Improved milk quantity

Abstract

The present disclosure relates to a method of improving milk quality in a suckling mammal comprising administering a composition comprising at least one casein-derived peptide.

Description

[0001] SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on May 16, 2024, is named P-625310-PC-ST26 and is 69,632 bytes in size. BACKGROUND

[0002] Casein comprises three fractions, a, b, and k, according to its electrophoretic mobility. Casein hydrolysate is a hydrolyzed form of casein, which includes active b-casein-derived peptides, among others. Casein hydrolysate has been shown to play a role in immune responses against microbial and viral infections.

[0003] The global dairy market is estimated to be over $500 billion with a 4% annual growth rate. Cow milk dominates the market, while plant-based alternatives are $1 billion in the US, and lactose-intolerant milk is estimated to be $700 million. Mammary gland produced milk is a very complex liquid, comprising thousands of ingredients. Mammary gland produced milk includes water, multiple different lipids, sugars, multiple different proteins, and multiple different inorganic salts and compounds.

[0004] Dietary protein is an essential nutrient for human health and growth. The World Health Organization recommends that dietary protein should provide about 10-15% of energy intake when energy balance and body weight are stable. Average daily protein intake in different countries indicates that these recommendations are consistent with the amount of protein consumed globally. Diets in which an average of 20-30% of energy comes from protein represent high-protein diets when consumed in energy balance.

[0005] The human body cannot synthesize certain amino acids that are essential for health and growth, and must obtain them from food. These amino acids, known as “essential amino acids,” are histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), threonine (T), tryptophan (W), and valine (V). Dietary proteins that provide all essential amino acids are referred to as “high-quality” proteins. Animal foods such as meat, fish, poultry, eggs, and dairy products are generally considered to be high-quality protein sources, providing a good balance of essential amino acids. Casein and whey (the proteins in the liquid remaining after milk has been curdled and filtered) are major sources of high-quality dietary protein. Foods that do not provide a good balance of essential amino acids are referred to as “low-quality” proteins. Most fruits and vegetables are poor protein sources. Some plant foods, including legumes, peas, lentils, nuts, and grains such as wheat, are better protein sources. Soy protein, a plant protein made from soybeans, is considered by some to be a high-quality protein.

[0006] Milk composition and characteristics are critical to control the quality of dairy products. There is still a great demand for high quality dietary product sources. SUMMARY

[0007] In some aspects, disclosed herein is a method for increasing milk quality in a lactating mammal comprising administering a composition comprising at least one casein- source peptide.

[0008] In some related aspects, the increased milk quality comprises increased milk protein, increased milk fat, increased lactose, increased energy-corrected milk (ECM), or any combination thereof.

[0009] In some related aspects, the percentage of milk protein in the milk is in the range of 2.5-6.5%. In some further related aspects, the percentage of milk protein in the milk is increased by 0.5-30% compared to the percentage of milk protein in a control lactating mammal. One of ordinary skill in the art will understand that the phrase "control lactating mammal" refers to a mammal that has not been administered any treatment, or that has been administered a treatment that is different from the composition comprising at least one casein-source peptide.

[0010] In some related aspects, the percentage of milk fat in the milk is in the range of 2.5-6.5%. In some further related aspects, the percentage of milk fat in the milk is increased by 0.5-30% compared to the percentage of milk fat in a control lactating mammal.

[0011] In some related aspects, the percentage of lactose in the milk is in the range of 3.5-7.8%. In some further related aspects, the percentage of lactose in the milk is increased by 0.5-30% compared to the percentage of lactose in a control lactating mammal.

[0012] In some related aspects, the ECM is increased by 0.5-20% compared to the ECM in a control lactating mammal.

[0013] In some embodiments, the milk quality is increased at any stage of the lactation cycle.

[0014] In some embodiments, the administration is performed at the beginning of the dry period. In some embodiments, the increase in milk quality is independent of the length of the dry period.

[0015] In some related aspects, the casein-source peptide comprises a natural peptide, a synthetic peptide, a semi-synthetic peptide, or any combination thereof.

[0016] In some further related aspects, the casein-derived peptide comprises one or more fragments of beta-casein, alphaSl-casein, alphaS2-casein, and kappa-casein. In some further related aspects, the casein-derived peptide further comprises amino acids of varying lengths.

[0017] In some further related aspects, the casein-derived peptide comprises a casein hydrolysate. In some further related aspects, the casein-derived peptide comprises a phosphopeptide. In some further related aspects, the phosphopeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO. 1 - SEQ ID NO. 26.

[0018] In some aspects, the composition is free of antimicrobial agents and comprises an acceptable carrier.

[0019] In some aspects, the method comprises administering 10 ng / ml to 500 mg / ml of the casein-derived peptide.

[0020] In some aspects, the administering comprises an intramammary infusion to a single teat or multiple teats.

[0021] In some aspects, the milk is substantially free of residues and can be used as raw milk for dairy production, for breastfeeding, baking, confectionery, feeding, or any combination thereof. In some further aspects, the dairy product comprises milk, whey, yogurt, cheese, cream, butter, high protein milk beverage, or combinations thereof.

[0022] In some aspects, disclosed herein is a composition comprising at least one casein-derived peptide for use in increasing milk quality in a lactating mammal. BRIEF DESCRIPTION OF DRAWINGS

