WO1992008489A1

WO1992008489A1 - Treatment for inflammatory bowel disease

Info

Publication number: WO1992008489A1
Application number: PCT/US1991/008257
Authority: WO
Inventors: Roy R. Lobb; Daniel K. Podolsky
Original assignee: Biogen, Inc.; The General Hospital Corporation
Priority date: 1990-11-08
Filing date: 1991-11-06
Publication date: 1992-05-29
Also published as: AU9055091A

Abstract

A method for the treatment of inflammatory bowel disease (IBD) is disclosed. The method comprises administration of an antibody, polypeptide or other molecule recognizing ELAM1, a protein induced on the surface of endothelial cells and found to be associated with IBD-involved intestinal tissue.

Description

TREATMENT FOR INFLAMMATORY BOWEL DISEASE

FIELD OF THE INVENTION The present invention relates to a treatment for inflammatory bowel disease (IBD). More particularly, this invention relates to the use of antibodies recognizing endothelial cell-leukocyte adhesion molecules (ELAMs) in the treatment of IBD. BACKGROUND OF THE INVENTION Inflammatory bowel disease, or IBD, is a collective term encompassing ulcerative colitis and Crohn's disease (ileitis), which are chronic inflammatory disorders of the gastrointestinal tract. Ulcerative colitis is confined to the large intestine (colon) and rectum, and involves only the inner lining of the intestinal wall. Crohn's disease may affect any section of the gastrointestinal tract (i.e., mouth, esophagus, stomach, small intestine, large intestine, rectum and anus) and may involve all layers of the intestinal wall. Both diseases are characterized by abdominal pain and cramping, diarrhea, rectal bleeding and fever. The symptoms of these diseases are usually progressive, and sufferers typically experience periods of remission followed by severe flareups. IBD affects an estimated two million people in the United States alone. Although IBD is not considered a fatal illness, prolonged disease can lead to severe malnutrition affecting growth or to the formation of abscesses or intestinal scar tissue, leading in turn to infection or bowel obstruction.

IBD has no cure, and the exact causes of IBD are not yet understood. Conventional treatments for IBD have involved anti-inflammatory drugs, immunosuppressive drugs and surgery. Sulfasalazine and related drugs having the bioactive 5-amino-salicylic acid (5-ASA) moiety are widely used to control moderate IBD symptoms and to maintain remission. Severe inflammation is often treated with powerful corticosteroids and sometimes ACTH or with immunosuppressants such as 6-mercaptopurine and azathioprine. The most common surgical treatments for severe chronic IBD are intestinal resections and, ultimately, colectomy, which is a complete cure only for ulcerative colitis. Severe side effects are associated with these drugs, including nausea, dizziness, . changes in blood chemistry (including anemia and leukopenia), skin rashes and drug dependence; and the surgical treatments are radical procedures which often profoundly alter the everyday life of the patient. Accordingly, there is a great need for treatments for IBD that are effective yet less severe in their side effects and are less invasive of the IBD sufferer's body and quality of life. The search for the causes of IBD and more effective treatments has led several investigators to study diseased and normal tissue on a cellular level. This has led to observations of variations in the normal content of intestinal mucin (Podolsky 1988 [1]) and to the observation of colonic glycoproteins which emerge only in diseased tissue (Podolsky and Fournier, 1988a [2], 1988b [3]}. It has now been discovered that during periods of acute inflammation high concentrations of neutrophils and lymphocytes are recruited to the intestinal submucosa as compared to periods of disease remission. This increase in leukocyte cell population may be important in the production of soluble proteins that mediate inflammation. With the recent isolation of specific endothelial cell surface molecules involved in the recruitment of leukocytes in inflammatory events, it has now been determined that one such molecule, ELAM1 , is expressed in active IBD tissues; and anti-ELAM1 monoclonal antibodies which block adhesion of leukocytes to endothelial cells may thus be useful in the treatment of IBD.

