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WO2024105668A1 - Compositions et procédés de modulation de troubles et d'états mammaires - Google Patents

Compositions et procédés de modulation de troubles et d'états mammaires Download PDF

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Publication number
WO2024105668A1
WO2024105668A1 PCT/IL2023/051181 IL2023051181W WO2024105668A1 WO 2024105668 A1 WO2024105668 A1 WO 2024105668A1 IL 2023051181 W IL2023051181 W IL 2023051181W WO 2024105668 A1 WO2024105668 A1 WO 2024105668A1
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Prior art keywords
milk
casein
peptide
milk production
another embodiment
Prior art date
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PCT/IL2023/051181
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English (en)
Inventor
Jose Mario Iscovich
Javier Iscovich
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Mileutis Ltd
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Mileutis Ltd
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Priority to EP23813896.0A priority Critical patent/EP4619011A1/fr
Priority to CN202380086612.4A priority patent/CN120379680A/zh
Priority to JP2025528504A priority patent/JP2025537820A/ja
Priority to AU2023380303A priority patent/AU2023380303A1/en
Publication of WO2024105668A1 publication Critical patent/WO2024105668A1/fr
Priority to MX2025005671A priority patent/MX2025005671A/es
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/01—Hydrolysed proteins; Derivatives thereof
    • A61K38/012—Hydrolysed proteins; Derivatives thereof from animals
    • A61K38/018—Hydrolysed proteins; Derivatives thereof from animals from milk
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/38—Albumins
    • A61K38/385—Serum albumin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals

Definitions

  • casein protein comprises three fractions, a, P and K, according to their electrophoretic mobility.
  • Casein hydrolysate is the hydrolyzed form of casein which includes, among others, the active beta-casein-derived peptide. It has been established that casein hydrolysate plays a role in immune responses against microbial and viral infections.
  • Intramammary infection plays a decisive role in breastfeeding humans and in the dairy industry impacting animal health, causing difficulties in maintaining milk quality and production, and negatively impacting welfare and comfort thus causing considerable economic losses.
  • IMI is a costly disease and needs to be identified as soon as possible to reduce the negative effect on milk quality and quantity and to maximize the chance of cure and prevent spreading.
  • Mastitis is a disease caused generally by IMI and caused by pathogens, mostly bacteria, but also yeast, fungi, or even algae. Mastitis can be clinical, with local (and in some cases general) clinical signs and milk abnormalities, or subclinical with production losses and lowered milk quality.
  • Antimicrobial treatment is used in order to keep bovine udder health, and economic aspects in balance.
  • AMR antimicrobial resistance
  • AMU extensive antimicrobialusage
  • a method for treating intramammary infection in lactating mammals during lactation comprising administering to the lactating mammals a composition comprising at least one milk-derived protein, wherein the lactating mammal cure period occurs during the same lactation.
  • the lactating mammal cure period comprises about 60 or less days posttreatment. In some related aspects, the lactating mammal cure period comprises about 45 or less days posttreatment. In some related aspects, the lactating mammal cure period comprises about 14 or less days posttreatment. In some related aspects, the lactating mammal cure period comprises about 7 or less days posttreatment.
  • the cure period enables re-initiation of milk production form the infected teat during the same lactation. In some further related aspects, the cure period enables continuation of milk production from the uninfected teats.
  • a method for continuous milk production and milking in lactating mammals during lactation comprising administering to the lactating mammals a composition comprising at least one milk-derived protein, wherein the milking is from an untreated single or plurality of udder quarters.
  • the sub-clinical disease comprises increased somatic cell count in milk, increased milk electrical conductivity, reduction in milk quantity or combination thereof.
  • the increased somatic cell count in milk, increased milk electrical conductivity, reduction in milk quantity or any combination thereof are a result of uninfected or infected udder quarters.
  • the lactating mammals continue milk production and milking from untreated single or plurality of udder quarters.
  • the milk is essentially free of residues and can be used as raw milk, for dairy production, for breastfeeding or any combination thereof .
  • the dairy product comprises milk, whey, yogurt, cheese, cream, butter, milk drinks with high protein or combination thereof.
  • milk-derived protein comprises a casein protein or casein derived peptide.
  • casein derived peptide comprises natural peptide, synthetic peptide, semi-synthetic peptide, or any combination thereof .
  • casein derived peptide comprises one or more fragments of P-casein, aS 1 -casein, aS2-casein andK-casein. In some further related aspects, the casein derived peptide further comprises amino acids with different lengths.
  • 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.
  • a method for treating intramammary infection in lactating mammals during lactation comprising administering to the lactating mammals a composition comprising at least one milk-derived protein, wherein the lactating mammal cure period occurs during the same lactation.
  • composition comprising at least one milk-derived protein, for use for in treating intramammary infection in lactating mammals during lactation, wherein the lactating mammal cure period occurs during the same lactation.
  • the lactating mammal cure period comprises 60 or less days posttreatment. In another embodiment, the lactating mammal cure period comprises 60 days posttreatment. In one embodiment, the lactating mammal cure period comprises 55 or less days posttreatment. In another embodiment, the lactating mammal cure period comprises 55 days posttreatment.