[0023] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, can best be understood by reference to the following detailed description, taken in conjunction with the accompanying drawings in which: Figure 1 is a graphical representation of the daily / average energy corrected milk (ECM) production (kg) over the subsequent 305 days of lactation in dry dairy cows following treatment with bovine casein hydrolysate (bCNH). Control - dairy cows treated with antibiotics. bCNH 11 - dairy cows treated with a single dose of bovine casein hydrolysate (bCNH). bCNH 22 - dairy cows treated with two doses of bovine casein hydrolysate (bCNH). p < 0.05. Control: 36.67, bCNH 11 : 39.83, bCNH 22: 39.62; Figure 2is a plot of energy-corrected milk (ECM) production (kg) per month over the subsequent 305-day lactation period for dry dairy cows treated with bovine casein hydrolysate (bCNH). Control - dairy cows treated with antibiotics. bCNH11 - dairy cows treated with a single dose of bovine casein hydrolysate (bCNH). bCNH22 - dairy cows treated with two doses of bovine casein hydrolysate (bCNH). p<0.05; Figure 3 is a plot of daily / average milk fat production (kg) over the subsequent 305-day lactation period for dry dairy cows treated with bovine casein hydrolysate (bCNH). Control - dairy cows treated with antibiotics. bCNH11 - dairy cows treated with a single dose of bovine casein hydrolysate (bCNH). bCNH22 - dairy cows treated with two doses of bovine casein hydrolysate (bCNH). p<0.05. bCNH11 : 1.45, bCNH22: 1.49; Figure 4 is a plot of milk fat production (kg) per month over the subsequent 305-day lactation period for dry dairy cows treated with bovine casein hydrolysate (bCNH). Control - dairy cows treated with antibiotics. bCNH11 - dairy cows treated with a single dose of bovine casein hydrolysate (bCNH). bCNH22 - dairy cows treated with two doses of bovine casein hydrolysate (bCNH). p<0.05; Figure 5 is a plot of daily / average milk protein production (kg) over the subsequent 305-day lactation period for dry dairy cows treated with bovine casein hydrolysate (bCNH). Control - dairy cows treated with antibiotics. bCNH11 - dairy cows treated with a single dose of bovine casein hydrolysate (bCNH). bCNH22 - dairy cows treated with two doses of bovine casein hydrolysate (bCNH). p<0.05. Control: 1.23, bCNH11 : 1.31, bCNH22: 1.36; Figure 6 is a plot of milk protein production (kg) per month over the subsequent 305-day lactation period for dry dairy cows treated with bovine casein hydrolysate (bCNH). Control - dairy cows treated with antibiotics. bCNH11 - dairy cows treated with a single dose of bovine casein hydrolysate (bCNH). bCNH22 - dairy cows treated with two doses of bovine casein hydrolysate (bCNH). p<0.05; Figure 7is a plot of daily / average milk lactose production (kg) over the subsequent 305 days of lactation for dry cows treated with bovine casein hydrolysate (bCNH). Control - cows treated with antibiotics. bCNH11 - cows treated with a single dose of bovine casein hydrolysate (bCNH). bCNH22 - cows treated with two doses of bovine casein hydrolysate (bCNH). p<0.01. Control: 1.91 (SE), bCNH11 : 1.94, bCNH22: 1.97; Figure 8 is a plot of milk lactose production (kg) by month over the subsequent 305 days of lactation for dry cows treated with bovine casein hydrolysate (bCNH). Control - cows treated with antibiotics. bCNH11 - cows treated with a single dose of bovine casein hydrolysate (bCNH). bCNH22 - cows treated with two doses of bovine casein hydrolysate (bCNH). p<0.01; Figure 9 is a plot of ECM by month. The monthly average ECM prior to entering the trial was used as a covariate. The energy-corrected milk production for the control group over the entire post-milking reinitiation period was 35.88 (SE = 4.06), and for the bCNH group was 39.86 (SE = 2.76), P = 0.43; Figure 10 is a plot of protein values (kg) by month. The monthly average protein production prior to entering the trial was used as a covariate. The protein production for the control group over the entire 3 months after the start of milking was 1.32 kg (SE = 0.098), and for the bCNH group was 1.38 kg (SE = 0.065), P = 0.08; Figure 11 is a plot of butterfat values (kg) by month. The monthly average butterfat production prior to entering the trial was used as a covariate. The butterfat production for the control group was 1.36 kg (SE = 0.14), and for the bCNH group was 1.49 kg (SE = 0.09), (P = 0.46); P = 0.46); Figure 12 is a plot of lactose values (kg) by month. The monthly average lactose production prior to entering the trial was used as a covariate. The lactose production for the control group was least squares mean of 1.82 (SE = 0.18), and for the bCNH group was 1.90 (SE = 0.12); Figure 13is a plot of the Composite - Bulk Milk Somatic Cell Count (BMSCC) around the month of the re- milking period. Bulk milk somatic cell count values were not normally distributed (Prob>chiSq = 0.026). Therefore, BMSCC values were transformed to log 10 Differences between each month of lactation (MIM) show that log 10 BMSCC was significantly higher in control cows than in experimental groups (P = 0.005) in the first month after re- milking started; P = 0.005); Figure 14 is a plot of the monthly milk production values (kg) by month. The average monthly milk production before entering the trial was used as a covariate. The average daily monthly milk production of the control group during the entire post-milking re-start period was 39.27 kg (SE = 3.56), and of the bCNH group was 39.92 kg (SE = 2.37, P = 0.88).

[0024] It should be appreciated that for simplicity and clarity the elements illustrated in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements are exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals have been repeated among the figures to indicate corresponding or analogous elements. DETAILED DESCRIPTION

[0025] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the application. However, it will be apparent to one skilled in the art that the application can be practiced without these specific details. In other instances, well-known methods, procedures and components have not been described in detail so as not to obscure the application.

[0026] Method of improving milk quality In some embodiments, disclosed herein is a method for increasing the quality of milk in a lactating mammal comprising administering a composition comprising at least one casein-derived peptide.

[0027] In some embodiments, the increased milk quality comprises increased milk protein, increased milk fat, increased milk lactose, increased energy-corrected milk (ECM), or any combination thereof. In one embodiment, the increased milk quality comprises increased milk protein. In another embodiment, the increased milk quality comprises increased milk fat. In another embodiment, the increased milk quality comprises increased milk lactose. In another embodiment, the increased milk quality comprises increased energy-corrected milk (ECM). In another embodiment, the increased milk quality comprises increased milk protein and increased milk fat. In another embodiment, the increased milk quality comprises increased milk protein and increased milk lactose. In another embodiment, the increased milk quality comprises increased milk protein and increased ECM. In another embodiment, the increased milk quality comprises increased milk fat and increased milk lactose. In another embodiment, the increased milk quality comprises increased milk fat and increased ECM. In another embodiment, the increased milk quality comprises increased milk lactose and increased ECM. In another embodiment, the increased milk quality comprises increased milk protein, increased milk fat, increased milk lactose, and increased energy-corrected milk (ECM).

[0028] A person skilled in the art will understand that energy-corrected milk (ECM) determines the energy content in milk based on the milk, fat, and protein contained. The determination of ECM can be made, for example, by the following formula: ECM (kg) = milk (kg) 0.1 + fat (%) milk (kg) 10 + protein (%) milk (kg) 15.8.

[0029] In one embodiment, disclosed herein is a method for increasing milk protein in a lactating mammal comprising administering a composition comprising at least one casein-derived peptide. In one embodiment, the milk protein is extracted from milk.

[0030] In one embodiment, disclosed herein is a method for increasing milk fat in a lactating mammal comprising administering a composition comprising at least one casein-derived peptide. In one embodiment, the milk fat is extracted from milk.

[0031] In one embodiment, disclosed herein is a method for increasing milk lactose in a lactating mammal comprising administering a composition comprising at least one casein-derived peptide. In one embodiment, the milk lactose is extracted from milk.

[0032] In one embodiment, disclosed herein is a method for increasing ECM in a lactating mammal comprising administering a composition comprising at least one casein source peptide.

[0033] In some embodiments, the percentage of milk protein in the milk is in the range of 2.5%-6.5%. In one embodiment, the percentage of milk protein in the milk is 2.5%. In another embodiment, the percentage of milk protein in the milk is 3.0%. In another embodiment, the percentage of milk protein in the milk is 3.5%. In another embodiment, the percentage of milk protein in the milk is 4.0%. In another embodiment, the percentage of milk protein in the milk is 4.5%. In another embodiment, the percentage of milk protein in the milk is 5.0%. In another embodiment, the percentage of milk protein in the milk is 5.5%. In another embodiment, the percentage of milk protein in the milk is 6.0%. In another embodiment, the percentage of milk protein in the milk is 6.5%.

[0034] In some embodiments, the percentage of milk protein in the milk is increased by 0.5%-30.0% compared to milk protein in a control lactating mammal. In some embodiments, the milk is increased by 1.0%-20.0% compared to milk protein in a control lactating mammal. In some embodiments, the milk is increased by 3.0%-10.0% compared to milk protein in a control lactating mammal. In some embodiments, the milk is increased by 5.0%-8.0% compared to milk protein in a control lactating mammal.

[0035] In one embodiment, the percentage of milk protein in the milk is increased by 0.5% compared to milk protein in a control lactating mammal. In another embodiment, the percentage of milk protein in the milk is increased by 1.0% compared to milk protein in a control lactating mammal. In another embodiment, the percentage of milk protein in the milk is increased by 5.0% compared to milk protein in a control lactating mammal. In another embodiment, the percentage of milk protein in the milk is increased by 10.0% compared to milk protein in a control lactating mammal. In another embodiment, the percentage of milk protein in the milk is increased by 15.0% compared to milk protein in a control lactating mammal. In another embodiment, the percentage of milk protein in the milk is increased by 20.0% compared to milk protein in a control lactating mammal. In another embodiment, the percentage of milk protein in the milk is increased by 25.0% compared to milk protein in a control lactating mammal. In another embodiment, the percentage of milk protein in the milk is increased by 30.0% compared to milk protein in a control lactating mammal.