SUMMARY OF THE INVENTION The present invention provides novel methods for the treatment of IBD and further provides new pharmaceutical compositions useful in the treatment of IBD. In particular, the present invention provides a method comprising the step of administering to an IBD sufferer an effective amount of an anti-ELAM1 antibody, such as antibody BB11 , raised against recombinant human ELAM1 expressed in COS cells. The anti-ELAMl antibody is advantageously administered in vivo to a patient with active IBD and serves to inhibit neutrophil migration and the associated release of inflammatory mediators and tissue damage associated with neutrophil accumulation. It is believed that the use of anti- ELAMl antibody in the treatment of IBD will be effective to ameliorate flareups and to induce and maintain remission of IBD symptoms.

DETAILED DESCRIPTION OF THE INVENTION The technology for producing monoclonal antibodies is well known. Briefly, an immortal cell line (typically myeloma cells) is fused to lymphocytes (typically splenocytes) from a mammal immunized with whole cells expressing a given antigen, e.g., ELAM1 , and the culture supernatants of the resulting hybridoma cells are screened for antibodies against the antigen. See, generally, Kohler et al., 1975 [4].

Immunization may be accomplished using standard procedures. The unit dose and immunization regimen depend on the species of mammal immunized, its immune status, the body weight of the mammal, etc. Typically, the immunized mammals are bled and the serum from each blood sample is assayed for particular antibodies using appropriate screening assays. For example, anti-ELAMl antibodies were identified by testing the ability of the immune serum to block HL-60 binding to IL-lβ-induced human umbilical vein endothelial cells (HUVECs). The lymphocytes used in the production of hybridoma cells typically are isolated from immunized mammals whose sera have already tested positive for the presence of anti-ELAMl antibodies using such screening assays.

Typically, the immortal cell line (e.g., a myeloma cell line) is derived from the same mammalian species as the lymphocytes. Preferred immortal cell lines are mouse myeloma cell lines that are sensitive to culture medium containing hypoxanthine, aminopterin and thymidine ("HAT medium").

Typically, HAT-sensitive mouse myeloma cells are fused to mouse splenocytes using polyethylene glycol ("PEG") 1500. Hybridoma cells resulting from the fusion are then selected using HAT medium, which kills unfused and unproductively fused myeloma cells (unfused splenocytes die after several days because they are not transformed). Hybridomas producing a desired antibody are detected by screening the hybridoma culture supernatants. _. For example, hybridomas prepared to produce anti-ELAMl antibodies were screened by testing the hybridoma culture supernatant for secreted antibodies having the ability to bind to a stable ELAM1-expressing cell line, such as a COS 7 cell line stably transfected with a recombinant gene for ELAM1. Supernatant antibodies were also assayed for the ability to bind cytokine-stimulated HUVECs but not unstimulated (control) HUVECs. To produce anti ELAM1-antibodies, hybridoma cells that tested positive in such screening assays were cultured in a nutrient medium under conditions and for a time sufficient to allow the hybridoma cells to secrete the monoclonal antibodies into the culture medium. Tissue culture techniques and culture media suitable for hybridoma cells are well known. The conditioned hybridoma culture supernatant may be collected and the anti-ELAM1 antibodies optionally further purified by well known methods.

Alternatively, the desired antibody may be produced by injecting the hybridoma cells into the peritoneal cavity of an unimmunized mouse. The hybridoma cells proliferate in the peritoneal cavity, secreting the antibody which accumulates as ascites fluid. The antibody may be- harvested by withdrawing the ascites fluid from the peritoneal cavity with a syringe.

Anti-ELAM1 monoclonal antibodies have been previously described (Benjamin et al. 1990 [5];

Bevilacqua et al., 1989 [6]). For the experiments herein, an anti-ELAM1 monoclonal antibody designated BB11 (obtained from Biogen, Inc., Cambridge, MA) was used. A hybrid cell line capable of producing BB11 is on deposit with In Vitro International, Inc.

(Linthicum, MD) and has been assigned accession no. IVI-10220.