  • the lactating mammal cure period comprises 50 or less days posttreatment. In another embodiment, the lactating mammal cure period comprises 50 days posttreatment. In another embodiment, the lactating mammal cure period comprises 45 or less days posttreatment. In one embodiment, the cure period comprises 45 days or less. In another embodiment, the cure period comprises 45 days. In another embodiment, the cure period comprises 40 days or less. In another embodiment, the cure period comprises 40 days. In another embodiment, the cure period comprises 30 days or less. In another embodiment, the cure period comprises 30 days. In another embodiment, the cure period comprises 21 days. In another embodiment, the cure period comprises 20 days. In another embodiment, the cure period comprises 18 days. In another embodiment, the cure period comprises 16 days. In another embodiment, the cure period comprises 14 days.
  • the cure period comprises 12 days. In another embodiment, the cure period comprises 10 days. In another embodiment, the cure period comprises 9 days. In another embodiment, the cure period comprises 8 days. In another embodiment, the cure period comprises 7 days. In another embodiment, the cure period comprises 6 days. In another embodiment, the cure period comprises 5 days. In another embodiment, the cure period comprises 4 days. In another embodiment, the cure period comprises 3 days. In another embodiment, the cure period comprises 2 days.
  • the cure period enables re-initiation of milk production form the infected teat during the same lactation.
  • the re-initiation of milk production is within the same lactation period.
  • the re-initiation of milk production is within the subsequent lactation period.
  • the reinitiation of milk production is from the treated single or plurality of udder quarters.
  • the re-initiation of milk production occurs within 60 days of treatment or less. In other embodiments the re-initiation of milk production occurs within 45 days or less. In additional embodiments the re-initiation of milk production occurs with 30 days or less. In additional embodiments the re-initiation of milk production occurs within 14 days or less. In other embodiments the re-initiation of milk production occurs with 7 days or less. In additional embodiments the re-initiation of milk production occurs within 5 days or less. In other embodiments the re-initiation of milk production occurs within 3 days or less.
  • the cure period enables continuation of milk production from the uninfected teats.
  • the milk production quantity from the re-initiation of milk production is equal to or higher from milk production quantity before treatment. In another embodiment, the milk production quantity from the re-initiation of milk production is equal to milk production quantity before treatment. In another embodiment, the milk production quantity from the re-initiation of milk production is higher than milk production quantity before treatment. In another embodiment, the milk production quantity from the re-initiation of milk production is higher than the milk production quantity of lactating mammals treated with antibiotics.
  • the milk production quantity from the re-initiation of milk production is equal to or higher from milk production quantity before treatment after 2-90 days of re-initiation of milk production. In another embodiment, the milk production quantity from the re-initiation of milk production is equal to or higher from milk production quantity before treatment after 2 days of re-initiation of milk production. In another embodiment, the milk production quantity from the re-initiation of milk production is equal to or higher from milk production quantity before treatment after 10 days of re-initiation of milk production. In another embodiment, the milk production quantity from the re-initiation of milk production is equal to or higher from milk production quantity before treatment after 30 days of re-initiation of milk production.
  • the milk production quantity from the re-initiation of milk production is equal to or higher from milk production quantity before treatment after 50 days of re-initiation of milk production. In another embodiment, the milk production quantity from the re-initiation of milk production is equal to or higher than milk production quantity before treatment after 70 days of re-initiation of milk production. In another embodiment, the milk production quantity from the re-initiation of milk production is equal to or higher from milk production quantity before treatment after 90 days of re-initiation of milk production.
  • the milk production quantity from the re-initiation milk production is higher than milk production quantity before treatment by 0.5%-10%. In another embodiment, the milk production quantity from the re-initiation milk production is higher from milk production quantity before treatment by 2%. In another embodiment, the milk production quantity from the re-initiation milk production is higher from milk production quantity before treatment by 3%. In another embodiment, the milk production quantity from the re-initiation milk production is higher than milk production quantity before treatment by 4%. In another embodiment, the milk production quantity from the reinitiation milk production is higher than milk production quantity before treatment by 5%. In another embodiment, the milk production quantity from the re-initiation milk production is higher than milk production quantity before treatment by 6%.
  • the milk production quantity from the re-initiation milk production is higher than milk production quantity before treatment by 7%. In another embodiment, the milk production quantity from the re-initiation milk production is higher than milk production quantity before treatment by 8%. In another embodiment, the milk production quantity from the reinitiation milk production is higher than milk production quantity before treatment by 9%. In another embodiment, the milk production quantity from the re-initiation milk production is higher than milk production quantity before treatment by 10%.
  • the milk production quantity from the re-initiation milk production is higher than milk production quantity before treatment by more than 10%.
  • milk production quantity before treatment comprises milk production quantity up to 60 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity 60 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity up to 30 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity 30 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity up to 25 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity 25 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity up to 20 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity 20 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity up to 15 days after treatment.
  • milk production quantity before treatment comprises milk production quantity 15 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity up to 14 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity 14 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity 12 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity 10 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity 8 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity 7 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity 6 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity 5 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity 4 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity 3 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity 2 days after treatment. In another embodiment, milk production quantity before treatment comprises milk production quantity 1 day after treatment.
  • a method for continuous milk production and milking in lactating mammals during lactation comprising administering to the lactating mammals a composition comprising at least one milk-derived protein, wherein the milking is from an untreated single or plurality of udder quarters.
  • a method for continuous milk production and milking in lactating mammals during lactation comprising administering to the lactating mammals a composition comprising at least one milk-derived protein, wherein the milking is from an untreated single or plurality of udder quarters.