[0036] In some embodiments, the percentage of milk fat in the milk is in the range of 2.5-6.5%. In one embodiment, the percentage of milk fat in the milk is 2.5%. In another embodiment, the percentage of milk fat in the milk is 3.0%. In another embodiment, the percentage of milk fat in the milk is 3.3%. In another embodiment, the percentage of milk fat in the milk is 3.4%. In another embodiment, the percentage of milk fat in the milk is 3.5%. In another embodiment, the percentage of milk fat in the milk is 3.6%. In another embodiment, the percentage of milk fat in the milk is 3.7%. In another embodiment, the percentage of milk fat in the milk is 3.8%. In another embodiment, the percentage of milk fat in the milk is 3.9%. In another embodiment, the percentage of milk fat in the milk is 4.0%. In another embodiment, the percentage of milk fat in the milk is 4.5%. In another embodiment, the percentage of milk fat in the milk is 5.0%. In another embodiment, the percentage of milk fat in the milk is 5.5%. In another embodiment, the percentage of milk fat in the milk is 6.0%. In another embodiment, the percentage of milk fat in the milk is 6.5%.

[0037] In some embodiments, the percentage of milk fat in the milk is increased by 0.5-30% compared to the milk fat in a control lactating mammal. In some embodiments, the percentage of milk fat in the milk is increased by 1-15% compared to the milk fat in a control lactating mammal. In some embodiments, the percentage of milk fat in the milk is increased by 2-6% compared to the milk fat in a control lactating mammal. In some embodiments, the percentage of milk fat in the milk is increased by 3-5% compared to the milk fat in a control lactating mammal.

[0038] In one embodiment, the percentage of milk fat in the milk is increased by 0.5% compared to the milk fat in a control lactating mammal. In another embodiment, the percentage of milk fat in the milk is increased by 1.0% compared to the milk fat in a control lactating mammal. In another embodiment, the percentage of milk fat in the milk is increased by 5.0% compared to the milk fat in a control lactating mammal. In another embodiment, the percentage of milk fat in the milk is increased by 10.0% compared to the milk fat in a control lactating mammal. In another embodiment, the percentage of milk fat in the milk is increased by 15.0% compared to the milk fat in a control lactating mammal. In another embodiment, the percentage of milk fat in the milk is increased by 20.0% compared to the milk fat in a control lactating mammal. In another embodiment, the percentage of milk fat in the milk is increased by 25.0% compared to the milk fat in a control lactating mammal. In another embodiment, the percentage of milk fat in the milk is increased by 30.0% compared to the milk fat in a control lactating mammal.

[0039] In some embodiments, the percentage of lactose in the milk is in the range of 3.5-7.8%. In one embodiment, the percentage of lactose in the milk is 3.5%. In another embodiment, the percentage of lactose in the milk is 4.0%. In another embodiment, the percentage of lactose in the milk is 4.5%. In another embodiment, the percentage of lactose in the milk is 5.0%. In another embodiment, the percentage of lactose in the milk is 5.5%. In another embodiment, the percentage of lactose in the milk is 6.0%. In another embodiment, the percentage of lactose in the milk is 6.5%. In another embodiment, the percentage of lactose in the milk is 7.0%. In another embodiment, the percentage of lactose in the milk is 7.5%. In another embodiment, the percentage of lactose in the milk is 7.8%.

[0040] In some embodiments, the percentage of lactose in the milk is increased by 0.5-30% compared to the lactose in a control lactating mammal. In some embodiments, the percentage of lactose in the milk is increased by 1-15% compared to the lactose in a control lactating mammal. In some embodiments, the percentage of lactose in the milk is increased by 2-6% compared to the lactose in a control lactating mammal. In some embodiments, the percentage of lactose in the milk is increased by 3-5% compared to the lactose in a control lactating mammal.

[0041] In one embodiment, the percentage of lactose in the milk is increased by 0.5% compared to the lactose in a control lactating mammal. In another embodiment, the percentage of lactose in the milk is increased by 1% compared to the lactose in a control lactating mammal. In another embodiment, the percentage of lactose in the milk is increased by 1.5% compared to the lactose in a control lactating mammal. In another embodiment, the percentage of lactose in the milk is increased by 2.0% compared to the lactose in a control lactating mammal. In another embodiment, the percentage of lactose in the milk is increased by 2.5% compared to the lactose in a control lactating mammal. In another embodiment, the percentage of lactose in the milk is increased by 3.0% compared to the lactose in a control lactating mammal. In another embodiment, the percentage of lactose in the milk is increased by 3.5% compared to the lactose in a control lactating mammal. In another embodiment, the percentage of lactose in the milk is increased by 4.0% compared to the lactose in a control lactating mammal. In another embodiment, the percentage of lactose in the milk is increased by 4.5% compared to the lactose in a control lactating mammal. In another embodiment, the percentage of lactose in the milk is increased by 5.0% compared to the lactose in a control lactating mammal. In another embodiment, the percentage of lactose in the milk is increased by 5.5% compared to the lactose in a control lactating mammal. In another embodiment, the percentage of lactose in the milk is increased by 6.0% compared to the lactose in a control lactating mammal.

[0042] In another embodiment, the percentage of lactose in the milk is increased by 10% compared to the lactose in a control lactating mammal. In another embodiment, the percentage of lactose in the milk is increased by 15% compared to the lactose in a control lactating mammal. In another embodiment, the percentage of lactose in the milk is increased by 20% compared to the lactose in a control lactating mammal. In another embodiment, the percentage of lactose in the milk is increased by 25% compared to the lactose in a control lactating mammal. In another embodiment, the percentage of lactose in the milk is increased by 30% compared to the lactose in a control lactating mammal.

[0043] In some embodiments, the ECM is increased by 0.5-20% compared to the ECM in a control lactating mammal. In some embodiments, the ECM is increased by 2.0-15% compared to the ECM in a control lactating mammal. In some embodiments, the ECM is increased by 5.0-10% compared to the ECM in a control lactating mammal. In some embodiments, the ECM is increased by 7.5-9% compared to the ECM in a control lactating mammal.

[0044] In some embodiments, the milk quality is also improved in a reduction in somatic cell count (SCC). In one embodiment, the reduction in SCC occurs after resumption of milking. In one embodiment, the reduction in SCC occurs in a treated subject as compared to an untreated subject.

[0045] In some embodiments, the milk quality is improved at any stage of the lactation cycle. One of ordinary skill in the art will appreciate that "lactation cycle" refers to the period between one calving and the next. The cycle is divided into several stages: early lactation, mid lactation, late lactation, and dry period.

[0046] In one embodiment, the milk quality is improved in early lactation, mid lactation, late lactation, or any combination thereof. In another embodiment, the milk quality is improved in early lactation. In another embodiment, the milk quality is improved in mid lactation. In another embodiment, the milk quality is improved in late lactation. In another embodiment, the milk quality is improved in early lactation and mid lactation. In another embodiment, the milk quality is improved in early lactation and late lactation. In another embodiment, the milk quality is improved in mid lactation and late lactation. In another embodiment, the milk quality is improved in early lactation, mid lactation, and late lactation.

[0047] In some embodiments, the milk quality is improved during the same stage of lactation as the administration of the composition comprising at least one casein-derived peptide. In some embodiments, the milk quality is improved during a subsequent stage of lactation as the administration of the composition comprising at least one casein-derived peptide.

[0048] In some embodiments, the administration is performed at the beginning of the dry period. In some embodiments, the administration is performed during the lactation period.

[0049] One of ordinary skill in the art will appreciate that "dry period" refers to the period before calving when the cow is not milked, currently about 6 to 9 weeks. The dry period serves multiple functions. The main function is to allow the cow to have a rest period before the next calving and to maximize milk yield in the next lactation. During the dry period, the rate of mammary cell turnover is faster than if the cow had been milked continuously until calving. At the beginning of the dry period, many dairy farmers administer antibiotics, one of the purposes being to treat the cow in the presence of persistent subclinical mastitis.