Antibodies such as BB11 and other anti-ELAM antibodies capable of inhibiting adhesion of leukocytes to IBD-involved tissue could specifically inhibit migration of leukocytes to inflamed sections of the gastrointestinal tract. This inhibition of leukocyte migration across endothelium could, in turn, prevent the secondary pathological effects of leukocyte infiltration, e.g., release of toxic substances, inducement of soluble inflammatory cell mediators, etc. The method of the present invention uses the specific binding activity of anti-ELAMl antibodies to reduce inflamination. The anti-ELAMl antibody can be administered in the form of a pharmaceutical composition comprising an effective amount of the antibody and a pharmaceutically acceptable carrier. For acute flareups of ulcerative colitis or Crohn's disease, dosages of from 0.1 mg/kg-patient/day to 2.0 mg/kg-patient/day may be used, although higher or lower dosages may be indicated with consideration to the age, sensitivity, tolerance, and other characteristics of the patient, the acuteness of the flareup, the history and course of the disease, and other similar factors ^•routinely considered by an attending physician. For • maintenance of remission from active disease, dosages from 0.1 mg/kg-patient/day to 2.0 mg/kg-patient/day may be used, although higher or lower dosages may be indicated and employed with advantageous effects considering the age, sensitivity, tolerance, and other characteristics of the patient, the pattern of flareups, the history and course of the disease, and other similar factors routinely considered by an attending physician.

Suitable pharmaceutical carriers include, e.g., sterile saline and like solutions. The pharmaceutical compositions may additionally be formulated to control the release of the active ingredients or prolong their presence in the patient's system. Numerous suitable drug delivery systems are known for this purpose and include, e.g., hydrogels, hydroxmethylcellulose, microcapsules, liposomes, microemulsions, microspheres, and the like. In addition to employing anti-ELAMl antibodies in the treatment of IBD, appropriately radiolabeled antibodies may also be used to monitor the course of the disease in patients. In an alternate embodiment of the present invention, anti-ELAMl antibody labeled with a radioisotope is administered to a patient suffering from IBD, the labeled antibody becomes localized at the IBD-involved tissues, and radioimaging of the IBD-involved tissues can be performed using known techniques. The selection of radioisotope is based on a number of factors, e.g., toxicity, biological half-life, and detectability. Preferred radioisotopes include ¹²⁵I, ¹²³I and ^1l1In. The antibodies may be labeled by any method known in the art, such as by employing a labeling reagent (e.g.,

¹²³I-Bolton Hunter Reagent). The radiolabeled antibody is administered to a patient, e.g., intravenously, and IBD-involved tissue is detected, e.g., by a radioactivity-sensitive camera coupled to computer imaging equipment. In this manner, the path of the disease, its spread or its pattern of flareup can be regularly and accurately monitored.

It will also be recognized that for the purposes of the present invention the anti-ELAM1 antibodies must be effective to block leukocyte binding to ELAM1 expressed in IBD-involved tissues. Accordingly, suitable recombinant antibodies capable of blocking leukocyte adhesion may be used alternatively to naturally produced antibodies. Such recombinant antibodies include antibodies produced via recombinant DNA techniques, e.g., by transforming a host cell with a suitable expression vector containing DNA encoding the light and heavy immunoglobulin chains of the desired antibody, and recombinant chimeric antibodies, wherein some or all of the hinge and constant regions of the heavy and/or the light chain of the anti-ELAM1 antibody have been substituted with corresponding regions of an immunoglobulin light or heavy chain of a different species (i.e., preferably the same species being treated for IBD, to minimize immune response to the administered antibody). (See, e.g., Jones et al., 1986 [7], Ward et al., 1989 [8], and U.S. Patent 4,816,397 (Boss et al.) [9], all incorporated herein by reference. ) Furthermore, ELAM1-binding fragments of anti-

