| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | December 16, 2003 |
| PATENT TITLE |
Antibodies to cytokines in the prevention and treatment of inflammatory bowel disease |
| PATENT ABSTRACT | Methods are described for treating inflammatory bowel disease in animals, including humans. Specific avian polyclonal antibodies directed to proinflammatory cytokines (such as IL-6 and TNF) are shown to have a beneficial effect in animal models predictive of human therapy for the treatment of colitis, including Crohn's disease |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | June 4, 1999 |
| PATENT REFERENCES CITED |
Beck et al. Cytokines in inflammatory bowel disease, Mediators of Inflammation, vol. 6, pp. 95-103, 1997.* Tsuboruka et al. Oral administration of antibodies as prohylaxis and therapy in Campylobacter jejuni-infected chickens, Clinical Experimental Immunology, vol. 108, pp. 451-455, 1997.* Opal et al. Potential hazard of combination immunotherapy in the treatment of experimental spetic shock, Journal of Infectious Diseases, vol. 173, pp. 1415-1421, 1996.* Polson et al., "Antibodies to Proteins from Yolk of Immunized Hens,"Immunol. Comm., 9:495-514 (1980). Okayasu et al.,"A Novel Method in the Induction of Reliable Experimental Acutra and Chronic Ulcerative Colitis in Mice," Gastroenterology, 98:694-702 (1990). Kojouharoff et al., "Neutralization of tumour necrosis facto (TNF) but not of IL-1 reduces inflammation in chronic dextran sulphate sodium-induced colitis in mice," Clin. Exp.Immunology, 107: 353-358 (1997). Olson et al.,"Antiserum to Tumor Necrosis Factor and failure to Prevent Murine Colitis," J. Pediatric Gastroenterology and Nutrition 21: 410-418 (1995). Stack et al., "The Effects of CDP571, An Engineered Human IgG.varies.4 Anti-TNF.varies. Antibody in Crohn's Disease", Gastroenterology, 110:A1018 (1996). Rutgeerts et al., "Retratment with Anti-TNF-.varies. Chimeric Antibody (cA2) Effecitively maintains cA3-Induced remission in Crohn's Disease," Gastroenterology 112:A1078 (1997). Van Dullemen et al., "Treatment of Crohn's Disease with Anti-Tumor Necrosis Factor Chimeric Monoclonal Antibody (cA2)," Gastroenterology 109:129-138 (1995). Targan et al., "A Short-Term Study of Chimeric Monoclonal Antibody cA2 to Tumor Necrosis Factor.varies. for Crohn's Disease," New England Journal of Medicine, 337:1029-1035 (1997). Plevy et al.,"A Role for TNF.varies. and Mucosal T Helper-1 Cytokines in the Pathogenesis of Crohn's Disease," Journal of Immunology, 6277-6282 (1997). Sartor, "Current Concepts of the Etiology and Pathogenesis of Ulcerative Colitis and Crohn's Disease," Inflammatory Bowel Disease, 24:475-507 (1995). Sartor, "Pathogenesis and Immune Mechanisms of Chronic Inflammatory Bowl Diseases," Gastroenterology, 92:5S-11S (1997). Robinson, "Optimizing Therapy for Inflammatory Bowel Diseaes," American Journal of Gastroenterology, 92:12-17 (1997). Targan and Shanahan, "Pseudomembranous Colitis and Clostrridium Difficle Infection," Inflammatory Bowel Disease From Bench to Bench, 51:743-755 1994. Ogorek and Fisher, "Differentiation Between Chrohn's Disease and Ulcerative Colitis," in Inflammatory Bowel Disease, Katz, ed., 78:1249-1257 (1994). Cameron, "Anti-TNF-.varies. treatments set to mop up in rheumatoid arthritis," Research and Development, pp. 9-10 (1998). Elliot et al., "Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis facto .varies. (cA2) verus placebo in rheumatoid arthritis," Lancet, 344:1105-1110 (1994). Elliott et al., "Repeated therapy with monoclonal antibody to tumour necrosis factor .varies. (cA2) in patients with rheumatoid arthritis," Lancet 344:1125-1127 (1994). Gibson, "Inflammatory Bowel Disease Current Concepts in Pathogenesis and Therapy," Clin. Immunother., 2(2):135-160 (1994). Bell adn Wallace, "Infammatory Bowel Disorders Current and Future Drugs that Modulate Adhesion Molecules," Biodrugs, 7(4):273-284 (1997). Opal et al., "Potential Hazards of Combination Immunotherapy in the Treatment of Experimental Septic Shock," J. Infect. Dis., 173:1415-1421(1996). Russell et al., "Combined Inhibition of Interleukin-1 and Tumor Necrosis Factor in Rodent Endotoxemia: Improved Survival and Organ Function," J. Infect. Dis., 171:1528-1538(1995). Levine et al., "Intravenous immunoglobulin Therapy for Active, Extensive and Medically Refractory Idiopathic Ulcerative or Crohn's Colitis" Am J Gastroenterol, 87:91-100 (1992). Neurath et al., "Predominant Pathogenic role of Tumor Necrosis Factor in Experimental Colitis in Mices," Eur J Immunol 27:1743-1750 (1997). Neurath et al., "Antibodies