[0050] In some embodiments, the increase in milk quality is independent of the length of the dry-off period. In one embodiment, the dry-off period comprises 28 to 120 days. In another embodiment, the dry-off period comprises 28 to 100 days. In another embodiment, the dry-off period comprises 28 to 80 days. In another embodiment, the dry-off period comprises 28 to 60 days. In another embodiment, the dry-off period comprises 28 to 40 days. In another embodiment, the dry-off period comprises 40 to 49 days. In another embodiment, the dry-off period comprises 50 to 59 days.

[0051] In some embodiments, the milk is substantially free of residues.

[0052] In some embodiments, the milk is used as raw milk, for dairy production, for breast feeding, for baking, for confectionery, for feeding, or any combination thereof. In one embodiment, the milk is used as raw milk. In another embodiment, the milk is used for dairy production. In another embodiment, the milk is used for breast feeding. In another embodiment, the milk is used for baking. In another embodiment, the milk is used for confectionery. In another embodiment, the milk is used for feeding.

[0053] In another embodiment, the milk is used for extracting protein. In another embodiment, the milk is used for extracting milk fat. In another embodiment, the milk is used for extracting lactose.

[0054] In one embodiment, the dairy product comprises milk, whey, yogurt, cheese, cream, butter, high protein milk beverage, or a combination thereof. In another embodiment, the dairy product comprises milk. In another embodiment, the dairy product comprises whey. In another embodiment, the dairy product comprises yogurt. In another embodiment, the dairy product comprises cheese. In another embodiment, the dairy product comprises cream. In another embodiment, the dairy product comprises butter. In another embodiment, the dairy product comprises high protein milk beverage.

[0055] In some embodiments, the dairy product comprises a high percentage of protein.

[0056] In one embodiment, the product obtained from the high quality milk is used to treat a disease. In one embodiment, the product obtained from the high quality milk is used to build and repair muscle, to build and repair skin, to build and repair other body tissues, to treat infection, to balance body fluids, to carry oxygen through the body, to support cancer treatment, or any combination thereof.

[0057] In some embodiments, the products obtained from the high quality milk can be used for applications in non-food areas. In one embodiment, the non-food areas include the manufacture of plastics and other solid materials, textile fibers, adhesives, the production of ethanol or methane, use in research areas as a barrier for non-polar substances such as oxygen, carbon dioxide and aromatic substances, use in various technical applications such as protective coatings and foams, paper coatings, adhesives or injection-molded disposable items, as emulsifiers, as detergents, drug delivery or any combination thereof.

[0058] In some embodiments, disclosed herein is a composition comprising at least one casein-derived peptide for use in increasing the quality of milk in a lactating mammal.

[0059] Casein peptides In some embodiments, the method comprises administering a composition comprising at least one casein-derived peptide.

[0060] Casein is a protein in the milk of non-human mammals, which is also present in human mammal milk, known to include the subgroups aS1, aS2, b and K. Casein is defined according to the amino acid sequence of each subgroup aS1, aS2, b and K. In the context of the present disclosure, when referring to casein, it is understood that also acid casein, casein salts, phosphorus-containing casein and chymosin casein are included.

[0061] The term "protein" as used herein refers to amino acid residues linked by peptide bonds. Protein sequences are typically described from the N-terminus, which contains a free amino group, to the C-terminus, which contains a free carboxyl group. Amino acids as used herein refer to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Amino acids can be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.

[0062] The casein-derived peptide can be a single peptide or a mixture of different peptides, which can independently be selected from a naturally occurring peptide, a semi-synthetic peptide, a synthetic peptide or a recombinant peptide. It is further noted that the peptides according to the present disclosure can be produced synthetically, or by recombinant DNA technology, or by any other technique. Methods for producing peptides are well known in the art.

[0063] In some embodiments, the casein-derived peptides can comprise casein breakdown products, which are products resulting from the cleavage of casein into peptide fragments by enzymes or acids (also referred to in the art as "casein hydrolysates"). Casein hydrolysates are to be understood as hydrolyzed forms of casein (protein). Casein hydrolysates include, for example, active beta-casein-derived peptides, alphaSl -casein-derived peptides, alphaS2 -casein-derived peptides, kappa-casein-derived peptides, known to the person skilled in the art. In some embodiments, the casein-derived peptides are casein hydrolysates or comprise casein hydrolysates.

[0064] In some embodiments, the casein-derived peptides comprise natural peptides, synthetic peptides, semi-synthetic peptides, or any combination thereof. In another embodiment, the casein-derived peptides comprise natural peptides. In another embodiment, the casein-derived peptides comprise synthetic peptides. In another embodiment, the casein-derived peptides comprise semi-synthetic peptides. In another embodiment, the casein-derived peptides comprise a combination of natural peptides and synthetic peptides. In another embodiment, the casein-derived peptides comprise a combination of natural peptides and semi-synthetic peptides. In another embodiment, the casein-derived peptides comprise a combination of synthetic peptides and semi-synthetic peptides. In another embodiment, the casein-derived peptides comprise a combination of natural peptides, synthetic peptides, and semi-synthetic peptides.

[0065] Natural casein-derived peptides are typically obtained by enzymatic hydrolysis, the enzyme can be: any mammalian peptidase, such as, but not limited to, fibrinolysin, pancreatin, trypsin, chymotrypsin, neutral protease, alkaline protease, pepsin, carboxypeptidase, cathepsin; and plant peptidases such as, but not limited to, papain, bromelain; and enzymes from microbial sources. For example, naturally occurring casein-derived peptides can be the result of the action of an enzyme activity (such as fibrinolysin) on casein subunits beta-casein, alphaSl -casein, and alphaS2 -casein or kappa-casein. In some embodiments, casein hydrolysates are obtained by cleavage of casein with trypsin.

[0066] Synthetic peptides can be obtained by any method known in the art of peptide synthesis, including chemical synthesis and recombinant DNA technology. For example, the peptides can be synthesized using standard solid-phase techniques.

[0067] In one embodiment, the synthetic peptides are recombinant peptides.

[0068] Semi-synthetic casein-derived peptides can be obtained by chemical hydrolysis of casein, for example by prolonged boiling in strong acids (acid-HVP) or strong bases, or by using chemical reagents such as cyanogen bromide (CNBr). The casein-derived peptides can also be obtained by molecular engineering, for example using recombinant DNA in molecular techniques known in the art. In such embodiments, the casein-derived peptides are recombinant peptides.

[0069] In one embodiment, the recombinant peptide is produced by fermentation, tissue culture, or a combination thereof. In another embodiment, the recombinant peptide is produced by fermentation. In another embodiment, the recombinant peptide is produced by tissue culture. In another embodiment, the recombinant peptide is produced by a combination of fermentation and tissue culture.

[0070] In one embodiment, the tissue culture comprises mammary gland bovine tissue.

[0071] In some embodiments, the casein-derived peptide comprises one or more fragments of β-casein, αSl -casein, αS2 -casein, κ-casein, or any combination thereof. In one embodiment, the casein-derived peptide comprises one or more fragments of β-casein. In another embodiment, the casein-derived peptide comprises one or more fragments of αSl -casein. In another embodiment, the casein-derived peptide comprises one or more fragments of αS2 -casein. In another embodiment, the casein-derived peptide comprises one or more fragments of κ-casein. In another embodiment, the casein-derived peptide comprises one or more fragments of a combination of β-casein, αSl -casein, αS2 -casein, and κ-casein.

[0072] In one embodiment, the casein-derived peptide further comprises amino acids of varying lengths.

[0073] In one embodiment, the casein-derived peptide comprises a casein hydrolysate.

[0074] In one embodiment, the casein-derived peptide comprises a phosphopeptide.

[0075] As used herein, the term "phosphopeptide" designates a phosphorylated peptide that exists in the form of a conjugated peptide, wherein the non-peptide moiety is a phosphate residue. The expression "phosphopeptide" or "phosphoserine" designates a conjugated serine, wherein the non-peptide moiety is a phosphate residue.