  • IMI intramammary infection
  • the sub-clinical disease comprises increased somatic cell count in milk, increased milk electrical conductivity, reduction in milk quantity or any combination thereof. In one embodiment, the sub-clinical disease comprises increased somatic cell count in milk. In another embodiment, the sub-clinical disease comprises increased milk electrical conductivity. In another embodiment, the sub-clinical disease comprises reduction in milk quantity. In another embodiment, the sub-clinical disease comprises increased somatic cell count in milk, increased milk electrical conductivity and reduction in milk quantity.
  • the increased somatic cell count in milk, increased milk electrical conductivity, reduction in milk quantity or any combination thereof are a result of uninfected or infected udder quarters.
  • the increased somatic cell count in milk is a result of uninfected or infected udder quarters.
  • the increased milk electrical conductivity is a result of uninfected or infected udder quarters.
  • the reduction in milk quantity is a result of uninfected or infected udder quarters.
  • the increased somatic cell count in milk, increased milk electrical conductivity and reduction in milk quantity are a result of uninfected or infected udder quarters.
  • a method for continuous milk production and milking in lactating mammals during lactation comprising administering to the lactating mammals a composition comprising at least one milk-derived protein, wherein the milking is from an untreated single or plurality of udder quarters.
  • a method for continuous milk production and milking in lactating mammals during lactation comprising administering to the lactating mammals a composition comprising at least one milk-derived protein, wherein the milking is from an untreated single or plurality of udder quarters.
  • a method for continuous milk production and milking in lactating mammals during lactation comprising administering to the lactating mammals a composition comprising at least one milk-derived protein, wherein the milking is from an untreated single or plurality of udder quarters.
  • a method for continuous milk production and milking in lactating mammals during lactation wherein somatic cell count in milk, milk electrical conductivity or combination thereof are increased and wherein milk quantity is reduced from one single quarter or a plurality of quarters, comprising administering to the lactating mammals a composition comprising at least one milk-derived protein, wherein the milking is from an untreated single or plurality of udder quarters.
  • the somatic cell count in milk is about 100,000 cells per ml or over. In another embodiment, the increase in somatic cell count in milk is about 150,000 cells per ml or over. In another embodiment, the increase in somatic cell count in milk is about 180,000 cells per ml or over. In another embodiment, the increase in somatic cell count in milk is about 1 million cells per ml or over. In another embodiment, the increase in somatic cell count in milk is about 5 million cells per ml or over. In another embodiment, the increase in somatic cell count in milk is about 10 million cells per ml or over.
  • a method for continuous milk production and milking in lactating mammals during lactation comprising administering to the lactating mammals a composition comprising at least one milk-derived protein.
  • a method for continuous milk production and milking in lactating mammals during lactation comprising administering to the lactating mammals a composition comprising at least one milk-derived protein, wherein the comfort during milking is increased.
  • the term "comfort” refers to the prevention of suffering and increasing the presence of positive feelings, usually called comfort or pleasure, resulting from, inter alia, an increase lying periods, an increase in ruminating time, a decrease in metabolic need, a decrease in udder pressure and/or teat leakage, decrease in incidence of mastitis and other diseases, and decrease in lameness effect due to high milk yield.
  • a method for continuous milk production and milking in lactating mammals during lactation comprising administering to the lactating mammals a composition comprising at least one milk-derived protein, wherein the period of treatment is at any stage of lactation, including drying off to one or plurality of udder quarters.
  • the increase of milk electrical conductivity is about 3.0 milliSiemens (mS) or more at 25 °C, from a single or multiple measures during an interval of hour up to several months between each.
  • the increase of milk electrical conductivity is about 4 milliSiemens (mS) or more at 25 °C.
  • the increase of milk electrical conductivity is about 5 milliSiemens (mS) or more at 25 °C.
  • the increase of milk electrical conductivity is about 6 milliSiemens (mS) or more at 25 °C.
  • the increase of milk electrical conductivity is about 7 milliSiemens (mS) or more at 25 °C.
  • the increase of milk electrical conductivity is about 8 milliSiemens (mS) or more at 25 °C. In another embodiment, the increase of milk electrical conductivity is about 9 milliSiemens (mS) or more at 25 °C. In another embodiment, the increase of milk electrical conductivity is about 10 milliSiemens (mS) or more at 25 °C.
  • a method for continuous milk production and milking in lactating mammals during lactation comprising administering to the lactating mammals a composition comprising at least one milk-derived protein.
  • the bacteriology is positive in a single or multiple measures. In one embodiment, the bacteriology is positive in one single quarter or a plurality of quarters.
  • the positive bacteriology in one single quarter or a plurality of quarters is associated with reduction of milk.
  • the reduction of milk production is by at least 2% compared to milk production from negative bacteriology in one single quarter or a plurality of quarters.
  • the reduction of milk production is by at least 10% compared to milk production from negative bacteriology in one single quarter or a plurality of quarters.
  • the reduction of milk production is by 10-50% compared to milk production from negative bacteriology in one single quarter or a plurality of quarters.
  • the reduction of milk production is by 10% compared to milk production from negative bacteriology in one single quarter or a plurality of quarters.
  • the reduction of milk production is by 20% compared to milk production from negative bacteriology in one single quarter or a plurality of quarters. In another embodiment, the reduction of milk production is by 23% compared to milk production from negative bacteriology in one single quarter or a plurality of quarters. In another embodiment, the reduction of milk production is by 25% compared to milk production from negative bacteriology in one single quarter or a plurality of quarters. In another embodiment, the reduction of milk production is by 30% compared to milk production from negative bacteriology in one single quarter or a plurality of quarters. In another embodiment, the reduction of milk production is by 35% compared to milk production from negative bacteriology in one single quarter or a plurality of quarters.