ELAMl antibodies, such as Fab, Fab'-, F(ab' )₂, and F(y) fragments; heavy chain monomers or dimers; light chain monomers or dimers; and dimers consisting of one heavy chain and one light chain are also contemplated herein. Such antibody fragments may be produced by chemical methods, e.g., by cleaving an intact antibody with a protease, such as pepsin or papain, or via recombinant DNA techniques, e.g., by using host cells transformed with truncated heavy and/or light chain genes. Heavy and light chain monomers may similarly be produced by treating an intact antibody with a reducing agent such as dithiothreitol or β-mercaptoethanol or by using host cells transformed with DNA encoding either the desired heavy chain or light chain or both. Also, from the foregoing discussion it will be apparent that other polypeptides and molecules which inhibit or block leukocyte binding to ELAM1 will be effec ive in the treatment of IBD in the same manner as anti-ELAM1 antibodies. For example, a soluble form of. an ELAM1 ligand or a fragment thereof may be administered to compete for the ELAM1 binding site with the leukocyte-bound form of the ligand, thereby decreasing the recruitment of leukocytes in a similar manner to the administration of anti-ELAMl antibodies. Small molecules such as oligosaccharides that mimic the binding domain of an ELAMl ligand and fit the receptor domain of ELAM1 may also be employed. (See, Devlin et al., 1990 [10], Scott and Smith, 1990 [11], and U.S. Patent- 4,833,092 (Geysen) [12], all incorporated herein by reference.) The use of such ELAM1-binding polypeptides or molecules that effectively inhibit binding between leukocytes and IBD-involved tissue is contemplated herein as an alternative method for treatment of IBD. When formulated in the appropriate vehicle, the pharmaceutical compositions contemplated herein may be administered by any suitable means such as orally, intranasally, subcutaneously, intramuscularly, intravenously, intra-arterially, or parenterally. Ordinarily intravenous (i.v.) or parenteral administration will be preferred to treat flareup conditions; oral administration in a timed release vehicle will be preferred to maintain remission.

EXAMPLE I ELAMl and VCAM1 Expression in the Colon

Experiments were performed to determine whether active IBD involved the. expression of endothelial cell surface proteins involved in leukocyte adhesion. .Expression of two particular surface proteins, ELAM1 and VCAM1 (see, Carlos et al., 1990 [13]), in colon tissue of IBD sufferers and normal or uninvolved colon tissue controls was evaluated. Furthermore, the expression of analogous proteins in the bowel of cotton-top tamarins (CTT; S. oedipus) afflicted with spontaneous chronic diffuse colitis was also examined. The cotton-top tamarin, because it often spontaneously develops a chronic ailment having physiological and histochemical similarities to IBD has been proposed as a valuable animal model for the study of the human disease. (Podolsky et al., 1985a [1 ], Podolsky et al., 1985b [15].) Prior studies have demonstrated parallel response in these animals to therapeutic compounds used in the management of the human disorder. (Madara et al., 1985 [16]).

Human colonoscopic biopsy tissue samples were obtained, with informed consent, and prepared either as frozen sections by mounting in OCT compound and quick freezing in isopentane/liquid nitrogen or as paraffin sections by fixing in 4% formaldehyde and embedding in paraffin. Frozen sections were also prepared from cotton-top tamarin colon samples. The human colon samples were from normal colon, active ulcerative colitis colon (UC-active), inactive ulcerative colitis colon (UC-inactive), and uninvolved ulcerative colitis colon, as well as biopsies of colon polyps and samples of cancer-involved ulcerative colitis colon (Cancer/UC) . The cotton-top tamarin samples were of active colitis, inactive colitis and intestinal tumor tissues.

Frozen sections (6μ) placed on gelatin-coated slides (1% gelatin, heated at 60[ 1-2 min. , air dried, 1% formaldehyde, room temp., air dried) were air dried, fixed in acetone for five to ten minutes, and air dried again. Paraffin sections were prepared for testing by cutting thin sections (~6μ) with a microtome and mounting on slides.

