transverse colon.

83) The method of any one of exemplary embodiments 75 to 78, wherein the integrin inhibitor is delivered at a location in the proximal portion of the descending colon.

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 integrin inhibitor as in exemplary embodiment 1 or 75; a different integrin inhibitor; or an agent having a different biological target from integrin.

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.

86) The method of exemplary embodiment 84 or 85, wherein the integrin inhibitor is administered prior to the second agent.

87) The method of exemplary embodiment 84 or 85, wherein the integrin inhibitor is administered after the second agent.

88) The method of exemplary embodiment 84 or 85, wherein the integrin inhibitor and the second agent are administered substantially at the same time.

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

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

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 integrin inhibitor and the second agent are both administered systemically. 92) The method of exemplary embodiment 91, wherein the second agent is an immunosuppressant.

93) In some aspects of these embodiments, the second agent is methotrexate.

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 600μί 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 600μί 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 1300μί may be used for drug release.

In some implementations, at the reservoir 135 or 161 for storing a therapeutically effective amount of the integrin inhibitor forms at least a portion of the device housing 101. The therapeutically effective amount of the integrin 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 integrin 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, DEHP (di-2-ethylhexyl phthalate), Tyvek, polyester film, poly olefin, polyethylene, polyurethane, or other materials that inhibit the integrin inhibitor from sticking to the reservoir and provide a sterile reservoir environment for the integrin inhibitor. The storage reservoir 161 can be hermetically sealed. The reservoir compartment 135 or storage reservoir 161 can be configured to store integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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.

I l l 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 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 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 integrin inhibitor for use in a method of treating a disease of the gastrointestinal tract as disclosed herein, wherein the integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 CN10447361 1 : "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 integrin 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 integrin inhibitor and collecting a sample inside the device. As an example, the method may comprise releasing an integrin 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 WO20151 12575 Al , 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 integrin 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 integrin inhibitor is triggered by generation in the composition of a gas in an amount sufficient to expel the integrin 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 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 predetermined drug release profile obtained prior to administration from the specific mammal. Accordingly, in some embodiments, releasing the integrin 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 integrin 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 integrin 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 integrin inhibitor is not dependent on the pH at or in the vicinity of the location. In some embodiments, releasing the integrin inhibitor is triggered by degradation of a release component located in the capsule. In some embodiments, the integrin inhibitor is not triggered by degradation of a release component located in the capsule. In some embodiments, wherein releasing the integrin inhibitor is not dependent on enzymatic activity at or in the vicinity of the location. In some embodiments, releasing the integrin 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 integrin inhibitor, wherein a first end of the reservoir is attached to the first end of the housing; a mechanism for releasing the integrin inhibitor from the reservoir; and; an exit valve configured to allow the integrin 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 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. In some embodiments, the ingestible device further comprises: a safety device placed within or attached to the housing,

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;

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 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,

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

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

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 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 intemational 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin inhibitor is delivered at a location in the distal portion of the ileum of the subj ect 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin inhibitor is delivered is proximate to one or more sites of disease. In some embodiments, the integrin inhibitor is delivered 50 cm or less from the one or more sites of disease. In some embodiments, the integrin inhibitor is delivered 40 cm or less from the one or more sites of disease. In some embodiments, the integrin inhibitor is delivered 30 cm or less from the one or more sites of disease. In some embodiments, the integrin inhibitor is delivered 20 cm or less from the one or more sites of disease. In some embodiments, the integrin inhibitor is delivered 10 cm or less from the one or more sites of disease. In some embodiments, the integrin inhibitor is delivered 5 cm or less from the one or more sites of disease. In some embodiments, the integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin inhibitor at a location that is not proximate to a site of disease.

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

In some embodiments, the integrin inhibitor is delivered to the location by mucosal contact.

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

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

In some embodiments, the amount of the integrin inhibitor that is administered is less than an amount that is effective when the integrin inhibitor is delivered systemically.

In some embodiments, the amount of the integrin 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 integrin inhibitor that is an induction dose, and (ii) an amount of the integrin 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 integrin inhibitor and a maintenance dose of integrin inhibitor are each administered to the subject by administering a pharmaceutical composition comprising a therapeutically effective amount of the integrin inhibitor, wherein the pharmaceutical composition is a device. In some embodiments an induction dose of integrin 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 integrin 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 integrin inhibitor in plasma.

In some embodiments, the method provides a concentration of the integrin 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 integrin inhibitor at the location in the gastrointestinal tract as a single bolus.

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

In some embodiments, the method comprises delivering the integrin inhibitor at the location in the gastrointestinal tract in a continuous manner. In some embodiments, the method comprises delivering the integrin 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 integrin inhibitor in the plasma of the subject that is less than 10 μg/ml. In some embodiments, the method provides a concentration of the integrin inhibitor in the plasma of the subject that is less than 3 μg/ml. In some embodiments, the method provides a concentration of the integrin inhibitor in the plasma of the subject that is less than 1 μg/ml. In some embodiments, the method provides a concentration of the integrin 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 integrin 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 integrin 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 integrin 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 integrin inhibitor rectally to the subject.