  • the reduction of milk production is by 40% compared to milk production from negative bacteriology in one single quarter or a plurality of quarters. In another embodiment, the reduction of milk production is by 45% compared to milk production from negative bacteriology in one single quarter or a plurality of quarters. In another embodiment, the reduction of milk production is by 50% compared to milk production from negative bacteriology in one single quarter or a plurality of quarters. In another embodiment, the reduction of milk production is by more than 50% compared to milk production from negative bacteriology in one single quarter or a plurality of quarters.
  • the method comprises administering to the lactating mammals at least one milk-derived protein.
  • the milk-derived protein comprises a casein protein or casein derived peptide.
  • the milk derived protein further comprises P-Lactoglobulin, a-Lactalbumin, Serum albumin, Immunoglobulin G1 (IgGl), Immunoglobulin G2 (IgG2), Immunoglobulin A7 (IgA), Immunoglobulin M(IgM), Secretory component (SC), Lactoferrin (LF) or any combination thereof.
  • Casein is a protein in non-human mammal’ s milk, also found in human mammal’ s milk known to include the subgroups aSl, aS2, p and K. Casein is defined according to the amino acid sequences of each of the subgroups aSl, aS2, p and K. In the context of the present disclosure, when referring to casein, it is to be understood as also including acid casein, salts of casein, phosphorous containing casein and rennet casein.
  • protein refers to amino acid residues, connected by peptide bonds. A protein sequence is generally reported from theN-terminal end containing free amino group to the C-terminal end containing free carboxyl group.
  • Amino acids 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 may 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.
  • the casein-derived peptide may be a single peptide or a mixture of different peptides which may be independently selected from a naturally occurring peptide, a semi -synthetic peptide, a synthetic peptide or a recombinant peptide. It should be further noted that the peptides according to the present disclosure may be produced synthetically, or by recombinant DNA technology, or by any other technology. Methods for producing peptides are well known in the art.
  • the casein-derived peptide may comprise a casein protein breakdown product which occurs when casein protein is cleaved by enzymes or acids to peptide fragments (also known in the art by the term "casein hydrolysate").
  • a casein hydrolysate is to be understood as the hydrolyzed form of casein (protein).
  • Casein hydrolysate includes, for example, the active beta-, alpha S1-, alpha S2-, kappa-caseinderived peptide known to those versed in the art.
  • the casein-derived peptide is or comprises a casein hydrolysate.
  • the casein derived peptide comprises natural peptide, synthetic peptide, semi -synthetic peptide, or any combination thereof.
  • the casein derived peptide comprises a natural peptide.
  • the casein derived peptide comprises a synthetic peptide.
  • the casein derived peptide comprises a semi-synthetic peptide.
  • the casein derived peptide comprises a combination of natural peptide, synthetic peptide and semi-synthetic peptide.
  • Natural casein-derived peptides are typically obtained following enzymatic hydrolysis, the enzyme may be any mammal peptidase, such as, without being limited thereto, plasmin, pancreatin, trypsin, chymotrypsin, neutrase, alcalase, pepsin, carboxypeptidase, cathepsin, as well as plant peptidase such as, without being limited thereto, papain, bromelain, as well as enzymes from microorganism source.
  • a naturally occurring casein-derived peptide may be the result of an enzyme activity such as plasmin on casein subunits P-casein, asl- and as2-casein or K-casein.
  • a casein hydrolysate is obtained by cleavage of the casein protein with trypsin.
  • a synthetic peptide may be obtained by any methods known in the art of peptide synthesis including chemical synthesis and recombinant DNA technology.
  • the peptides may be synthesized by using standard solid phase techniques.
  • the synthetic peptide is a recombinant peptide.
  • a semi-synthetic casein-derived peptide may be obtained by chemical hydrolysis of casein, e.g. by prolonged boiling in a strong acid (acid-HVP) or strong base or using a chemical agent such as Cyanogen bromide (CNBr).
  • the casein -derived peptide may also be obtained by molecular engineering, e.g. using recombinant DNA, in molecular techniques known in the art. In such an embodiment, the casein-derived peptide is a recombinant peptide.
  • the recombinant peptide is produced by fermentation, tissue culture or 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.
  • the tissue culture comprises mammary gland bovine tissue .
  • the casein derived peptide comprises one or more fragments of P-casein, aS 1 -casein, aS2-casein, K-casein or any combination thereof.
  • the casein derived peptide comprises one or more fragments of P-casein.
  • the casein derived peptide comprises one or more fragments of aSl- casein.
  • the casein derived peptide comprises one or more fragments of aS2-casein.
  • the casein derived peptide comprises one or more fragments of K-casein.
  • the casein derived peptide comprises one or more fragments of combination of P-casein, aS 1 -casein, aS2-casein and K-casein.
  • the casein derived peptide further comprises amino acids with different lengths.
  • the casein derived peptide comprises a casein hydrolysate .
  • the casein derived peptide comprises a phosphopeptide .
  • phosphopeptide designates a phosphorylated peptide in form of a conjugated peptide in which the non-peptide portion is a residue of phosphoric acid.
  • phosphopeptide or phosphoserine designates conjugated serine in which the non-peptide portion is a residue of phosphoric acid.
  • the casein-derived peptide is a single peptide or mixture of a phosphopeptide, namely, which contains a single phosphorous group or is a phosphorus- enriched peptide.