Slides bearing test samples were washed three times with phosphate buffered saline (PBS) for five minutes, and endogenous peroxidase activity was quenched using 0.3% H₂0₂ in ethanol (30 min., room temp.). The slides were then washed with PBS for 20 minutes, incubated with dilute normal serum (3 drops in 10 ml PBS) for 30 minutes. The excess fluid was blotted, and monoclonal antibody BB11 , which recognizes ELAM1 ; monoclonal antibody 4B9, recognizing VCAM1 ; and an anti-bovine serum albumin (anti-BSA) antibody (negative control) were applied to separate samples of each type of tissue as follows: The antibodies were diluted 1:25 in phosphate buffered saline/1% fetal bovine serum/0.1% sodium azide and the solution applied to cover the samples on each slide for 60 minutes. The samples were then washed twice in phosphate buffered saline/0.2% gelatin and exposed to peroxidase- conjugated rabbit anti-mouse immunoglobulins (Dako Corp., Santa Barbara, CA) in phosphate buffered saline/1% fetal bovine serum/0.1% sodium azide/1% baboon serum for 60 minutes. The samples were then washed as before, then exposed to 0.25 mg/ml 3-amino- 9-ethylcarbazole (Aldrich Chemical Co., Milwaukee, WI) in 2% N,N-dimethylformamide/0.1M acetate buffer (pH 5.2) with 0.08 hydrogen peroxide for six minutes. The samples were washed with water and counterstained with 1% methyl green. The anti-ELAMl and anti-VCAM1 antibodies were obtained from Biogen, Inc. (Cambridge, MA). Anti-BSA antibody was obtained commercially from Sigma Chemical Co. (St. Louis, MO).

The results of these tests are set forth in the following TABLE I:

TABLE I Endothelial Cell Staining In Human and CTT Tissue

BB11 4B9 BSA

I. HUMAN COLON Frozen Section

Normal -

UC active ++ -

UC inactive -

UC inactive - Paraffin Section

Normal - - . -

Polyp -

Cancer/UC -

UC active - UC active -

UC inactive -

UC uninvolved -

II. COTTON-TOP TAMARIN

Frozen Section colitis-active + - - colitis-active + - - colitis-inactive - colitis-inactive - colitis-tumor - From the data set forth in TABLE I, there is a clear indication that active ulcerative colitis tissue exhibits ELAM1 but not VCAM1. Healthy endothelial cells can be induced in the presence of inflammatory cytokines such as IL-lβ or TNF to produce both ELAM1 and VCAMI , with ELAM1 production peaking at 4-6 hours and decreasing to basal levels by 24 hours, and with VCAM1 production increasing more slowly and maintaining a high level of production even 48 hours after induction (Carlos et al., 1990 [13]). The foregoing experiments show that the cell biology of inflammatory bowel disease may involve the preferential production in intestinal endothelial cells of ELAM1 , which in turn may account for the accumulation of ELAMl-binding leukocytes observed in IBD-involved tissues (Krisner and Shorter, 1988 [17]). It follows that blocking of ELAM1/leukocyte binding could effectively ameliorate the inflammation associated with leukocyte recruitment to and infiltration of IBD- involved tissues. The experiments also' show that the analogous structure to human ELAM1 appear in colitis-involved tissue in cotton-top tamarins. This further supports the validity of the using the cotton-top tamarin as an animal model for the study of human IBD.

EXAMPLE II

Northern Blot Analysis of Biopsied Tissue mRNA from colon tissue biopsy samples taken as above was isolated by chromatography using an oligo- dT-Cellulose gel (Collaborative Research, Waltha , MA) and immobilized on Nytran nitrocellulose membranes (Micron Separations, Inc.) following the method of Chirgwin et al. (1979) [18]. The immobilized mRNA was hybridized under relatively stringent conditions (30% formamide, 5 x SSC, 60[) with probes specific for ELAM1 (obtained from Biogen, Inc., Cambridge, MA) ³²P-labelled by nick translation using standard conditions. The results of hybridization with the labeled probe are shown in TABLE II: - 14 -

TABLE II

I. HUMAN COLON ELAMl Probe Hybridization

Normal

UC active +

UC inactive

II. COTTON-TOP TAMARIN colitis-active + colitis-active + colitis-active + colitis-inactive- colitis-inactive

These results confirm the indications of Example I that ELAM1 is produced in the endothelial cells of active IBD tissue.