to Interleukin 12 Abrogate Established Experimental Colitis in mice," J Exp Med 182:1281-1290 (1995). Feldmann et al., "Cytokine Expression and Networks in Rheumatoid Arthritis: Rationale for Anti-TNFanpha Antibody Therapy and its Mechanism of Action," J Inflamation 47:90-96 (1996). Reimund et al., "Increased production of tumor necrosis factor-alpha, interleukin-1-beta and interleukin-6 by morphologically normal intestinal biopsies from patients with Crohn's disease" Gut 39:684-689 (1996). Duchmann et al., "Tolerance toweards resistant intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12," Eur J Immunol 26:934-936 (1996). Tsubokura et al., "Oral administration of antibodies as prophylaxis and therapy in Campylobacter jejuni-infected chickens," Clin Exp Immunol 108:451-455 (1997). Nicholls et al., "Cytokines in stools of children with inflammatory bowel disease or infective diarrhoea," J Clin Path 46:757-760 (1993). Tjellstrom et al., "Oral immunoglobulin treatment in Crohn's disease," Acta Paediatr 86:221-223 (1997). Rubalteli et al.,"Prevention of necrotizing enterocolitis in neonates at risk by oral administration of monomeric IogG," Dev Pharmacol Ther 17:138-143 (1991). Armstrong et al., "Tumor necrosis factor and inflammatory bowel disease," British Journal of Surgery 84:1051-1058 (1997). Monteleone et al., "Interleukin 12 (IL-12) is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells (LPMCs)," Gastroenterology 112:1169-1178 (1997). Starnes et al., "Anti-IL-6 monoclonal antibodies protect against lethal Escherichia coli infection and lethal tumor necrosis factor-alpha challenge in mice" J Immuno 12:4185-4191 (1990). Doherty et al., "Evidence for IFN-gama as a mediator of the lethality of endotoxin and tumor necrosis factor-alpha" J Immuno 5:1666-1670 (1992). Manthey et al., "The role of cytokines in host responses to endotoxin" Reviews in Med Microbio 3:72-79 (1992). Dalekos, et al., "High concentrations of soluable interleukin-2 receptors and interleukin-6 in active ulcerative cells" Hellenic J Gastro 8:319-327 (1995). Evans, et al., "Treatment of ulcerative colitis with an engineered human anti-TNF-alpha antibody CDP571" Aliment Pharmacol Ther 11:1031-1035 (1997). Hoang, et al.,"Symposium: Role of cytokines in inflammatory bowel disease" Acte Gastro-Enterologica Belgica 57:219-223 (1994). van Hogezand, et al., "Selective immunomodulation in patients with inflammatory bowel disease-future therpay or reality?" Netherlands J of Med 48:64-67 (1996). Zacharchuk et al., "Macrophage-mediated cytotoxicity: Role of a soluble macrophage cytotoxic factor similar to lymphotoxin and tumor necrosis factor," PNAS USA 80:6341-6345 (1983). Zacharchuk, Charles Michael, "A Macrophage Cytotoxic Factor: Immunochemical and Functional Characterization," Dissertation Abstract 1985. Pennica et al., "Human tumor necrosis factor; precursor structure, expression and homology to lymphotoxin," Nature 312:724-729 (1984). Ruff, Michael Roland, "Mechanism of Action of a Serum Oncolytic Protein, Rabbit Tumor Necrosis Factor," Dissertation Abstract 1980. Beck et al., "Cytokines in inflammatory bowel disease," Mediatros of Inflammation 6:95-103 (1997). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A method of treatment, comprising: a) providing: i) a mammal having a symptom of inflammatory bowel disease, wherein said symptoms are associated with diseases selected from the group consisting of ulcerative colitis, proctitis, and Crohn's disease, ii) a therapeutic enteric formulation comprising avian polyclonal antibodies directed to TNF, and; b) orally administering said formulation to said mammal under conditions such that said symptom is reduced. 2. The method of claim 1, wherein said mammal is a human. 3. The method of claim 1, wherein said avian antibodies are chicken antibodies. 4. The method of claim 3, wherein said chicken antibodies are derived from chicken eggs. 5. A method of treatment, comprising: a) providing: i) a human patient with a symptom of inflammatory bowel disease, ii) a therapeutic formulation comprising polyclonal antibodies directed to IL-6, and; b) orally administering said formulation to said patient under conditions such that said symptom is reduced. 6. The method of claim 5, wherein said human is a child. 7. The method of claim 5, wherein said human has symptoms of ulcerative colitis. 8. The method of claim 5, wherein said human has symptoms of proctitis. 9. The method of claim 5, wherein said human has symptoms of Crohn's disease. 10. The method of claim 5, wherein said formulation is an enteric formulation. 