  • the casein-derived peptide is any phosphoserine, phosphotyrosine, phosphothreonine, and/or phosphohystidine-enriched casein-derived peptides (casein phosphopeptide, CPP) and monovalent cation phosphocaseinates, such as sodium, potassium, calcium or ammonium phosphocaseinates.
  • the casein-derived peptide is a phosphor-peptide.
  • the phosphor-peptide may be genetically engineered casein-derived peptides as well as peptidomimetics of casein-derived peptides. For example, phosphorylation of amino acids such as at least one serine residue may be performed by any method as is known in the art.
  • casein-derived peptide also encompasses peptide fragments or peptidomimetic products obtained from or corresponding to one or more sections of casein protein.
  • the peptidomimetic peptide may be for example a peptoid or a semipeptoid, which are peptide analogs, having, for example, modifications such as, but are not limited to, cyclization, N-terminus modification, C-terminus modification, peptide bond modification, including, but not limited to, CH 2 -NH, CH 2 -S, CH 2 -S-O, O-C-NH, CH 2 -O, CH 2 -CH 2 , S-C- NH, CH-CH or CF-CH, backbone modification and residue modification.
  • modifications such as, but are not limited to, cyclization, N-terminus modification, C-terminus modification, peptide bond modification, including, but not limited to, CH 2 -NH, CH 2 -S, CH 2 -S-O, O-C-NH, CH 2 -O, CH 2 -CH 2 , S-C- NH, CH-CH or CF-CH, backbone modification and residue modification.
  • casein-derived peptide further encompasses any derivatives, analogues, variants or homologues of any of the peptides.
  • derivative is used to define amino acid sequences (peptide), with any insertions, deletions, substitutions and modifications to the amino acid sequences (peptide) that do not alter the activity of the original peptides.
  • derivative it is also referred to homologues, variants and analogues thereof, as well as covalent modifications of polypeptides made according to the present invention.
  • the modified, synthetic, semi -synthetic or other types of analogs of the naturally occurring casein-derived peptides are in some embodiments at least 75%, at times 85%, 90%, 95% and even 99% identical (in sequence) to a naturally occurring casein-derived peptide when the two sequences are optimally aligned.
  • any non-natural occurring casein-derived peptide to be used in accordance with the present disclosure may retain at least part of the biological activity of the naturally occurring casein protein.
  • the present disclosure also encompasses homologues of the casein-derived peptide.
  • the term "homologues” is used to define amino acid sequences (peptide) which maintain a minimal homology to the amino acid sequences defined by the invention, e.g. have at least about 65%, at least about 75%, at least about 85%, or at least about 95% overall sequence homology with the amino acid sequence of any of the peptide as structurally defined above, e.g. of a specified sequence.
  • the casein-derived peptide may also include a chemical modification of a naturally occurring peptide, e.g. where one or more amino acids are deleted, substituted or modified, e.g. by removal of a side group, substitution of a side group or the introduction of a chemical group.
  • the chemical modification may 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 similar process.
  • the replacement is a conservative substitution.
  • one or more amino acid residues within a casein sequence is substituted by another amino acid of a similar polarity or charge.
  • the non-polar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan and methionine.
  • the polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine.
  • the positively charged (basic) amino acids include arginine, lysine and histidine.
  • the negatively charged (acidic) amino acids include aspartic acid and glutamic acid. Nonetheless, non-conservative substitutions may also take place as long as it does not significantly change the desired (casein like) biological activity of the resulting caseinderived peptide analog.
  • a casein-derived peptide in accordance with the present disclosure is characterized by a molecular weight of between about an average 100 to an average 10,000 Dalton (e.g. between 2 to 100 amino acids) at times between about an average 100 to an average 7,000 Dalton and at times between an average 1,000 to an average 5,000 Daltons.
  • a casein-derived peptide in accordance with the disclosure is characterized by a length of from 2 to 200, from 2 to 100 amino acids, at times between 4 amino acids to 40 amino acids, at times from 4 amino acids to 30 amino acids, at times 4 amino acids to 10 amino acids, at times between 10 amino acids to 50 amino acids.
  • the casein-derived peptide comprises an amino acid sequence selected form the group consisting of SEQ ID NO. 1 - SEQ ID NO. 26.
  • the phosphopeptide comprises an amino acid sequence denoted 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 denoted herein as Ser(p) or S(p)).
  • the phosphopeptide comprises an amino acid sequence denoted 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.
  • the phosphopeptide comprises an amino acid sequence denoted as Ser(p)-Ser(p)-Ser(p)-Glu-Glu (SEQ ID NO:3).
  • the phosphopeptide comprises an amino acid sequence denoted as RELEELNVPGEIVES(p)LS(p)S(p)S(p)EESITR (SEQ ID NON).
  • the phosphopeptide comprises an amino acid sequence denoted as QMEAESIS(p)S(p)S(p)EEIVPDSVEQK (SEQ ID NO:5).
  • the phosphopeptide comprises an amino acid sequence denoted as
  • the phosphopeptide comprises an amino acid sequence denoted as
  • the phosphopeptide comprises an amino acid sequence denoted as
  • the phosphopeptide comprises an amino acid sequence denoted as
  • the phosphopeptide comprises an amino acid sequence denoted as
  • the phosphopeptide comprises an amino acid sequence denoted as QMEAES(p)IS(p)S(p)S(p)EEIVPNS(p)VEQK (SEQ ID NO: 11).
  • the phosphopeptide comprises an amino acid sequence denoted as KNTMEHVS(p)S(p)S(p)EESIIS(p)QETYK (SEQ ID NO: 12).