EXAMPLE III Cotton-Top Tamarin Trials Stock solutions of 5-10 mg/ml in sterile saline of the anti-ELAMl antibody, BBI1 (IgG2b), F(ab'). fragments of BB11 , a control murine IgG antibody, and F(ab' )₂ fragments of the control IgG antibody are prepared for administration to cotton-top tamarins (CTTs) exhibiting symptoms of spontaneous colitis

(i.e., diarrhea, etc.). The doses of each preparation are calculated based on the weight of the cotton-top tamarins to provide approximately 2 mg/kg antibody per animal. The preparations are administered by i.v. injection CTTs grouped as follows: Group Dose Schedule

A 1 dose/day of BB11 for 14 days B 1 dose/day of IgG (control) for 14 days C 1 dose/day of BB11 F(ab' )₂ for 14 days D 1 dose/day of IgG F(ab' )₂ for 14 days

Serum samples are taken from each animal at 0, 1, 12, 24 hours and daily thereafter until 3-5 days after the last injection to determine average serum levels of antibody and half-life. Biopsies of colon tissue are taken at the same times to assess leukocyte infiltration, Ig coating of the CTT endothelium, and possible vasculitis during the course of therapy. These experiments are expected to show that administration of anti-ELAMl antibodies to cotton-top tamarins exhibiting a spontaneous colitis analogous to human ulcerative colitis leads to marked reduction of tamarin colitis symptomology.

CITED PUBLICATIONS

[1] D. K. Podolsky, "Colonic Glycoproteins in Ulcerative Colitis: Potential Meaning in Heterogeneity", Inflammatory Bowel Diseases: Basic Research and Clinical Implications, Falk Symposium, Titisee, Germany, June 7-9, 1987 (Kluwer Academic Publishers; Boston 1987) pp. 449-56.

[2] D. K. Podolsky and D. A. Fournier, "Alterations in Mucosal Content of Colonic Glycoconjugates in Inflammatory Bowel Disease Defined by Monoclonal

Antibodies", Gastroenteroloσv. 95, pp. 379-87 (1988).

[3] D. K. Podolsky and D. A. Fournier, "Emergence of Antigenic Glycoprotein Structures in Ulcerative Colitis Detected Through Monoclonal Antibodies", Gastroenteroloαv. 95, pp. 371-8 (1988).

[4] Kohler and Milstein, "Continuous Cultures of Fused Cells Secreting Antibody of Predefined Specificity", Nature. 256, pp. 495-7 (1975).

[5] C. Benjamin et al., "A Blocking Monoclonal Antibody to Endothelial-Leukocyte Adhesion Molecule-1 (ELAMl)", Biochem. Biophys. Res. Comm.. 171(1), pp. 348-53 (1990).

[6] M. P. Bevilacqua et al., "Identification of an Inducible Endothelial-Leukocyte Adhesion Molecule", Proc. Natl Acad. Sci. USA, 84, pp. 9238-42 (1987)

[7] P. T. Jones et al., "Replacing the Complementarity- Determining Regions in a Human Antibody with Those From a Mouse", Nature. 321, pp. 522-525 (1986).

[8] E. S. Ward et al., "Binding Activities of a Repertoire of Single Immunoglobulin Variable Domains Secreted From Escherichia coli", Nature, 341, pp. 544- 546 (1989).

[9] U.S. Patent No. 4,816,397, Boss et al., "Multichain Polypeptides Or Proteins And Processes For Their Production", March 28, 1989.

[10] J. J. Devlin et al., "Random Peptide Libraries: A Source of Specific Protein Binding Molecules", Science, 249, pp. 40-406 (1990). [11] J. K. Scott and G. P. Smith, "Searching for Peptide Ligands with an Epitope Library", Science, 249, pp. 386-390 (1990). [12] U.S. Patent No. 4,833,092, Geysen, "Method For Determining Mimotopes", May 23, 1989.

[13] T. Carlos et al., "Vascular Cell Adhesion Molecule-1 Mediates Lymphocyte Adherence to Cytokine- Activated Cultured Human Endothelial Cells", Blood, 76(5), pp. 965-70 (1990).