11. The method of claim 5, wherein said polyclonal antibodies are avian antibodies. 12. The method of claim 11, wherein said avian polyclonal antibodies are chicken antibodies. 13. The method of claim 12, wherein said chicken antibodies are purified antibodies. 14. The method of claim 13, wherein said chicken antibodies are purified from chicken eggs. 15. A method of treatment, comprising: a) providing: i) a human patient with a symptom of Crohn's disease, ii) a therapeutic formulation comprising polyclonal antibodies directed to IL-6, and; b) orally administering said formulation to said patient under conditions such that said symptom is reduced. 16. The method of claim 15, wherein said formulation is an enteric formulation. 17. The method of claim 15, wherein said polyclonal antibodies are avian antibodies. 18. The method of claim 17, wherein said avian polyclonal antibodies are chicken antibodies. 19. The method of claim 18, wherein said chicken antibodies are purified antibodies. 20. The method of claim 19, wherein said chicken antibodies are purified from chicken eggs. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION The present invention relates to therapeutics for the prevention and treatment of inflammatory bowel disease, and in particular the prevention and treatment of inflammatory bowel disease in humans as well as other animals through the use of antibodies to inflammatory mediators including but not limited to proinflammatory cytokines. BACKGROUND OF THE INVENTION Inflammatory bowel diseases (IBD) are defined by chronic, relapsing intestinal inflammation of obscure origin. IBD refers to two distinct disorders, Crohn's disease and ulcerative colitis (UC). Both diseases appear to result from the unrestrained activation of an inflammatory response in the intestine. This inflammatory cascade is thought to be perpetuated through the actions of proinflammatory cytokines and selective activation of lymphocyte subsets. In patients with IBD, ulcers and inflammation of the inner lining of the intestines lead to symptoms of abdominal pain, diarrhea, and rectal bleeding. Ulcerative colitis occurs in the large intestine, while in Crohn's, the disease can involve the entire GI tract as well as the small and large intestines. For most patients, IBD is a chronic condition with symptoms lasting for months to years. It is most common in young adults, but can occur at any age. It is found worldwide, but is most common in industrialized countries such as the United States, England, and northern Europe. It is especially common in people of Jewish descent and has racial differences in incidence as well. The clinical symptoms of IBD are intermittent rectal bleeding, crampy abdominal pain, weight loss and diarrhea. Diagnosis of IBD is based on the clinical symptoms, the use of a barium enema, but direct visualization (sigmoidoscopy or colonoscopy) is the most accurate test. Protracted IBD is a risk factor for colon cancer, and treatment of IBD can involve medications and surgery. Some patients with UC only have disease in the rectum (proctitis). Others with UC have disease limited the rectum and the adjacent left colon (proctosigmoiditis). Yet others have UC of the entire colon (universal IBD). Symptoms of UC are generally more severe with more extensive disease (larger portion of the colon involved with disease). The prognosis for patients with disease limited to the rectum (proctitis) or UC limited to the end of the left colon (proctosigmoiditis) is better then that of full colon UC. Brief periodic treatments using oral medications or enemas may be sufficient. In those with more extensive disease, blood loss from the inflamed intestines can lead to anemia, and may require treatment with iron supplements or even blood transfusions. Rarely, the colon can acutely dilate to a large size when the inflammation becomes very severe. This condition is called toxic megacolon. Patients with toxic megacolon are extremely ill with fever, abdominal pain and distention, dehydration, and malnutrition. Unless the patient improves rapidly with medication, surgery is usually necessary to prevent colon rupture. Crohn's disease can occur in all regions of the gastrointestinal tract. With this disease intestinal obstruction due to inflammation and fibrosis occurs in a large number of patients. Granulomas and fistula formation are frequent complications of Crohn's disease. Disease progression consequences include intravenous feeding, surgery and colostomy. Colon cancer is a known complication of chronic IBD. It is increasingly common in those patients