  • the phosphopeptide comprises an amino acid sequence denoted as
  • the phosphopeptide comprises an amino acid sequence denoted as
  • the phosphopeptide comprises an amino acid sequence denoted as ELEELNVPGEIES(p)LS(p)S(p)S(p)EESITR(SEQ ID NO: 15).
  • the phosphopeptide comprises an amino acid sequence denoted as Xi( n )- Ser(P)-Ser(P)-Ser(P)-X2(m) (SEQ ID NO: 16), wherein at least one of Xi and X2 is independently selected from a positively charged amino acid and wherein each one of n and m is independently selected from 0, 1 and 2.
  • 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 some other embodiments, the positively charged amino acid is arginine. In some other embodiments, the positively charged amino acid is histidine.
  • the formula of SEQ ID NO:16 further comprises a blocking group (also denoted herein as a protecting group) at the C-terminus.
  • a blocking group also denoted herein as a protecting group
  • the carboxyl group at the C terminus of the peptide is protected with 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 with a primary amine (NH2), secondary amine, or tertiary amine) or ester (i.e. the hydroxyl group at the C terminus is replaced with an ester).
  • the blocking group is selected from the group consisting of amide and ester.
  • the blocking group is amide.
  • the phosphopeptide comprises an amino acid sequence denoted as Lys-Lys-Ser(P)-Ser(P)-Ser(P) (SEQ ID NO: 17). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Lys-Lys-Ser(P)-Ser(P)- Ser(P)-Lys (SEQ ID NO: 18). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Lys-Lys-Ser(P)-Ser(P)-Ser(P)-Lys-Lys (SEQ ID NO: 19).
  • the phosphopeptide comprises an amino acid sequence denoted as Lys-Ser(P)- Ser(P)-Ser(P)-Lys-Lys (SEQ ID NO:20). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Lys- Ser(P)-Ser(P)-Ser(P)- Lys (SEQ ID NO:21). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Lys-Ser(P)-Ser(P)-Ser(P) (SEQ ID NO:22).
  • the phosphopeptide comprises an amino acid sequence denoted as Ser(P)-Ser(P)-Ser(P)- Lys-Lys (SEQ ID NO:23). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Ser(P)-Ser(P)-Ser(P)-Lys (SEQ ID NO:24). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Lys-Lys- Ser(p)-Ser(p)-Ser(p)-NH2 (SEQ ID NO:25). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as RELEELNVPGEIVES(p)LS(p)S(p)S(p)EESITRINK (SEQ ID NO:26).
  • the casein-derived peptide according to the invention may comprise “L” as well as “D” form residues. While the amino acid residues of the peptide sequences set forth in SEQ ID NOs: l-26 are all in the "L” isomeric form, residues in the "D" isomeric form can substitute any L-amino acid residue so long as the resulting peptide analog retains at least part 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 stability of the peptide to proteolytic degradation.
  • the composition is free of antimicrobials and comprises an acceptable carrier .
  • the milk derived protein is measured by UV at a range from 204 to 220 nm.
  • the methods of the present disclosure comprise administering between lOng/ml to 500mg/ml of the milk derived protein. In one embodiment, the methods of the present disclosure comprise administering between Img/ml to 500mg/ml of the milk derived protein. In another embodiment, the methods of the present disclosure comprise administering between lOmg/ml to 450mg/ml of the milk derived protein. In another embodiment, the methods of the present disclosure comprise administering between 50mg/ml to 400mg/ml of the milk derived protein. In another embodiment, the methods of the present disclosure comprise administering between 50mg/ml to 70mg/ml of the milk derived protein.
  • the methods of the present disclosure comprise administering between lOOmg/ml to 350mg/ml of the milk derived protein. In another embodiment, the methods of the present disclosure comprise administering between 150mg/ml to 300mg/ml of the milk derived protein. In another embodiment, the methods of the present disclosure comprise administering between 200mg/ml to 250mg/ml of the milk derived protein. In another embodiment, the methods of the present disclosure comprise administering between 5mg/ml to 30mg/ml of the milk derived protein.
  • the methods of the present disclosure comprise intramammary infusion to a single teat or a plurality of teats. In one embodiment, the methods of the present disclosure comprise intramammary infusion to a single teat. In another embodiment, the methods of the present disclosure comprise intramammary infusion to a plurality of teats.
  • the methods of the present disclosure comprise between one to eight administrations. In one embodiment, the methods of the present disclosure comprise one administration. In one embodiment, the methods of the present disclosure comprise two administrations. In one embodiment, the methods of the present disclosure comprise three administrations. In one embodiment, the methods of the present disclosure comprise four administrations. In one embodiment, the methods of the present disclosure comprise five administrations. In one embodiment, the methods of the present disclosure comprise six administrations. In one embodiment, the methods of the present disclosure comprise seven administrations. In one embodiment, the methods of the present disclosure comprise eight administrations.
  • the administrations of the present disclosure comprise intervals of from about 1 hour to about 72 hours . In one embodiment, the administrations comprise intervals of about 1 hour. In one embodiment, the administrations comprise intervals of about 4 hours. In one embodiment, the administrations comprise intervals of about 5 hours. In one embodiment, the administrations comprise intervals of about 8 hours. In one embodiment, the administrations comprise intervals of about 10 hours. In one embodiment, the administrations comprise intervals of about 12 hours. In one embodiment, the administrations comprise intervals of about 15 hours.