[0076] In some embodiments, the casein-derived peptide is a single peptide or a mixture of phosphopeptides, i.e., it contains a single phosphorus group or is a phosphorus-rich peptide. In some embodiments, the casein-derived peptide is any phosphoserine-, phosphotyrosine-, phosphothreonine-, and / or phosphohistidine-rich casein-derived peptide (casein phosphopeptide, CPP) and a monovalent cationic caseinate salt, such as a sodium, potassium, calcium, or ammonium caseinate salt.

[0077] In some embodiments, the casein-derived peptide is a phosphor-peptide.

[0078] The phosphopeptides can generally be genetically engineered casein-derived peptides and peptidomimetics of casein-derived peptides. For example, phosphorylation of amino acids, such as at least one serine residue, can be performed by any method known in the art. The term "casein-derived peptides" also includes peptide fragments or peptidomimetic products obtained from or corresponding to one or more portions of casein. The peptidomimetics can be, for example, peptidomimetics or semipeptidomimetics, which are peptide analogs having, for example, modifications including but not limited to cyclization, N-terminal modifications, C-terminal modifications, modifications of the peptide bond including but not limited to CH2-NH, CH2-S, CH2-S-O, O-C-NH, CH2-O, CH2-CH2, S-C-NH, CH-CH, or CF-CH, backbone modifications, and residue modifications.

[0079] The term "casein-derived peptides" as used herein further encompasses any derivative, analog, variant, or homolog of any of the peptides. The term "derivative" is used to define an amino acid sequence (peptide) having any insertions, deletions, substitutions, and modifications to the amino acid sequence (peptide) that do not alter the activity of the original peptide. The term "derivative" also refers to covalent modifications of the polypeptides prepared according to the present application, as well as homologs, variants, and analogs thereof.

[0080] In some embodiments, the modified, synthetic, semi-synthetic, or other types of analogs of naturally occurring casein-derived peptides are in some embodiments at least 75%, sometimes 85%, 90%, 95%, even 99% identical (in sequence) to the naturally occurring casein-derived peptides when optimally aligned. In addition, any non-naturally occurring casein-derived peptides used according to the present disclosure can retain at least a portion of the biological activity of the naturally occurring casein protein.

[0081] The present disclosure also encompasses homologs of the casein-derived peptides. The term "homolog" is used to define an amino acid sequence (peptide) that maintains a minimum homology to the amino acid sequence defined by the present application, for example, having at least about 65%, at least about 75%, at least about 85%, or at least about 95% overall sequence homology to the amino acid sequence of any of the peptides defined by the structures described above (e.g., the particular sequences).

[0082] In some embodiments, the casein-derived peptide can also include chemical modifications of naturally occurring peptides, e.g., in which one or more amino acids are deleted, substituted, or modified, e.g., by removal of a side group, substitution of a side group, or introduction of a chemical group. Without being limited thereto, the chemical modifications can include acetylation, acylation, amidation, ADP-ribosylation, glycosylation, GPI anchor formation, covalent attachment of a lipid or lipid derivative, methylation, myristoylation, pegylation, prenylation, phosphorylation, ubiquitination, or any like process. When referring to the replacement of one amino acid sequence with another, the replacement can be a conservative substitution. For example, one or more amino acid residues within a casein sequence are replaced with another amino acid having similar polarity or charge. For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine. Polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine. Positively charged (basic) amino acids include arginine, lysine, and histidine. Negatively charged (acidic) amino acids include aspartic acid and glutamic acid. Nonetheless, non-conservative substitutions can also occur so long as the desired (casein-like) biological activity of the resulting casein-derived peptide analog is not significantly altered.

[0083] The casein-derived peptides according to the present disclosure are characterized by a molecular weight of between about average 100 to about average 10,000 Daltons (e.g., between 2 to 100 amino acids), sometimes between about average 100 to about average 7,000 Daltons, and sometimes between average 1,000 to average 5,000 Daltons.

[0084] The casein-derived peptides according to the present disclosure are characterized by a length of 2 to 200, 2 to 100 amino acids, sometimes between 4 amino acids to 40 amino acids, sometimes 4 amino acids to 30 amino acids, sometimes 4 amino acids to 10 amino acids, sometimes between 10 amino acids to 50 amino acids.

[0085] In some embodiments, the casein-derived peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO. 1 - SEQ ID NO. 26.

[0086] In one embodiment, the phosphopeptide comprises an amino acid sequence represented as Ser-Ser-Ser-Glu (SEQ ID NO: 1), wherein at least one Ser residue, at least two Ser residues, or three Ser residues are phosphorylated (phosphorylated serine is represented herein as Ser(p) or S(p)).

[0087] In another embodiment, the phosphopeptide comprises an amino acid sequence represented as Ser-Ser-Ser-Glu-Glu (SEQ ID NO: 2), wherein at least one Ser residue, at least two Ser residues, or three Ser residues are phosphorylated.

[0088] In another embodiment, the phosphopeptide comprises an amino acid sequence represented as Ser(p)-Ser(p)-Ser(p)-Glu-Glu (SEQ ID NO: 3).

[0089] In another embodiment, the phosphopeptide comprises an amino acid sequence represented as RELEELNVPGEIVES(p)LS(p)S(p)S(p)EESITR (SEQ ID NO: 4). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as QMEAESIS(p)S(p)S(p)EEIVPDSVEQK (SEQ ID NO: 5). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as KNTMEHVS(p)S(p)S(p)EESIISNETYK (SEQ ID NO: 6). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as KVNELSKNIGS(p)ES(p)TEDQ (SEQ ID NO: 7). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as PTLNREQLS(p)TS(p)EENSKKTVD (SEQ ID NO: 8). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as ELEELNVPGEIVES(p)LS(p)S(p)S(p)EESITR (SEQ ID NO: 9). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as RELEELNVPGEIES(p)LS(p)S(p)S(p)EESITR (SEQ ID NO: 10). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as QMEAES(p)IS(p)S(p)S(p)EEIVPNS(p)VEQK (SEQ ID NO: 11). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as KNTMEHVS(p)S(p)S(p)EESIIS(p)QETYK (SEQ ID NO: 12). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as KVNELSKDIGS(p)ES(p)TEDQ (SEQ ID NO: 13). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as ESIIS(p)QETYKQEKNMAINPSKENLCSTFCKEVVRNANEEETSIGS(p)S(p)S(p)EES(p)AEVATEEVKITVDDKHYQKALNEINQFYQKFPGYLQYLYQGPIVLNPWNQVLRNAVPITPTLNREQLS(p)TS(p)EENSKKTVN (SEQ ID NO: 14). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as ELEELNVPGEIES(p)LS(p)S(p)S(p)EESITR (SEQ ID NO: 15).

[0090] In another embodiment, the phosphopeptide comprises an amino acid sequence represented as X 1(n) - Ser(P)-Ser(P)-Ser(P)-X 2(m) - Lys (SEQ ID NO: 16), wherein at least one of X1and X2is independently selected from a positively charged amino acid, and wherein n and m are each independently selected from 0, 1 and 2.

[0091] In some embodiments, the positively charged amino acid is selected from the group consisting of lysine, arginine and histidine. In some embodiments, the positively charged amino acid is lysine. In other embodiments, the positively charged amino acid is arginine. In other embodiments, the positively charged amino acid is histidine.

[0092] According to some embodiments, the expression of SEQ ID NO: 16 further comprises a blocking group (also referred to herein as a protecting group) at the C-terminus. In some embodiments, the carboxyl group at the C-terminus of the peptide is protected by a protecting group. The protecting group is selected from, but not limited to, an amide (i.e., the hydroxyl group at the C-terminus is replaced by a primary, secondary or tertiary amine (NH2)) or an ester (i.e., the hydroxyl group at the C-terminus is replaced by an ester). According to some embodiments, the blocking group is selected from the group consisting of an amide and an ester. According to some embodiments, the blocking group is an amide.