who have had extensive IBD over many years. The risk for cancer begins to rise significantly after eight to ten years of IBD. IBD may be treated medicinally. The most commonly used medications to treat IBD are anti-inflammatory drugs such as the salicylates. The salicylate preparations have been effective in treating mild to moderate disease. They can also decrease the frequency of disease flares when the medications are taken on a prolonged basis. Examples of salicylates include sulfasalazine, olsalazine, and mesalamine. All of these medications are given orally in high doses for maximal therapeutic benefit. These medicines are not without side effects. Azulfidine can cause upset stomach when taken in high doses, and rare cases of mild kidney inflammation have been reported with some salicylate preparations. Corticosteroids are more potent and faster-acting than salicylates in the treatment of IBD, but potentially serious side effects limit the use of corticosteroids to patients with more severe disease. Side effects of corticosteroids usually occur with long term use. They include thinning of the bone and skin, infections, diabetes, muscle wasting, rounding of faces, psychiatric disturbances, and, on rare occasions, destruction of hip joints. In IBD patients that do not respond to salicylates or corticosteroids, medications that suppress the immune system are used. Examples of immunosuppressants include azathioprine and 6-mercaptopurine. Immunosuppressants used in this situation help to control IBD and allow gradual reduction or elimination of corticosteroids. However, immunosuppressants render the patient immuno-compromised and susceptible to many other diseases. Clearly there is a great need for agents capable of preventing and treating IBD. It would be desirable if such agents could be administered in a cost-effective and timely fashion, with a minimum of adverse side effects. DEFINITIONS The present invention contemplates the treatment and prevention of IBD through the use of antibodies to inflammatory mediators, and in particular, antibodies to proinflammatory cytokines. The term "inflammatory mediator" refers to a variety of classes of molecules involved in an inflammatory response, including but not limited to proinflammatory phospholipids, chemokines [having both the C--C (e.g., Rantes, MIP-1.alpha.) and CXC (e.g., GRO-.alpha., IP-10, etc.) motifs), adherence proteins (e.g., ICAM-1, selectin, VCAM, etc), leukotrienes, and cytokines (e.g., interleukins). The phrase "symptoms of IBD" is herein defined to detected symptoms such as abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite, and other more serious complications, such as dehydration, anemia and malnutrition. A number of such symptoms are subject to quantitative analysis (e.g. weight loss, fever, anemia, etc.). Some symptoms are readily determined from a blood test (e.g. anemia) or a test that detects the presence of blood (e.g. rectal bleeding). The phrase "wherein said symptoms are reduced" refers to a qualitative or quantitative reduction in detectable symptoms, including but not limited to a detectable impact on the rate of recovery from disease (e.g. rate of weight gain). The phrase "at risk for IBD" is herein defined as encompassing the segment of the world population that has an increased risk for IBD. IBD is most commonly found in young adults, but can occur at any age. It occurs worldwide, but is most common in the United States, England, and northern Europe. It is especially common in people of Jewish descent. An increased frequency of this condition has been recently observed in developing nations. The present invention contemplates administration to or at the lumen. The phrase "administered to or at the lumen" or the like is herein defined as delivery to the space in the interior of the intestines. Such delivery can be achieved by a variety of routes (e.g., oral, rectal, etc.) in a variety of vehicles (e.g., tablet, suppository, etc.). In one embodiment, administration to or at the lumen results in delivery of antibody to the lamina propria (or regions of the intenstinal wall or radial to the mucosa). The lamina propria is classified as a loose, areolar, connective tissue but with lymphatic tendencies, the lymphoid material presumably functioning as a defense barrier against bacterial infection. When the antibody of the present invention is administered, the presence of the antibody in the intestinal wall can be readily detected by conventional means (e.g., staining and histology, labeled antibody and imaging, etc.). SUMMARY OF THE