In some embodiments, the method does not comprise delivering an integrin inhibitor via an enema to the subject.

In some embodiments, the method does not comprise delivering an integrin inhibitor via suppository to the subject.

In some embodiments, the method does not comprise delivering an integrin 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 integrin 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 integrin inhibitor in the manner disclosed herein disclosed herein result in a reduced immunosuppressive properties relative to methods of administration of the integrin inhibitor systemically.

In some embodiments, the methods comprising administering the integrin inhibitor in the manner disclosed herein disclosed herein result in reduced immunogenicity relative to methods of administration of the integrin 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 integrin inhibitor. In some embodiments, monitoring the progress of the disease comprises determining the Harvey-Bradshaw Index (HBI) following administration of the integrin 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 integrin inhibitor levels in serum over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the integrin inhibitor, including at the 6-8 week time point. In some embodiments, monitoring the progress of the disease comprises measuring integrin inhibitor levels in serum over a period of about 52 weeks following administration of the integrin 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 integrin 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 integrin 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 integrin inhibitor, including at the 6-8 week time point, or over a period of about 52 weeks following administration of the integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin inhibitor and a maintenance dose of integrin inhibitor are each administered to the subject by administering a pharmaceutical composition comprising a therapeutically effective amount of the integrin inhibitor. In some embodiments an induction dose of integrin 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 integrin inhibitor administered in an ingestible device as disclosed herein. In some embodiments, the maintenance dose is a dose of the integrin inhibitor administered in an ingestible device as disclosed herein.

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

In some embodiments, the induction dose is a dose of the integrin 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 integrin 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 integrin 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 integrin 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 integrin inhibitor, including at the 6-8 week time point, or over a period of about 52 weeks following administration of the integrin 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 integrin inhibitor, including at the 6-8 week time point, or over a period of about 52 weeks following administration of the integrin inhibitor, including at the 52 week time point.

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

In some embodiments, the method does not comprise administering an integrin inhibitor with a spray catheter.

Pharmaceutical Formulations

As used herein, a "formulation" of an integrin inhibitor may refer to either the integrin inhibitor in pure form - such as, for example, the lyophilized integrin inhibitor - or a mixture of the integrin inhibitor with one or more physiologically acceptable carriers, excipients or stabilizers. Thus, therapeutic formulations or medicaments can be prepared by mixing the integrin 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

(HYLENEX<®>, 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 integrin 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 integrin 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. Drug Deliv. Reviews 57(11): 1666-1691, 2005; Bemkop-Schnurch, ^<iv. Drug Deliv. 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, Com 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 metabisulfite, 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 integrin 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( -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 integrin inhibitor, wherein the reservoir is configured to fit into an ingestible device. In some embodiments, the reservoir comprising a therapeutically effective amount of an integrin inhibitor is attachable to an ingestible device. In some embodiments, the reservoir comprising a therapeutically effective amount of an integrin 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 integrin 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 integrin 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- hydroxy ethyl-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-gly colic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-gly colic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene- vinyl acetate and lactic acid-gly colic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated integrin 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 integrin 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 integrin inhibitor can be achieved by implants and microencapsulated delivery systems, which can include biodegradable, biocompatible polymers (e.g., ethylene vinyl acetate, polyanhydrides, polygly colic acid, collagen, polyorthoesters, and polylactic acid; Alza Corporation and Nova Pharmaceutical, Inc.).

In some embodiments, the integrin inhibitor is present in a pharmaceutical formulation within the device.

In some embodiments, the integrin inhibitor is present in solution within the device.

In some embodiments, the integrin 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 integrin inhibitor. The

effectiveness and dosing of any integrin 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 integrin 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 integrin inhibitor (e.g., using any of the examples of formulations described herein). In some embodiments, the subject is administered a dose of the integrin 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 integrin 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 integrin 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 integrin 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); non-steroidal 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; Ianeway, 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 TGFfi 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 integrin inhibitor as described herein can be administered with one or more of: a CHST15 inhibitor, a IL-6 receptor inhibitor, an IL-12/IL-23 inhibitor, a TNF 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, an integrin 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 integrin inhibitor as disclosed herein, and (ii) a second agent orally, intravenously or subcutaneously, wherein the second agent in (ii) is the same integrin inhibitor in (i); a different integrin inhibitor; or an agent having a different biological target from the integrin inhibitor.