[0093] In another embodiment, the phosphopeptide comprises an amino acid sequence represented as Lys-Lys-Ser(P)-Ser(P)-Ser(P) (SEQ ID NO: 17). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as Lys-Lys-Ser(P)-Ser(P)-Ser(P)-Lys (SEQ ID NO: 18). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as Lys-Lys-Ser(P)-Ser(P)-Ser(P)-Lys-Lys (SEQ ID NO: 19). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as Lys-Ser(P)-Ser(P)-Ser(P)-Lys-Lys (SEQ ID NO: 20). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as Lys-Ser(P)-Ser(P)-Ser(P)-Lys (SEQ ID NO: 21). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as Lys-Ser(P)-Ser(P)-Ser(P) (SEQ ID NO: 22). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as Ser(P)-Ser(P)-Ser(P)-Lys-Lys (SEQ ID NO: 23). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as Ser(P)-Ser(P)-Ser(P)-Lys (SEQ ID NO: 24). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as Lys-Lys-Ser(p)-Ser(p)-Ser(p)-NH2 (SEQ ID NO: 25). In another embodiment, the phosphopeptide comprises an amino acid sequence represented as RELEELNVPGEIVES(p)LS(p)S(p)S(p)EESITRINK (SEQ ID NO: 26).

[0094] The casein-derived peptides according to the present application can comprise both "L" and "D" form residues. While the amino acid residues of the peptide sequences set forth in SEQ ID NOs: 1-26 are all in the "L" isomer form, "D" isomer form residues can be substituted for any of the L-amino acid residues, provided that the resulting peptide analog retains at least some of the biological activity of the corresponding "L" isomer. One reason for designing casein-derived peptides comprising at least one D-amino acid is to increase the stability of the peptide to proteolytic degradation.

[0095] In one embodiment, the composition is free of antimicrobial agents and comprises an acceptable carrier. In another embodiment, the composition is also free of hormones, genetically modified organisms, or combinations thereof. Those skilled in the art will appreciate that a genetically modified organism (GMO) is an animal, plant, or microorganism whose DNA has been altered using genetic engineering techniques.

[0096] In one embodiment, the milk-derived protein is measured by UV in the range of 204 to 220 nm.

[0097] Dosage and administration In some embodiments, the methods of the present application comprise administering the milk-derived protein at 10 ng / ml to 500 mg / ml per administration. In one embodiment, the methods of the present application comprise administering the milk-derived protein at 1 mg / ml to 500 mg / ml per administration. In another embodiment, the methods of the present application comprise administering the milk-derived protein at 10 mg / ml to 450 mg / ml per administration. In another embodiment, the methods of the present application comprise administering the milk-derived protein at 50 mg / ml to 400 mg / ml per administration. In another embodiment, the methods of the present application comprise administering the milk-derived protein at 50 mg / ml to 70 mg / ml per administration. In another embodiment, the methods of the present application comprise administering the milk-derived protein at 100 mg / ml to 350 mg / ml per administration. In another embodiment, the methods of the present application comprise administering the milk-derived protein at 150 mg / ml to 300 mg / ml per administration. In another embodiment, the methods of the present application comprise administering the milk-derived protein at 200 mg / ml to 250 mg / ml per administration. In another embodiment, the methods of the present application comprise administering the milk-derived protein at 5 mg / ml to 30 mg / ml per administration.

[0098] In one embodiment, the concentration of milk-derived protein in the composition is between 0.1% and 30%. In another embodiment, the concentration of milk-derived protein in the composition is 0.1%. In another embodiment, the concentration of milk-derived protein in the composition is 1%. In another embodiment, the concentration of milk-derived protein in the composition is 5%. In another embodiment, the concentration of milk-derived protein in the composition is 10%. In another embodiment, the concentration of milk-derived protein in the composition is 10%. In another embodiment, the concentration of milk-derived protein in the composition is 15%. In another embodiment, the concentration of milk-derived protein in the composition is 20%. In another embodiment, the concentration of milk-derived protein in the composition is 25%. In another embodiment, the concentration of milk-derived protein in the composition is 30%.

[0099] In one embodiment, the administration comprises oral, intraoral, topical, on- skin, transdermal, subcutaneous, intrarectal, intravaginal, parenteral, or any combination thereof. In another embodiment, the administration comprises oral administration. In another embodiment, the administration comprises intraoral administration. In another embodiment, the administration comprises topical administration. In another embodiment, the administration comprises on-skin administration. In another embodiment, the administration comprises transdermal administration. In another embodiment, the administration comprises subcutaneous administration. In another embodiment, the administration comprises intrarectal administration. In another embodiment, the administration comprises intravaginal administration. In another embodiment, the administration comprises parenteral administration.

[0100] In another embodiment, the administration comprises intramammary infusion to a single teat or multiple teats. In another embodiment, the administration comprises intramammary infusion to a single teat. In another embodiment, the administration comprises intramammary infusion to multiple teats.

[0101] In some embodiments, the methods of the present application comprise one to eight administrations to a single teat. In one embodiment, the methods of the present application comprise one administration. In another embodiment, the methods of the present application comprise two administrations. In another embodiment, the methods of the present application comprise three administrations. In another embodiment, the methods of the present application comprise four administrations. In another embodiment, the methods of the present application comprise five administrations. In another embodiment, the methods of the present application comprise six administrations. In another embodiment, the methods of the present application comprise seven administrations. In another embodiment, the methods of the present application comprise eight administrations.

[0102] In some embodiments, the administration of the present application comprises a subsequent administration. In one embodiment, the administration is one administration immediately followed by another administration.

[0103] In some embodiments, the administration of the present application comprises an interval of about 1 hour to about 72 hours. In one embodiment, the administration comprises an interval of about 1 hour. In one embodiment, the administration comprises an interval of about 4 hours. In one embodiment, the administration comprises an interval of about 5 hours. In one embodiment, the administration comprises an interval of about 8 hours. In one embodiment, the administration comprises an interval of about 10 hours. In one embodiment, the administration comprises an interval of about 12 hours. In one embodiment, the administration comprises an interval of about 15 hours. In one embodiment, the administration comprises an interval of about 16 hours. In one embodiment, the administration comprises an interval of about 20 hours. In one embodiment, the administration comprises an interval of about 24 hours. In one embodiment, the administration comprises an interval of about 25 hours. In one embodiment, the administration comprises an interval of about 28 hours. In one embodiment, the administration comprises an interval of about 30 hours. In one embodiment, the administration comprises an interval of about 35 hours. In one embodiment, the administration comprises an interval of about 36 hours. In one embodiment, the administration comprises an interval of about 40 hours. In one embodiment, the administration comprises an interval of about 45 hours. In one embodiment, the administration comprises an interval of about 50 hours. In one embodiment, the administration comprises an interval of about 55 hours. In one embodiment, the administration comprises an interval of about 60 hours. In one embodiment, the administration comprises an interval of about 65 hours. In one embodiment, the administration comprises an interval of about 70 hours. In one embodiment, the administration comprises an interval of about 72 hours.

[0104] In one embodiment, the administration comprises an interval of about 1 hour to about 24 hours.

[0105] In one embodiment, the administration is performed during the lactation period.

[0106] In one embodiment, the administration comprises administration during one or several lactation periods. In one embodiment, the administration comprises administration during one lactation period. In another embodiment, the administration comprises administration during several lactation periods. In another embodiment, the administration comprises administration during two lactation periods. In another embodiment, the administration comprises administration during three lactation periods. In another embodiment, the administration comprises administration during four lactation periods. In another embodiment, the administration comprises administration during five lactation periods. In another embodiment, the administration comprises administration during six lactation periods. In another embodiment, the administration comprises administration during seven lactation periods. In another embodiment, the administration comprises administration during eight lactation periods. In another embodiment, the administration comprises administration during nine lactation periods. In another embodiment, the administration comprises administration during ten lactation periods.