INVENTION The present invention relates to therapeutics for the prevention and treatment of IBD. Specifically, the present invention contemplates the prevention and treatment of IBD in humans as well as other animals through the use of antibody therapy. It is not intended that the present invention be limited to a particular type of antibody. Polyclonal and monoclonal antibodies are contemplated in the context of the present invention. Such antibodies may be made in a variety of animals [e.g., rabbits, horses, cows (e.g., in the milk), and birds]. The present invention also contemplates human and "humanized" antibodies. It is preferred that the antibodies not be complement fixing. More specifically, avian antibodies (e.g., chicken antibodies from eggs) are preferred. It is contemplated that the treatment with such antibodies will have the desired result of reducing the symptoms (as well as morbidity and mortality) caused by IBD. In one embodiment, the present invention contemplates a method comprising the administration of antibodies which bind to inflammatory mediators such as TNF. Preferably, the antibody is reactive with TNF across species. Specifically, the present invention demonstrates that immunization with human TNF generates neutralizing antibody capable of reacting with endogenous murine TNF. Thus, the present invention provides anti-TNF antibody that will react with mammalian TNF generally. It is not intended that the present invention be limited to antibodies to TNF.alpha.. As demonstrated herein, antibodies to mediators believed to be downstream in the inflammatory cascade from TNF, such as IL-6 or IL-12 are effective. Such antibodies can be used preventively or (as demonstrated in an experimental model of IBD) during the acute stage of pathogenesis. While some previous work described in the literature has suggested that the use of TNF antibodies in the acute phase of IBD is contraindicated, the data contained herein indicates otherwise. In another embodiment, the antibodies are combined with other reagents including but not limited to other antibodies. In one such embodiment, therapy comprises administration of a formulation comprising antibodies to a first cytokine and a second cytokine (e.g. antibodies to both TNF and IL-6). In another embodiment, the present invention contemplates a method of relieving symptoms of and rescuing mammals (including humans) from episodes of acute or chronic IBD utilizing anti-cytokine antibodies such as anti-TNF antibodies. In another embodiment, the present invention contemplates a method of relieving symptoms of and rescuing-mammals (including humans) from episodes of acute or chronic IBD utilizing a combination comprising anti-TNF antibodies. The present invention contemplates a method of treatment, comprising: (a) providing i) a mammal for treatment; ii) a therapeutic preparation, comprising anti-TNF polyclonal antibodies and (b) administering said antibodies to the lumen of said mammal. In another embodiment, the present invention also contemplates a method of treatment, comprising: a) providing: i) a human patient with symptoms of inflammatory bowel disease, ii) a therapeutic formulation comprising avian polyclonal antibodies directed to TNF, and; b) administering said formulation to said patient. In another embodiment, the present invention also contemplates a method of treatment, comprising: a) providing: i) a human patient with symptoms of inflammatory bowel disease, ii) a therapeutic formulation comprising avian polyclonal antibodies directed to IL-6, and; b) administering said formulation to said patient. In another embodiment, the present invention also contemplates a method of treatment, comprising: a) providing: i) a human patient with symptoms of inflammatory bowel disease, ii) a therapeutic formulation comprising avian polyclonal antibodies directed to IL-6 and TNF, and; b) administering said formulation to said patient. In another embodiment, the present invention also contemplates a method of treatment, comprising: a) providing: i) a human patient with symptoms of Crohn's disease, ii) a therapeutic formulation comprising avian polyclonal antibodies directed to TNF, and; b) administering said formulation to said patient. In another embodiment, the present invention also contemplates a method of treatment, comprising: a) providing: i) a human patient with symptoms of Crohn's disease, ii) a therapeutic formulation comprising avian polyclonal antibodies directed to IL-6, and; b) administering said formulation to said patient. In another embodiment, the present invention