In some embodiments, the methods disclosed herein comprise administering (i) the integrin 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 integrin inhibitor is administered prior to the second agent. In some embodiments, the integrin inhibitor is administered after the second agent. In some embodiments, the integrin inhibitor and the second agent are administered substantially at the same time. In some embodiments, the integrin inhibitor is delivered prior to the second agent. In some embodiments, the integrin inhibitor is delivered after the second agent. In some embodiments, the integrin 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 integrin 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 integrin inhibitor systemically. In some embodiments comprising administering the integrin inhibitor in the manner disclosed herein and a second agent systemically, delivery of the integrin 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 integrin inhibitor systemically and the second agent systemically. In some embodiments, the method comprises administering the integrin 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 integrin inhibitor and the second agent are both administered systemically. In some aspects of these embodiments, the second agent is an integrin inhibitor.

In some embodiments, the method comprises administering the integrin 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. Vedolizumab (2.5 mg/kg)

3. Vedolizumab (5 mg/kg)

4. Vedolizumab (10 mg/kg)

The control or agent is applied to a damaged mucosal surface of the bowel 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 integrin w n levels are determined in blood, feces, and tissue (tissue levels are determined after animal sacrifice). For tissue samples, levels HER2 are additionally determined, and the level of integrin w n is normalized to the level of HER2. 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 Vedolizumab 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: Vedolizumab (40mg in 3.2mL saline); subcutaneous; (n=2)

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

4. Vedolizumab (med): Vedolizumab (80mg in 3.2 mL saline); intra-rectal; (n=4)

5. Vedolizumab (high): Vedolizumab (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 TNBS-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 vedolizumab levels (local mucosal tissue levels and systemic circulation levels), and for levels of integrin (u i.

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 vedolizumab 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 integrin inhibitor at a location in the gastrointestinal tract of the subj ect 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 integrin 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 integrin 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 integrin 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 integrin inhibitor in the plasma of the subj ect that is less than 3 μg/ml.

6. The method of claim 5, wherein the method provides a concentration of the

integrin 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

integrin inhibitor in the plasma of the subject that is less than 0.01 μg/ml.

8. The method of any one of claims 1 to 4, wherein the method provides a C24 value of the integrin inhibitor in the plasma of the subject that is less than 3 pg/ml.

9. The method of claim 8, wherein the method provides a C24 value of the integrin inhibitor in the plasma of the subject that is less than 0.3 μg/ml.

10. The method of claim 9, wherein the method provides a C24 value of the integrin inhibitor in the plasma of the subject that is less than 0.01 μg/ml.

11. The method of any one of claims 1 to 10, wherein the integrin inhibitor is an α2β1 integrin inhibitor.

12. The method of any one of claims 1 to 10, wherein the integrin inhibitor is an αΐβΐ integrin inhibitor.

13. The method of any one of claims 1 to 10, wherein the integrin inhibitor is an α4β7 integrin inhibitor.

14. The method of any one of claims 1 to 10, wherein the integrin inhibitor is an integrin α4β1 inhibitor.

15. The method of any one of claims 1 to 10, wherein the integrin inhibitor is an E- selectin inhibitor.

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

17. The method of claim 16, wherein the formulation is a solution of the integrin inhibitor in a liquid medium.

18. The method of claim 17, wherein the formulation is a suspension of the integrin 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 integrin 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 integrin inhibitor is released at a location in the ascending colon of the subj ect.

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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin inhibitor is released by mucosal contact.

56. The method of any one of the preceding claims, wherein the integrin inhibitor is delivered to the location by a process that does not comprise systemic transport of the integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin inhibitor is triggered by a remote electromagnetic signal.

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

70. The method of any one of claims 1 to 60, wherein releasing the integrin 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 integrin 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 integrin inhibitor comprises releasing the therapeutically effective amount of the integrin 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 integrin 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 integrin 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

integrin 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 integrin inhibitor is selected from vedolizumab (Entyvio®, Millennium Pharmaceuticals), natalizumab (Tysabri®), etrolizumab (Genentech/Roche), and AJM300 (Ajinomoto

Pharmaceuticals); generic equivalents thereof; modifications thereof having at least 90% sequence homology; modifications thereof differing in the

glycosylation partem; and modifications thereof having at least 90% sequence homology and differing in the glycosylation partem.

84. The method of claim 83, wherein the integrin inhibitor is PF00547659 (Shire Pharmaceuticals/Roche), or a generic equivalent thereof.

85. The method of any one of claims 1 to 84, wherein the amount of the integrin inhibitor is less than an amount that is effective when integrin inhibitor is administered systemically.

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

87. The method of claim 86, further comprising (ii) administering an amount of the integrin 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 integrin 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 integrin 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 integrin inhibitor at the location in the gastrointestinal tract in a continuous manner.

102. The method of claim 101, wherein the method comprises delivering the integrin 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 integrin inhibitor rectally to the subject.

104. The method of any one of claims 1 to 102, wherein the method does not comprise delivering an integrin 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 integrin 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 integrin 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 claims 1 to 107, wherein the integrin inhibitor is an inhibitory nucleic acid.