[0107] In one embodiment, the administration comprises administration during one or several dry periods. In one embodiment, the administration comprises administration during one dry period. In another embodiment, the administration comprises administration during several dry periods. In another embodiment, the administration comprises administration during two dry periods. In another embodiment, the administration comprises administration during three dry periods. In another embodiment, the administration comprises administration during four dry periods. In another embodiment, the administration comprises administration during five dry periods. In another embodiment, the administration comprises administration during six dry periods. In another embodiment, the administration comprises administration during seven dry periods. In another embodiment, the administration comprises administration during eight dry periods. In another embodiment, the administration comprises administration during nine dry periods. In another embodiment, the administration comprises administration during ten dry periods.

[0108] Example Example 1 - Intramammary administration of casein hydrolysate as dry cow therapy The objective of this randomized, blinded, controlled study was to evaluate the association between intramammary administration of bovine casein hydrolysate (bCNH) and subsequent lactation milk yield and subsequent lactation protein, fat and lactose yield. Milk yield was measured by milk production, energy-corrected milk (ECM) and combined protein, fat and lactose yield. Local tolerance of the infusion and general well-being were also evaluated during the subsequent lactation period.

[0109] A total of 306 enrolled Israel Holstein Friesians dairy cows were included in the analysis. Eligibility criteria included good overall condition, no clinical mastitis or any other intramammary infection. Fourteen (14) cows were excluded from the total eligible and enrolled cows in the study due to management events (5 cows), abortion (6 cows) and udder condition (3 cows). Enrolment of cows was performed according to farm routine in the pre-dry period.

[0110] There were two bCNH experimental groups and one positive control group. The experimental groups included the following: (i) 109 cows treated with a single syringe (20 mL containing 1200 mg bCNH) (bCNH-11); (ii) 96 cows treated with two syringes of 20 mL each (40 mL) in succession (bCNH-22). The control group consisted of 101 cases treated with the conventional dry cow therapy (DCT) Nefpenzal® DC.

[0111] Energy-corrected milk (ECM) analysis Energy-corrected milk (ECM) determines the energy content in milk based on milk composition (particularly fat and protein). ECM is calculated for measuring the feed efficiency (FE) of the cow, i.e. the ability of the cow to convert dry matter feed into milk yield (kg), which is calculated by dividing ECM by dry matter intake. Feed efficiency is used for genetic evaluation as well as for assessing the effect of the temperature-humidity index.

[0112] The results of the linear mixed model for ECM yield (kg) in milk by month over the subsequent 305-day lactation period are shown in Figure 1 and Figure 2 Analysis of differences between each bCNH treatment group and the control group showed that bCNH11 and bCNH22 were significantly different from the control group (P < 0.05). The ECM yield in the bCNH11 group was 3.07 kg per day higher than the control group and the bCNH22 group was 2.96 kg per day higher than the control group over the 305-day lactation period. The difference between the control group and these bCNH groups was 965 kg per cow for the bCNH11 group and 902 kg per cow for the bCNH22 group over the entire 305-day lactation period. The average ECM yield of the bCNH treatments was higher than the average ECM yield of the control group at all time points of the 305-day lactation period.

[0113] Milk fat yield analysis The results of the linear mixed model for milk fat yield (kg) in milk by month over the subsequent 305-day lactation period are shown in Figure 3 and Figure 4

[0114] Protein yield analysis ​Linear mixed model results for protein yield (kg) by month over the subsequent 305 days of lactation are shown in Figure 5 and Figure 6

[0115] Lactose yield analysis Linear mixed model results for lactose yield by month over the subsequent 305 days of lactation are shown in Figure 7 and Figure 8

[0116] The above results regarding the use of bCNH to increase energy-corrected milk and milk bio-components (primarily protein, milk fat, and lactose) during the lactation period are innovative and surprising findings. In comparison to antibiotics, the use of bCNH treatment did not have any negative impact on milk yield. Furthermore, the significance of higher milk fat and protein yields (expressed later as higher ECM) reinforces the point that bCNH is a very effective dry-off treatment.

[0117] Example 2 - Field study to evaluate the effects of bovine casein hydrolysate on milk quality during lactation The current field study aims to evaluate the clinical benefits of bCNH in-mast infusion to the milk string during lactation and after milking resumes (after a five-day dry-off period following bCNH administration).

[0118] ​​Twenty-three (23) pregnant Israeli Holstein-Friesian cows of any parity were enrolled after clinical examination confirmed the presence of subclinical mastitis (determined by elevated SCC) and two consecutive bacteriological tests positive for non Staphylococcus aureus (NAS) during the screening period (study days -7 and -6). On treatment day (day 0), after clinical examination and morning milking, eligible cows (1 or 2 infected quarters per cow) were randomly assigned to receive bCNH or no treatment (negative control). Following bCNH treatment, treated quarters were subjected to a 6 (±1) days of no-milking period, followed by resumption of milking. Other quarters, whether control (untreated) or not enrolled in the study (uninfected), continued to be milked according to the normal milking management routine. Milk samples were collected from the infected quarters for bacteriological, somatic cell count (SCC), lactose, sodium-potassium ratio and milk electrical conductivity analysis, before treatment on treatment day (D 0), on resumption day (D6 ±1), 12 hours later, on the following morning milking day, and 14 and 21 days after treatment. Following treatment, all cows were managed according to the routine management procedures. All cows were monitored for clinical signs of mastitis or other diseases until study day 21. Daily milk production data were collected from the NOA system (Israeli Dairy Herd Management Program developed by the Israeli Cattle Breeders Association) until day 35 after treatment. In addition, routine monthly data of milk production and milk components were collected for up to three months before and up to three months after the start of the study (treatment).

[0119] Each cow in the study received treatment only on its infected quarters, i.e., infected quarters of each cow received 1200 mg bCNH (T2), or 2400 mg bCNH (T3), or 4800 mg bCNH (T4), or no treatment (T1).

[0120] Treated quarters of each participating cow were not milked for a consecutive 6 (±1) days, after which resumption of milking was initiated. Untreated quarters from treated cows were milked normally, and their milk was not discarded.

[0121] The effect of treatment on milk production, energy-corrected milk (ECM), milk fat (kg), protein (kg), lactose (kg) and composite SCC was tested.

[0122] Monthly milk yield, ECM, fat, protein, lactose, and composite SCC data were collected for the first 3 months of treatment and for the 3 months after resumption of milking. Differences between the control and active treatment groups were analyzed using JMP 16.2.0 software with a linear mixed model with LSmeans differences Student's t-test. The model included parity (1, 2, 3+), month-in-milk (MIM) after resumption of milking, treatment (control, T2), and the interactions of treatment with MIM and parity. The mean of each variable during the pre-trial period was calculated and used as a covariate.

[0123] Energy-corrected milk (ECM) values (kg) during the three months before and after the resumption of milking period Energy-corrected milk (kg) was calculated according to the following formula: ECM = 0.1 Milk + 0.1 10 + 0.1 15.8. The mean of the monthly ECM before the trial was used as a covariate. The energy-corrected milk yield during the entire post-milking resumption period was 35.88 (SE = 4.06) for the control group and 39.86 (SE = 2.76) for the bCNH group, P = 0.43. As shown in Figure 1, a significant difference was observed in the second month. Figure 9

[0124] Composite protein values in milk (kg) during the 35 days before and after the resumption of milking period The mean of the monthly protein yield before the trial was used as a covariate. The protein yield during the entire 3 months after the start of milking was 1.32 kg (SE = 0.098) for the control group and 1.38 kg (SE = 0.065) for the bCNH group, P = 0.08. As shown in Figure 2, protein yield became higher in the second and third months of measurement. Figure 10

[0125] Composite fat values in milk (kg) during the 35 days before and after the resumption of milking period The mean of the monthly fat yield before the trial was used as a covariate. The fat yield was 1.36 kg (SE = 0.14) for the control group and 1.49 kg (SE = 0.09) for the bCNH group, (P = 0.46). As shown in Figure 3, fat yield became higher in the second and third months of measurement. Figure 11