also contemplates a method of treatment, comprising: a) providing: i) a human patient with symptoms of Crohn's disease, ii) a therapeutic formulation comprising avian polyclonal antibodies directed to IL-6 and TNF, and; b) administering said formulation to said patient. In the above embodiments, it is preferred that said administering is done under conditions such that said symptoms of IBD (e.g. symptoms of Crohn's disease) are reduced. It is not intended that the present invention be limited to specific preparations of antibodies. However, polyclonal antibodies are preferred. Most importantly, it is preferred that the antibodies not be complement fixing. More specifically, avian antibodies (e.g. chicken antibodies from eggs) are preferred. The treatment with the antibodies has the unexpected result of reducing mortality rates in animals when administered after the onset of a chronic or acute IBD episode. DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing results of the cell based TNF neutralization assay with antibodies of the present invention compared to a control antibody. FIGS. 2A through 2D show results of a dose response study in a rat model for IBD using different concentrations of one embodiment of the anti-cytokine antibody of the present invention (i.e. anti-TNF IgY). FIGS. 3A through 3D are bar graphs showing the results after pre-challenge treatment with vehicle, preimmune IgY, or an anti-TNF IgY antibody of the present invention. FIGS. 4A through 4D are bar graphs showing the results after post-challenge (48 hours) treatment with vehicle, sulfasalazine, or an anti-TNF IgY antibody of the present invention. FIGS. 5A through 5D are bar graphs showing the results after pre-challenge treatment with vehicle, dexamethasone, or an anti-TNF IgY antibody of the present invention. FIGS. 6A through 6C are bar graphs showing the results of anti-TNF treatment started 17 days after initiation of an inflammatory reaction in a rat model for IBD. FIG. 7 is a bar graph showing MPO activity in colons of anti-TNF treated mice and survivors of preimmune and vehicle treated mice. FIGS. 8A through 8C are bar graphs showing the treatment results in a mouse model (C3H/HeJ mice) of IBD involving treatment rectally with anti-TNF, vehicle, or preimmune immediately following a single five day cycle of 5% DSS. FIGS. 9A and 9B are bar graphs showing the treatment results in a mouse model (CBA/J mice) of IBD after 3 cycles of 5% DSS. FIG. 10 is a bar graph showing the treatment results in a mouse model (C3H/HeJ mice) after 3 cycles of 3.5% DSS. FIGS. 11A through 11D are bar graphs showing results after post-challenge (48 hours) treatment with preimmune, anti-IL-6, anti-IL-8 or anti-IL-12 (heterodimer)IgY. FIG. 12 is a graph showing the kinetics of body weights of mice with acute colitis in various treatment groups. DESCRIPTION OF THE INVENTION The present invention relates to therapeutic compositions and methods for the prevention treatment of IBD, and in particular the prevention and treatment of IBD in humans as well as other animals. The antibodies of the present invention have particular application to the prevention and treatment of Crohn's disease. The present invention further teaches treatments comprising anti-cytokine antibody (and combinations of antibodies to cytokines) and compositions and methods used after the onset of symptoms of IBD. As noted above, the present invention also contemplates treatment comprising administering formulations comprising anti-cytokine antibody (e.g. anti-TNF, anti-IL-6, and/or anti-IL-12). In accordance with the present invention, such formulations are administered via intravenous, parenteral, rectal or oral route, although the present invention is not limited to these methods of administration. It is not intended that the present invention be limited by the particular nature of a formulation or combination. The present invention contemplates combinations as simple mixtures as well as chemical hybrids. An example of the latter is where the receptor is covalently linked to a pharmaceutical such as a corticosteroid, or where two receptor types are covalently joined. Covalent binding can be accomplished by any one of many commercially available crosslinking compounds. It is not intended that the present invention be limited by the particular nature of the therapeutic preparation. For example, such compositions can be provided together with physiologically tolerable liquid, gel or solid carriers, diluents, adjuvants and excipients. These therapeutic preparations can be administered to mammals