  • the administrations comprise intervals of about 16 hours, In one embodiment, the administrations comprise intervals of about 20 hours, In one embodiment, the administrations comprise intervals of about 24 hours, In one embodiment, the administrations comprise intervals of about 25 hours, In one embodiment, the administrations comprise intervals of about 28 hours, In one embodiment, the administrations comprise intervals of about 30 hours, In one embodiment, the administrations comprise intervals of about 35 hours, In one embodiment, the administrations comprise intervals of about 36 hours, In one embodiment, the administrations comprise intervals of about 40 hours, In one embodiment, the administrations comprise intervals of about 45 hours, In one embodiment, the administrations comprise intervals of about 50 hours, In one embodiment, the administrations comprise intervals of about 55 hours, In one embodiment, the administrations comprise intervals of about 60 hours, In one embodiment, the administrations comprise intervals of about 65 hours, In one embodiment, the administrations comprise intervals of about 70 hours. In one embodiment, the administrations comprise intervals of about 72 hours.
  • the administrations of the present disclosure comprise immediate administrations of a double dose.
  • the lactating mammals continue milk production and milking from untreated single or plurality of udder quarters. In one embodiment, the lactating mammals continue milk production and milking from untreated single udder quarter. In another embodiment, the lactating mammals continue milk production and milking from untreated plurality of udder quarters.
  • the milk is essentially free of residues.
  • the residues comprise antibiotic residues.
  • the milk can be used as raw milk, for dairy production, for breastfeeding or any combination thereof .
  • the milk can be used as a raw milk.
  • the milk can be used for dairy production.
  • the milk can be used for breastfeeding.
  • the milk can be used as a raw milk, for dairy production and for breastfeeding.
  • the dairy product comprises milk, whey, yogurt, cheese, cream, butter, milk drinks with high protein or combination thereof .
  • the dairy product comprises milk.
  • the dairy product comprises whey.
  • the dairy product comprises yogurt.
  • the dairy product comprises cheese.
  • casein generally refers to a family of related proteins (aSl, aS2, P, K) commonly found in mammalian milk.
  • treatment concerns improvement of at least one undesired manifestation of the disease such as increase in disease free periods, decrease in acute disease periods (in time and severely), decrease in severity of the disease, improvement in life quality, improvement in comfort and welfare, decreased mortality, decrease in the rate of disease progression as well as prophylactic treatment before disease occurs. More specifically, the term “treatment or prevention” as used herein, refers to the complete range of therapeutically positive effects of administrating to a subject including inhibition, reduction, alleviation and relief from a disorder or any related condition and illness, symptoms or undesired side effects or related disorders.
  • the term “reduction” or as referred to herein relate to the retardation, restraining or reduction of a process by any one of about 1% to 99.9%, about 1% to about 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, about 75% to 80%, about 80% to 85% about 85% to 90%, about 90% to 95%, about 95% to 99%, or about 99% to 99.9%.
  • the term “average molecular weight” refers to the mean plus or minus standard deviation of the molecular weight of the peptide or protein as measured by a method known to a person skilled in the art. Such methods include, for example, SDS-gel electrophoresis and size exclusion chromatography in an apparatus such as HPLC, wherein the sample is run against Standards with known molecular weight.
  • Example 1 Inducing a short non-milking period in infected teats, followed by re-initi- ation of milk production from the infected teat during the same lactation.
  • the objective is to determine the cure of intramammary infection during lactating period, by intramammary administration of casein protein or casein-derived peptides followed by re-initiation of milk production from the infected teat during the same lactation.
  • Dairy cows were eligible for inclusion in the study with positive bacteriology results for the same pathogens from two bacteriological milk samples in conjunction with elevated quarter somatic cell count (QSCC) > 200,000 cells/ml, the last from one pre-treatment (last milking) sample.
  • QSCC quarter somatic cell count
  • Dairy cows were not eligible for inclusion in the study if they were in the herd less than 3 months, lactating less than 30 days from estimated dry-off day, less than 3 functional udder quarters, any antimicrobial, hormone, an anti-inflammatory medication has been administrated within 10 days before inclusion in the study, or in the Investigator’s opinion. Animals after treatment were maintained in their regular housing according to standard farming practices during lactation. Cows were regularly milked from the untreated quarters. During treatment and follow-up periods dairy cows are housed, feed and managed as per standard farm practice.
  • a physical examination of the cow included rectal temperature, pulse, respiratory rate.
  • Safety assessment parameters were registered from general clinical examination and clinical observation, and by farm staff informing of the cow on feed intake of the cow and water intake.
  • Milk samples for bacteriology tests were collected separately from all quarters or the target udder quarter as summarized in the below Table 1 ‘Study Schedule of Events’. Milk samples for bacteriology tests were collected into sterile 30 ml tubes. The volume of milk collected was approximately 5 ml.
  • Milk samples for SCC were collected separately from all quarters once before treatment as summarized in the below Table 1 - ‘Study Schedule of Events’. Milk samples, for SCC, were collected into 55 ml tubes. The volume of milk collected was approximately 35 ml.
  • the laboratory provided laboratory results to the Investigator.
  • SCC somatic cell counts.
  • Treatment (T2) and controls (Tl) were randomly selected, the treatment group (T2) was treated with the investigational product in the infected and eligible udder quarter with one intramammary infusion of casein protein or casein-derived peptides. Treatment was carried out after post-milking procedure. Before treatment the teats were thoroughly cleaned and disinfected before each infusion.