[0126] Composite lactose values in milk (kg) during the 35 days before and after the resumption of milking period ​​​Mean monthly lactose yield prior to entry into the trial was used as a covariate. Least squares mean lactose yield was 1.82 (SE = 0.18) for the control group and 1.90 (SE = 0.12) for the bCNH group. As shown in Figure 1, lactose yield became higher in the second and third month after treatment. Figure 12

[0127] Bulk milk somatic cell count (BMSCC) during the pre- and post-restart periods Bulk milk somatic cell count values were not normally distributed (Prob>chiSq = 0.026). Therefore, BMSCC values were transformed to log 10 BMSCC. To understand the effect of treatment on log 10 BMSCC after restart of milking independent of pre-treatment levels, pre-treatment log 10 BMSCC was used as a covariate. Least squares mean log 10 BMSCC was 5.58 (SE = 0.18) for the control group and 5.14 (SE = 0.13) for the bCNH group, P = 0.051. Differences between individual months in milk (MIM) showed that log 10 BMSCC was significantly higher for control cows than for the experimental group in the first month after restart of milking (P = 0.005) ( Figure 13 ).

[0128] Monthly milk yield values (kg) during the 35-day period prior to and after the pre- and post-restart periods Mean daily monthly milk yield was 39.27 kg (SE = 3.56) for the control group and 39.92 kg (SE = 2.37, P = 0.88) for the bCNH group during the entire post-restart period. As shown in Figure 2, a higher average milk yield was observed for the bCNH treatment group. Therefore, there appeared to be a trend for milk yield to become higher over time for the experimental (bCNH) group. Figure 14

[0129] While certain features of the application have been illustrated and described, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the application.​​

Claims

1. A method of increasing milk quality in a lactating mammal comprising administering a composition comprising at least one casein-derived peptide.

2. The method of claim 1, wherein the increased milk quality comprises increased milk protein, increased milk fat, increased lactose, increased energy-corrected milk (ECM), or any combination thereof.

3. The method of claim 2, wherein the increased milk quality comprises increased milk protein.

4. The method of claim 2, wherein the increased milk quality comprises increased milk fat.

5. The method of claim 2, wherein the increased milk quality comprises increased lactose.

6. The method of claim 2, wherein the increased milk quality comprises increased measured energy-corrected milk (ECM).

7. The method of claims 2 and 3, wherein the percentage of milk protein in the milk is in the range of 2.5-6.5%.

8. The method of claims 2 and 3, wherein the percentage of milk protein in the milk is increased by 0.5-30% compared to milk protein in a control lactating mammal.

9. The method of claim 8, wherein the percentage of milk protein in the milk is increased by 1-20% compared to milk protein in a control lactating mammal.

10. The method of claims 8 and 9, wherein the percentage of milk protein in the milk is increased by 3-10% compared to milk protein in a control lactating mammal.

11. The method of claims 8-10, wherein the percentage of milk protein in the milk is increased by 5-8% compared to milk protein in a control lactating mammal.

12. The method of claims 2 and 4, wherein the percentage of milk fat in the milk is in the range of 2.5-6.5%.

13. The method of claims 2 and 4, wherein the percentage of milk fat in the milk is increased by 0.5-30% compared to milk fat in a control lactating mammal.

14. The method of claim 13, wherein the percentage of milk fat in the milk is increased by 1-15% compared to milk fat in a control lactating mammal.

15. The method of claims 13 and 14, wherein the percentage of milk fat in the milk is increased by 2-6% compared to milk fat in a control lactating mammal.

16. The method of claims 13-15, wherein the percentage of milk fat in the milk is increased by 3-5% compared to milk fat in a control lactating mammal.

17. The method of claims 2 and 5, wherein the percentage of lactose in the milk is in the range of 3.5-7.8%.

18. The method of claims 2 and 5, wherein the percentage of lactose in the milk is increased by 0.5-30% compared to lactose in a control lactating mammal.

19. The method of claim 18, wherein the percentage of lactose in the milk is increased by 1-15% compared to lactose in a control lactating mammal.

20. The method of claim 18, wherein the percentage of lactose in the milk is increased by 2-6% as compared to lactose in a control lactating mammal.

21. The method of claims 18-20, wherein the percentage of lactose in the milk is increased by 3-5% as compared to lactose in a control lactating mammal.

22. The method of claims 2 and 6, wherein the ECM is increased by 0.5-20% as compared to ECM in a control lactating mammal.

23. The method of claim 22, wherein the ECM is increased by 2-15% as compared to ECM in a control lactating mammal.

24. The method of claims 22 and 23, wherein the ECM is increased by 5-10% as compared to ECM in a control lactating mammal.

25. The method of any of the preceding claims, wherein the milk quality further comprises a decrease in somatic cell count (SCC).

26. The method of any of the preceding claims, wherein the milk quality is increased at any stage of the lactation cycle.

27. The method of claim 26, wherein the milk quality is increased at early lactation, mid lactation, late lactation, or any combination thereof.

28. The method of claims 1-27, wherein the milk quality is increased during the same lactation period in which the composition comprising at least one casein-derived peptide is administered.

29. The method of claims 1-27, wherein the milk quality is increased during a subsequent lactation period in which the composition comprising at least one casein-derived peptide is administered.

30. The method of claim 29, wherein the administration occurs at the beginning of the dry period.

31. The method of any of the preceding claims, wherein the increase in milk quality is independent of the length of the dry period.

32. The method of claim 31, wherein the dry period comprises 28 to 120 days.

33. The method of claim 31, wherein the dry period comprises 28 to 60 days.

34. The method of claim 31, wherein the dry period comprises 40 to 49 days.

35. The method of claim 31, wherein the dry period comprises 50 to 59 days.

36. The method of any of the preceding claims, wherein the casein-derived peptide comprises a natural peptide, a synthetic peptide, a semi-synthetic peptide, or any combination thereof.

37. The method of claim 36, wherein the synthetic peptide is a recombinant peptide.

38. The method of claim 37, wherein the recombinant peptide is produced by fermentation, tissue culture, or a combination thereof.

39. The method of claim 38, wherein the tissue culture comprises bovine mammary gland tissue.

40. The method of any of the preceding claims, wherein the casein-derived peptide comprises one or more fragments of beta-casein, alphaSl-casein, alphaS2-casein, kappa-casein, optionally further comprising amino acids of varying lengths or any combination thereof.

41. The method of any one of the preceding claims, wherein the casein- source peptide comprises a casein hydrolysate.

42. The method of any one of the preceding claims, wherein the casein- source peptide comprises a phosphopeptide.

43. The method of claim 42, wherein the phosphopeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO. 1 - SEQ ID NO.

26.

44. The method of any one of the preceding claims, wherein the composition is free of antimicrobial agents and comprises an acceptable carrier.

45. The method of any one of the preceding claims, comprising administering 10 ng / ml to 500 mg / ml of the casein-source peptide.

46. The method of any one of the preceding claims, wherein the administering comprises an intramammary infusion to a single teat or multiple teats.

47. The method of any one of the preceding claims, wherein the administering comprises one to eight administrations per teat.

48. The method of any one of the preceding claims, wherein the administering comprises a spacing of about 1 hour to about 72 hours.

49. The method of any one of the preceding claims, wherein the administering comprises a continuous administration during a lactation period or several lactation periods.

50. The method of any one of the preceding claims, wherein the milk is substantially free of residues, and wherein the milk is useful as raw milk, for dairy production, for breast feeding, baking, confectionery, feeding, or any combination thereof.

51. The method of claim 50, wherein the dairy product comprises milk, whey, yogurt, cheese, cream, butter, high protein milk beverage, or a combination thereof.

52. A composition comprising at least one casein-source peptide for use in increasing milk quality in a lactating mammal.

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