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(12) Patent Application Publication (10) Pub. No.: US 2016/0346364 A1 BRUNS Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0346364 A1 BRUNS Et Al US 2016.0346364A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0346364 A1 BRUNS et al. (43) Pub. Date: Dec. 1, 2016 (54) MEDICAMENT AND METHOD FOR (52) U.S. Cl. TREATING INNATE IMMUNE RESPONSE CPC ........... A61K 38/488 (2013.01); A61K 38/482 DISEASES (2013.01); C12Y 304/23019 (2013.01); C12Y 304/21026 (2013.01); C12Y 304/23018 (71) Applicant: DSM IPASSETS B.V., Heerlen (NL) (2013.01); A61K 9/0053 (2013.01); C12N 9/62 (2013.01); A23L 29/06 (2016.08); A2ID 8/042 (72) Inventors: Maaike Johanna BRUINS, Kaiseraugst (2013.01); A23L 5/25 (2016.08); A23V (CH); Luppo EDENS, Kaiseraugst 2002/00 (2013.01) (CH); Lenneke NAN, Kaiseraugst (CH) (57) ABSTRACT (21) Appl. No.: 15/101,630 This invention relates to a medicament or a dietary Supple (22) PCT Filed: Dec. 11, 2014 ment comprising the Aspergillus niger aspergilloglutamic peptidase that is capable of hydrolyzing plant food allergens, (86). PCT No.: PCT/EP2014/077355 and more particularly, alpha-amylase/trypsin inhibitors, thereby treating diseases due to an innate immune response S 371 (c)(1), in humans, and/or allowing to delay the onset of said (2) Date: Jun. 3, 2016 diseases. The present invention relates to the discovery that (30) Foreign Application Priority Data the Aspergillus niger aspergilloglutamic peptidase is capable of hydrolyzing alpha-amylase/trypsin inhibitors that are Dec. 11, 2013 (EP) .................................. 13196580.8 present in wheat and related cereals said inhibitors being strong inducers of innate immune response. Furthermore, Publication Classification the present invention relates to a method for hydrolyzing alpha-amylase/trypsin inhibitors comprising incubating a (51) Int. Cl. composition for food consumption comprising alpha-amy A6 IK 38/48 (2006.01) lase/trypsin inhibitors with the Aspergillus niger aspergillo A2.3L 5/20 (2006.01) glutamic peptidase, wherein the inhibitors are hydrolyzed. It A2.3L 29/00 (2006.01) also relates to an enzyme composition comprising the Asper A2ID 8/04 (2006.01) gillus niger aspergilloglutamic peptidase and an additional A6 IK 9/00 (2006.01) enzyme, and to foodstuff comprising the Aspergillus niger CI2N 9/62 (2006.01) aspergilloglutamic peptidase. Patent Application Publication Dec. 1, 2016 Sheet 1 of 5 US 2016/0346364 A1 Figure 1 Patent Application Publication Dec. 1, 2016 Sheet 2 of 5 US 2016/0346364 A1 Figure 2 Patent Application Publication Dec. 1, 2016 Sheet 3 of 5 US 2016/0346364 A1 Figure 3 Patent Application Publication Dec. 1, 2016 Sheet 4 of 5 US 2016/0346364 A1 Figure 4 Patent Application Publication Dec. 1, 2016 Sheet 5 of 5 US 2016/0346364 A1 Figure 5 E. E. E. Š: X : s & E. re US 2016/0346364 A1 Dec. 1, 2016 MEDCAMIENT AND METHOD FOR tributing to diseases like celiac disease. Moreover, alpha TREATING INNATE IMMUNE RESPONSE amylase/trypsin inhibitors are also key contributing factors DISEASES to diseases or conditions like gluten sensitivity, irritable bowel syndrome, inflammatory bowel disease, but also BRIEF DESCRIPTION OF THE INVENTION non-intestinal inflammation. 0001. This invention relates to a medicament or a dietary 0005 Celiac disease, also known as celiac sprue, gluten Supplement comprising the Aspergillus niger aspergilloglu sensitive enteropathy, or gluten intolerance is one of the tamic peptidase that is capable of hydrolyzing plant food most frequent food intolerances worldwide, with highest allergens, and more particularly, alpha-amylase/trypsin prevalence in Europe, North and South America, and Aus inhibitors, thereby treating diseases due to an innate immune tralia. Celiac disease is an inflammatory disease of the upper response in humans, and/or allowing to delay the onset of Small intestine in genetically predisposed persons triggered said diseases. The present invention relates to the discovery by the ingestion of wheat, barley, rye and their cross-related that the Aspergillus niger aspergilloglutamic peptidase is varieties leading to a mal-absorption syndrome. capable of hydrolyzing alpha-amylase/trypsin inhibitors that 0006 Gluten is a common dietary protein present in are present in wheat and related cereals said inhibitors being wheat, barley, rye and their cross-related varieties. Gluten is strong inducers of innate immune response. Furthermore, a complex mixture of glutamine- and proline-rich glutenin the present invention relates to a method for hydrolyzing and prolamine molecules, which is thought to be the respon alpha-amylase/trypsin inhibitors comprising incubating a sible factor for celiac disease induction in sensitive human composition for food consumption comprising alpha-amy individuals. Because of their unusual structure, with a high lase/trypsin inhibitors