for veterinary use, such as with domestic animals, and clinical use in humans in a manner similar to other therapeutic agents. In general, the dosage required for therapeutic efficacy will vary according to the type of use and mode of administration, as well as the particularized requirements of individual hosts. Unlike convention treatment approaches with drugs (e.g. steroids), treatment with the antibodies of the present invention do not run the risk (from a practical standpoint) of overdosing the patient. Excess antibody administered orally or rectally will simply pass through the treated subject. Such compositions are typically prepared as sprays (e.g., intranasal aerosols) for topical use. However, they may also be prepared either as liquid solutions or suspensions, or in solid forms. Oral formulations (e.g., for gastrointestinal inflammation) usually include such normally employed additives such as binders, fillers, carriers, preservatives, stabilizing agents, emulsifiers, buffers and excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations, or powders, and typically contain 1%-95% of active ingredient, preferably 2%-70%. The compositions are also prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection may also be prepared. The antibodies of the present invention are often mixed with diluents or excipients which are physiological tolerable and compatible. Suitable diluents and excipients are, for example, water, saline, dextrose, glycerol, or the like, and combinations thereof. In addition, if desired the compositions may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, stabilizing or pH buffering agents. Additional formulations which are suitable for other modes of administration, such as topical administration, include salves, tinctures, creams, lotions, and, in some cases, suppositories. For salves and creams, traditional binders, carriers and excipients may include, for example, polyalkylene glycols or triglycerides. In a preferred embodiment, enteric formulations are employed, including but not limited to encapsulated antibodies. The terms "encapsuled" or "encapsulating" refers to the covering of a solid (e.g., lyophilized) form of antibody. The covering may comprise an enteric coating or a capsule. The terms "enteric coating" or "enteric film" are used interchangeably and refer to a material or compound which is resistant to acid pH (i.e., an acid-resistant compound), such as that found in the stomach. An enteric coating when applied to a solid inhibits the dissolution of the solid in the stomach. Standard techniques are known to the art for the encapsulation of solid compositions. These techniques include microencapsulation of a solid composition wherein an enteric coating is applied to the solid composition. The coated material may be delivered orally to a subject by suspending the microencapsulated particles in pharmaceutical suspension solutions known to the art. When a solid antibody is to be encapsulated using an enteric coating, the enteric coating may be applied using a one step coating process in which the enteric film is directly applied to the solid antibody; the coated antibody is said to be overcoated with the enteric film. Alternatively, a two step coating process may be employed wherein the solid antibody is first used to overcoat a non-pariel (i.e., a sugar particle of about 40-60 mesh size) and then the antibody-coated non-pariel is overcoated with the enteric film. Desirable enteric coatings for the delivery of antibody include polymethacrylates such as Eudragit.RTM. L30D (Rohm Tech, Inc.) Solid antibody may formulated for oral delivery by insertion of the desired quantity of antibody into a capsule; the capsule would preferable have the characteristic of being resistant to dissolution in the stomach and being capable of dissolving in the intestines. Numerous suitable capsule formulations are available to the art; in addition standard techniques are available for the filling of capsules including the use of inert filler materials to provide sufficient bulk of the filling of a capsule with a therapeutic composition in a solid form. In addition to the use of microencapsulated antibody, the solid antibody may be delivered orally in tablet or pill form. The solid antibody may be combined with inert materials to provide sufficient bulk for the pressing of the tablet or pill. Once formed, the tablet or pill may then be coated with an enteric film to prevent dissolution in the stomach and to enhance dissolution in the intestines |
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