[14] D. K. Podolsky, et al. , "Colonic Mucin Composition in Primates Selective Alterations Associated with Spontaneous Colitis in the Cotton-top Tamarin", Gastroenterology, 88, pp. 20-5 (1985). [15] D. K. Podolsky et al., "Spontaneous Colitis In Cotton-Top Tamarins: Histologic, Clinical and Biochemical Features of an Animal Model of Chronic Colitis", Digestive Diseases and Sciences, 30(4), Abstract, p. 396 (1985). [16] J. L. Madara et al., "Characterization of

Spontaneous Colitis in Cotton-Top Tamarin (Sacruii-us oedipuε ) and Its Response to Sulfasalazine", Gastroenterology. 88, pp. 13-9 (1985).

[17] J. Krisner and R. G. Shorter, eds., Inflammatory Bowel Disease, (Lea & Febiger, Philadelphia) 3rd Ed. (1988) .

[18] Chirgwin et al., "Isolation of Biologically Active

Ribonucleic Acid from Sources Enriched in

Ribon clease", Biochemistry, 18, pp. 5295-99 (1979).

It will be recognized from the foregoing description of the preferred embodiments that a wide variety of other anti-ELAMl antibodies than those specifically mentioned, as well as fragments of such antibodies and other polypeptides and molecules that inhibit ELAM1 binding to leukocytes, will be useful embodiments of the present invention. All such embodiments, and other embodiments that are obvious in view of the teachings herein, are specifically contemplated and included within the scope of the invention as defined in the following claims.

Claims

WE CLAIM:

1. A method for the treatment of inflammatory bowel disease (IBD) comprising administering to an IBD sufferer a therapeutically effective amount of an anti-ELAM1 antibody.

2. The method of claim 1 wherein the anti- ELAMl antibody is administered intravenously or parenterally.

3. The method of claim 1 wherein the anti- ELAMl antibody is BB11 (IVI-10220), or a fragment thereof capable of binding to ELAM1.

4. The method of claim 1 wherein the anti- ELAMl antibody is administered in a dosage of from 0.1 to 2.0 mg/kg-patient/day.

5. A method for the treatment of inflammatory bowel disease (IBD) comprising administering to an IBD sufferer a therapeutically effective amount of an antibody, a recombinant antibody, a chimeric antibody, fragments of such antibodies, a polypeptide or a small molecule capable of inhibiting leukocyte- binding to ELAMl , or combinations of any of the foregoing, capable of inhibiting leukocyte binding to ELAM1.

6. The method of claim 5 wherein the antibody, polypeptide, molecule or fragment is administered intravenously or parenterally.

7. The method of claim 5 wherein the antibody, polypeptide or molecule is selected from monoclonal antibody BB11 (IVI-10220); Fab, Fab', F(ab' )₂, or F(v) fragments of such antibody; soluble ELAM1 ligands; or oligosaccharides that bind to the leukocyte-binding domain of ELAM1.

8. The method of claim 5 wherein the antibody, polypeptide, molecule or fragment is administered in a dosage of from 0.1 to 2.0 mg/kg- patient/day.

9. A method for ex vivo imaging of inflammatory bowel disease-involved tissue in an inflammatory bowel disease sufferer comprising

(a) administering to the sufferer an antibody, antibody fragment, polypeptide or small molecule capable of binding to ELAM1 labeled with a radioisotope, and

(b) detecting the position in the sufferer of the labeled antibody, antibody fragment, polypeptide or small molecule using an apparatus capable of detecting radioactivity.

10. The method according to claim 9, wherein the radioisotope is selected from ¹²⁵I, ¹²³I and ^l1lIn.

11. The method according to claim 10, wherein the antibody, polypeptide or molecule is selected from monoclonal antibody BB11 (IVI-10220); Fab, Fab', F(ab')₂, or F(v) fragments of such antibody; soluble ELAM1 ligands; or oligosaccharides that bind ELAM1.