with the Aspergillus niger aspergillo proline and glutamine content, the gluten proteins are partly glutamic peptidase, wherein the inhibitors are hydrolyzed. It resistant to intestinal enzymes, which lead to several non also relates to an enzyme composition comprising the Asper degraded immunogenic peptides that can be sensed by the gillus niger aspergilloglutamic peptidase and an additional intestinal immune system. Ingestion of Such proteins by enzyme, and to foodstuff comprising the Aspergillus niger sensitive individuals produces flattening of the normally aspergilloglutamic peptidase. luxurious, rug-like, epithelial lining of the Small intestine known to be responsible for efficient and extensive terminal digestion of peptides and other nutrients. Clinical symptoms BACKGROUND OF THE INVENTION of Celiac Sprue include fatigue, chronic diarrhea, mal 0002 Plant food allergens are a widespread group of absorption of nutrients, weight loss, abdominal distension, plant proteins comprising cupin and prolamin Superfamilies anemia, as well as a Substantially enhanced risk for the as well as proteinaceous molecules of the plant defense development of osteoporosis and intestinal malignancies system. The prolamin Superfamily includes several impor (lymphoma and carcinoma). The disease has an incidence of tant types of allergens of legumes, tree nuts, cereals, fruits, approximately 1 in 200 in European and North American and vegetables, and the cereal alpha-amylase and protease populations. inhibitors. Cereal prolamine are major storage proteins of 0007. The current essential treatment of gluten intoler the cereal grain endosperm and are named glutenins and ance is a permanent strict withdrawal of gluten form the diet gliadins in wheat, Secalins in rye, and hordeins in barley. The which is difficult to maintain. It is however important to proteinaceous alpha-amylase inhibitors are non-gluten pro define two categories of gluten intolerance in order to teins. Based on structural similarity, proteinaceous alpha understand how the illness is affected by enzyme action in amylase inhibitors with plant origin are usually classified in the gut. Celiac sprue is an autoimmune condition, a genetic six families including lectin-like, knottin-like, CM-proteins. inflammatory disorder of the small intestine. When gluten Kunitz-like, c-purothionin-like, and thaumatin-like (Rich proteins break down during digestion, they fragment. These ardson, 1990). CM (Chloroform-methanol)-proteins are a protein fragments are called peptides. In celiac Sufferers, an large protein family from cereal seeds containing 120 to 160 inappropriate immune system response in the Small intestine amino acid residues and five disulfide bonds. They show a is initiated by one type of peptide, and the intestinal cells are typical double-headed alpha-amylase/trypsin domain. This damaged. feature makes it possible that they inhibit the activity of 0008. A second type of gluten intolerance results when alpha-amylase and trypsin-like enzymes. The alpha-amylase the gut is injured by Something other than celiac disease— inhibitor 0.19 is one of the most studied inhibitor of this the negative effect of a bacteria or yeast infection, for family; it has a broad specificity, and inhibits alpha-amylases example, resulting in the loss of the intestinal enzymes from insects, birds and mammals. which in turn leads to poor gluten digestion. While Supple 0003. Furthermore, plant defensive proteins also com menting individuals with enzymes may be beneficial to prise protease inhibitors. Most plant storage organs such as celiac Sufferers, they must remain on a strictly gluten free seeds and tubers contain 1-10% of their total proteins as diet because of the possible strength of the autoimmune protease inhibitors with different biochemical and structural reaction when traces of gluten are left undigested. properties inhibiting different types of proteases. Protein 0009. Using specific enzymes as supplement can be inhibitors are classified based on the type of enzyme they effective in minimizing the need for a gluten-free diet for inhibit: serine protease inhibitors, cysteine protease inhibi those individuals at risk of developing gluten intolerance, tors, aspartic protease inhibitors, or metallocarboxy-protease for gluten sensitive individuals, or wherein gluten intoler inhibitors. ance is due to gut injury. 0004 WO 2011/137322 recently disclosed that members 0010. The use of exogenous proteolytic enzymes for of the non-gluten alpha-amylase/trypsin inhibitor family gluten detoxification has been one of the most promising contained in wheat and related cereals are strong inducers of strategies for celiac disease management. Such enzymes innate immune response in human intestine, thereby con have been used in both pretreatment of gluten containing
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