ORAL COMPOSITION OF ANTI-TNF ALPHA ANTIBODIES

Abstract

The present invention relates to a pharmaceutical composition for oral delivery, including an anti tumour necrosis factor alpha (TNF) antibody, preferably a monoclonal antibody produced in the milk of a transgenic non-human animal, and which can be combined advantageously with caprylic acid, and is preferably in a form that is suitable for targeted release of the antibody in the intestine.

Claims

1. A pharmaceutical composition suitable for oral administration, comprising a monoclonal anti-tumor necrosis factor alpha (TNF) antibody produced in the milk of a transgenic non-human animal.

2. The pharmaceutical composition according to claim 1, the composition being in a form suitable for targeted release of the antibody in the intestine.

3. The pharmaceutical composition according to claim 1, wherein the anti-TNF antibody is adalimumab or has the protein sequence of adalimumab.

4. The pharmaceutical composition according to claim 1, wherein the transgenic non-human animal is a goat.

5. The pharmaceutical composition according to claim 1, further comprising caprylic acid or a caprylate salt.

6. A method for treating an inflammatory disease in a patient, which method comprises administering to said patient a pharmaceutical composition suitable for oral administration, comprising a monoclonal anti-tumor necrosis factor alpha (TNF) antibody produced in the milk of a transgenic non-human animal.

7. The method according to claim 6, wherein the inflammatory disease is inflammatory bowel disease, such as Crohn s disease.

8. The method according to claim 6 wherein the pharmaceutical composition is administered orally at a daily dose of 8 to 200 mg, preferably 8 to 35 or 15 to 70 mg of anti-TNF antibody.

9. A method for treating an inflammatory disease in a patient, which method comprises orally administering to the patient an anti-TNF antibody, in combination with preferably oral administration of caprylic acid or a caprylate salt.

10. The method according to claim 9, wherein the inflammatory disease is inflammatory bowel disease, preferably Crohn's disease.

11. The method according to claim 9, wherein said antibody is adalimumab or has the protein sequence of adalimumab.

12. The method according to claim 9, wherein said antibody is a monoclonal antibody produced in the milk of a transgenic non-human animal, preferably a goat.

13. The method according to claim 9, wherein, the antibody and the caprylic acid or the caprylate salt are administered separately, simultaneously or sequentially.

14. The method according to claim 9, wherein said antibody is in a form suitable for targeted release of the antibody in the intestine.

15. Kit comprising, within the same package: A first container containing a pharmaceutical composition for oral administration, comprising an anti-TNF antibody, which is preferably a monoclonal antibody produced in the milk of a transgenic non-human animal, preferably a goat; A second container containing a pharmaceutical composition for oral administration, comprising caprylic acid or a caprylate salt.

Description

FIGURE LEGEND

[0091] The appended FIG. is a histogram showing the levels of interleukin-8 secretion by Caco-2 cells, subjected to various conditions. Secretion is most strongly inhibited in the presence of a combination of caprylic acid+anti-TNF antibody.

EXAMPLE

Anti-Inflammatory Effect on the Caco-2 Line

[0092] Materials and Methods:

[0093] Caco-2 cells, a colon cancer cell line, are an established cell model of the human intestinal epithelium (Pinto et al., 1983, Biol. Cell, 47, 323-330). These cells secrete interleukin-8 (IL-8), which is one of the major interleukins in the pathogenesis of inflammatory bowel diseases, after activation by interleukin-1 beta (IL-1 beta).

[0094] The inventors used the Caco-2 cell line as a model of epithelial cells, and evaluated the effect of compositions according to the invention on interleukin-8 (IL-8) secretion by these cells after activation by interleukin-1 beta (IL-1 beta).

[0095] To that end, Caco-2 cells, deposited in 24well plates, were cultured for 14 days until the cells were confluent and in a stable differentiation state. On day 14, the cells were precultured in the presence of caprylic acid, transgenically-produced anti-TNF antibody (adalimumab), and a combination of the two. Twenty-four hours later, the cells were stimulated with 1 ng/ml IL-1 beta for 12 hours. IL-8 levels present in the culture supernatants were measured by ELISA.

[0096] Results:

[0097] The addition of anti-TNF antibody induces a decrease in IL-8 levels, and thus an anti inflammatory potential. The combination of caprylic acid+anti-TNF antibody appears to be a stronger inhibitor of IL-8 secretion (see the figure), showing a more strongly anti inflammatory effect.

[0098] The use of Caco-2 cells differentiated after 14 days of culture, and the addition of IL-1 beta, made it possible to reproduce in vitro conditions similar to intestinal inflammation in vivo. The results observed show that a composition according to the invention has a potential therapeutic benefit in vivo.