109. The method of any one of claims 1 to 107, wherein the integrin inhibitor is an antibody or antigen-binding fragment thereof.

110. The method of any one of claims 1 to 107, wherein the integrin inhibitor is a fusion protein.

111. The method of any one of claims 1 to 107, wherein the integrin inhibitor is a cyclic peptide.

112. The method of any one of claims 1 to 107, wherein the integrin inhibitor is a small molecule.

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 integrin 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 integrin inhibitor, a mechanism for releasing the integrin inhibitor from the reservoir; and; an exit valve configured to allow the integrin inhibitor to be released out of the housing from the reservoir.

122. The method of claim 121 , wherein the ingestible 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,

123. The method of claim 121 or 122, 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.

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 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 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,

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

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 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 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 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; 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.

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 integrin 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 integrin inhibitor, wherein the method does not comprise releasing more than 20% of the integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin inhibitor in the plasma of the subject that is less than 3 μg/ml.

136. The method of claim 135, wherein the method provides a concentration of the integrin 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 integrin 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 integrin inhibitor in the plasma of the subject that is less than 3

139. The method of any one of claims 130 to 134, wherein the method provides a C24 value of the integrin 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 integrin inhibitor in the plasma of the subject that is less than 0.01 μg/ml.

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 integrin inhibitor is not a cyclic peptide.

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

144. The method of claim 143, wherein the formulation is a solution of the integrin inhibitor in a liquid medium.

145. The method of claim 143, wherein the formulation is a suspension of the integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin inhibitor; a different integrin inhibitor; or an agent having a different biological target from the integrin inhibitor, wherein the second agent is an agent suitable for treating an inflammatory bowel disease.

156. The method of claim 155, wherein the integrin inhibitor is administered prior to the second agent.

157. The method of claim 155, wherein the integrin inhibitor is administered after the second agent.

158. The method of claim 155, wherein the integrin 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 integrin inhibitor and the second agent are both administered systemically.

162. The method of claim 161, wherein the second agent is an integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin inhibitor.

172. The method of any one of claims 1 to 171, wherein the method does not comprise administering an integrin inhibitor with a spray catheter.

173. The method of any one of claims 1 to 172, wherein the method comprises administering an integrin inhibitor with a spray catheter.

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

comprising:

releasing an integrin inhibitor at a location in the gastrointestinal tract of the subj ect 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 integrin 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 integrin 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 integrin inhibitor administered in an ingestible device.

178. The method of claim 176 or 177, wherein the maintenance dose is a dose of the integrin 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 integrin inhibitor delivered systemically.

180. The method of claim 176, wherein the induction dose is a dose of the integrin inhibitor delivered systemically.

181. The method of claim 176 or 180, wherein the maintenance dose is a dose of the integrin 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 integrin inhibitor administered in an ingestible device.

184. An integrin inhibitor delivery apparatus comprising: an ingestible housing comprising a reservoir having a pharmaceutical composition comprising a therapeutically effective amount of the integrin 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 integrin inhibitor at the respective disease site.

185. The integrin 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 integrin 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 integrin inhibitor delivery apparatus according to claim 185, wherein the controller is configured to cause the pump to pump the therapeutically effective amount of the integrin inhibitor from the reservoir according to the following protocol.

187. The integrin inhibitor delivery apparatus according to claim 184, wherein the valve system comprises a dissolvable coating.

188. The integrin 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 integrin inhibitor delivery apparatus according to claim 184, wherein the valve system comprises an electrostatic shield.

190. The integrin inhibitor delivery apparatus according to claim 184, wherein the reservoir comprises a pressurized cell.

191. The integrin 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 integrin inhibitor delivery apparatus according to claim 184, herein the actuatable anchor is retractable.

193. A composition comprising a therapeutically effective amount of the integrin inhibitor of any one of the preceding claims, wherein the composition is capable of releasing the integrin 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

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 integrin 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 integrin inhibitor, wherein the integrin 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 integrin inhibitor for use of claim 199, wherein the integrin 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 integrin 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 integrin 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 integrin inhibitor, for use in a method of treatment, wherein the method comprises orally administering the composition to the subject, wherein the integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin inhibitor, wherein the device is controllable to release the integrin 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 integrin 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 integrin inhibitor wherein a first end of the reservoir is connected to the first end of the housing;

a mechanism for releasing the integrin inhibitor from the reservoir;

and

an exit value configured to allow the integrin inhibitor to be released out of the housing from the reservoir.

211. The integrin 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 integrin inhibitor stored therein;

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

212. The integrin 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 integrin 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 integrin 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 integrin 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 integrin 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 integrin 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.

. The integrin inhibitor for use, the attachable reservoir compartment for use, the composition for use, or the device according to any one of claims 1 19 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.