  • Cow’s treated quarters were not milked following the intramammary administration. After seven days of milking intermission, milking was re-initiated. The rest of the quarters (healthy quarters) and the untreated control (Tl) quarter were milked regularly.
  • the treatment unit and the statistical unit was the individual quarter. At least a total of 10 cows per treatment group were enrolled (including drop-out). Results and Conclusion
  • NAS non-aureus staphylococci
  • results from both bacteriology culture tests performed at days 7 and 14 post-treatment indicated negative for 8 out of 10 received casein protein or caseinderived peptides, compared to 3 out of 10 in untreated controls (below Table 2).
  • the present high cure results provide an advantage in management of lactating animals as it is safe, increases comfort, no discarded milk following treatment, and no use of antimicrobials.
  • Example 2 Inducing a short non-milking period in infected teats, followed by re-initi- ation of milk production from the infected teat during the same lactation.
  • the objectives of the present example were to determine whether lactation function from an individual udder quarter could be reinitiated after induced involution by intramammary administration of casein protein or casein-derived peptides without affecting or increasing the milk quality and production.
  • Dairy cows allocated to Example 1 were participants in the current multicenter case-controlled study.
  • Table 5 Composite Somatic Cell Counts from Dairy Cows Receiving Casein Protein or Casein-derivate Peptides by Trial Periods (expressed in ‘000 cells/ml).
  • Treatment group during lactation indicated a decrease of composite SCC in the immediate posttreatment time after reinstating the milking process.
  • Examples 1 and 2 showed that treatment with casein protein or casein-derivate peptides enable a re-initiation of milking within 7 days post treatment and exhibited a significant economic value by decreasing somatic cell and increasing milk yield.

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Abstract

La présente invention concerne des compositions et des procédés pour traiter une infection intramammaire chez des mammifères en lactation pendant la lactation et fournir une production de lait et une traite continue chez des mammifères en lactation pendant la lactation, le nombre de cellules somatiques dans le lait, la conductivité électrique du lait ou une combinaison de ceux-ci étant augmentés.
PCT/IL2023/051181 2022-11-17 2023-11-15 Compositions et procédés de modulation de troubles et d'états mammaires Ceased WO2024105668A1 (fr)

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EP23813896.0A EP4619011A1 (fr) 2022-11-17 2023-11-15 Compositions et procédés de modulation de troubles et d'états mammaires
CN202380086612.4A CN120379680A (zh) 2022-11-17 2023-11-15 用于调节乳腺病症和病状的组合物和方法
JP2025528504A JP2025537820A (ja) 2022-11-17 2023-11-15 乳房の障害および状態を調節するための組成物および方法
AU2023380303A AU2023380303A1 (en) 2022-11-17 2023-11-15 Compositions and methods for modulating mammary disorders and conditions
MX2025005671A MX2025005671A (es) 2022-11-17 2025-05-14 Composiciones y métodos para modular trastornos y afecciones mamarias

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Citations (3)

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US6391849B1 (en) * 1999-11-19 2002-05-21 Agricultural Research Organization, The Volcani Center Method and pharmaceutical composition for disrupting lactation in a mammary gland and for treating and preventing mastitis
WO2006117784A2 (fr) * 2005-05-02 2006-11-09 Mileutis Ltd. Compositions pharmaceutiques comprenant des peptides derives de caseine et procedes d'utilisation de celles-ci
WO2011132191A1 (fr) * 2010-04-21 2011-10-27 Mileutis Ltd. Peptide de caséine utilisé pour traiter des infections utérines

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Publication number Priority date Publication date Assignee Title
US6391849B1 (en) * 1999-11-19 2002-05-21 Agricultural Research Organization, The Volcani Center Method and pharmaceutical composition for disrupting lactation in a mammary gland and for treating and preventing mastitis
WO2006117784A2 (fr) * 2005-05-02 2006-11-09 Mileutis Ltd. Compositions pharmaceutiques comprenant des peptides derives de caseine et procedes d'utilisation de celles-ci
WO2011132191A1 (fr) * 2010-04-21 2011-10-27 Mileutis Ltd. Peptide de caséine utilisé pour traiter des infections utérines

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PURBA FIKA YULIZA ET AL: "Effect of temporary cessation of milking and estradiol combination on the antimicrobial components in goat milk", RESEARCH IN VETERINARY SCIENCE, BRITISH VETERINARY ASSOCIATION, LONDON, GB, vol. 152, 8 September 2022 (2022-09-08), pages 387 - 394, XP087221049, ISSN: 0034-5288, [retrieved on 20220908], DOI: 10.1016/J.RVSC.2022.09.006 *
PYÃ RÃ LÃ S: "Treatment of mastitis during lactation", IRISH VETERINARY JOURNAL, BIOMED CENTRAL LTD, LONDON, UK, vol. 62, no. Suppl 4, 1 April 2009 (2009-04-01), pages S40 - 44, XP021097530, ISSN: 2046-0481, DOI: 10.1186/2046-0481-62-S4-S40 *
SHOSHANI EZRA ET AL: "Effects of bovine casein hydrolysate as a dry cow therapy on prevention and cure of bovine intramammary infection, milk production, and somatic cell count in the subsequent lactation", JOURNAL OF DAIRY SCIENCE, AMERICAN DAIRY SCIENCE ASSOCIATION, US, vol. 105, no. 5, 10 March 2022 (2022-03-10), pages 4354 - 4369, XP087031129, ISSN: 0022-0302, [retrieved on 20220310], DOI: 10.3168/JDS.2021-20703 *

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