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WO1993010818A1 - Preparation lactee pour nouveau-nes et additif pour cette preparation - Google Patents

Preparation lactee pour nouveau-nes et additif pour cette preparation Download PDF

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Publication number
WO1993010818A1
WO1993010818A1 PCT/US1992/010432 US9210432W WO9310818A1 WO 1993010818 A1 WO1993010818 A1 WO 1993010818A1 US 9210432 W US9210432 W US 9210432W WO 9310818 A1 WO9310818 A1 WO 9310818A1
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WO
WIPO (PCT)
Prior art keywords
iga
antibodies
iga protease
infant formula
colostrum
Prior art date
Application number
PCT/US1992/010432
Other languages
English (en)
Inventor
Andrew G. Plaut
Original Assignee
New England Medical Center Hospitals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by New England Medical Center Hospitals, Inc. filed Critical New England Medical Center Hospitals, Inc.
Publication of WO1993010818A1 publication Critical patent/WO1993010818A1/fr

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to infant formulas and infant formula additives that help protect against infection.
  • the maternal/infant collaboration consists of initial "passive" antibodies from the mother's milk during the period in which the child's secretory immune system matures, and then the child's own “active" antibodies.
  • Bacterial colonization involves the attachment and proliferation of bacteria to mucosal surfaces—often harmlessly. Under certain circumstances these microorganisms can cause disease. Certain bacteria that colonize and infect infants continuously secrete IgA proteases that can cleave both maternal and infant IgA. For example, all strains of Hemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae produce these IgA proteases, and cause serious infections in children (otitis media, pneumonia, bronchitis, sinusitis, septicemia and meningitis) . Such infections are a major problem in all countries and even in major U.S. cities.
  • IgA proteases cleave and inactivate human IgA on mucosal surfaces and in this way allow bacterial pathogens to evade the mucosal immune mechanisms.
  • IgA cleavage not only impairs function by dissociating the Fab and Fc regions of IgA, but free Fab fragments may also bind key microbial antigens, blocking access by other protective antibodies. It is important to note, however, that bacteria often colonize the infant ucosa without causing illness, and these strains all produce IgA protease as well. It is not clearly known what events can cause a previously colonizing organism to give rise to clinical illness.
  • Human milk inhibits IgA proteases, thereby protecting the IgAl of both mother and child.
  • the inhibitor is itself a secretory antibody.
  • the invention features an infant formula and infant formula additives that include IgA protease inhibitors, e.g., antibodies, that protect infants that drink the formula from infections caused by bacteria that produce IgA proteases and possibly other infectious agents, e.g., viruses, whose control by mucosal immunity in the upper respiratory tract may depend on IgA.
  • IgA protease inhibitors e.g., antibodies
  • Other inhibitors include peptides such as the protease inhibitors described in U.S. Patent No. 4,935,493, which is incorporated herein by reference.
  • the term "infant formula” includes colostral or other milk preparations that include the inhibitors or antibodies of the invention as well as purified inhibitors that are fed to an infant orally in any other suitable beverage.
  • antibody includes not only complete antibodies but i munologically-active fragments thereof, which include any antibody fragments that are effective, e.g, to inhibit IgA protease activity.
  • the invention features an infant formula including non-human milk which contains an IgA protease antibody, e.g., bovine IgG.
  • the non-human milk may be, e.g., cow's milk.
  • the invention also features a method of preparing an infant formula by immunizing a non-human mammal with an IgA protease; collecting milk including IgA protease antibodies from the mammal; and using the milk to prepare the infant formula.
  • the immunization is done during the last month of gestation and the collected milk comprises colostrum.
  • protease includes not only the complete protease but immunologically-active fragments thereof, which include any peptide fragments that give rise to antibodies, e.g., against IgA protease, when used as an immunogen.
  • the invention also features a method of producing n ⁇ n-human milk that protects against IgA protease producing pathogens by immunizing a non-human mammal with an IgA protease, and collecting milk from the mammal comprising IgA protease antibodies.
  • the invention further features a method of producing an infant formula additive by immunizing a pregnant non-human mammal during the last month of gestation; collecting colostrum from the mammal after parturition; and, preferably, removing fat and casein from the colostrum to produce the infant formula additive.
  • this method includes the step of reducing the volume of the colostrum by filtering through a 100,000 M filter.
  • the bovine IgA protease antibodies can be purified from the colostrum and used directly as the formula additive.
  • FIG. 1 is a schematic diagram of the primary structure of the heavy chain hinge region of human IgAl (SEQ ID NO: 1) and the most common allotype of IgA2 (SEQ ID NO: 2) .
  • Fig. 2 is a graph showing the difference in inhibiting titre against various IgA proteases having the same or different serogroups as the immunizing enzyme.
  • Fig. 3 is a graph showing the difference in inhibiting titre against various IgA proteases having different cleavage types.
  • Fig. 4A is an autoradiogram of an electrophoresis gel showing the activity of IgA protease when added to infant formulas.
  • Fig. 4B is an autoradiogram of an electrophoresis gel showing the inactivity of IgA protease when added to infant formulas supplemented with the bovine antibodies of the invention.
  • IgA proteases are encoded as a single large polypeptide chain by iga genes in the bacterial chromosome. The proteases are secreted from bacterial cells by an enzymatic mechanism. It is believed that the IgA protease inhibitors, e.g., antibodies, of the invention could block this enzymatic mechanism as one way of preventing the proteolytic effect of these proteases. Moreover, it is clear that the IgA protease antibodies of the invention block the proteolytic mechanism of the mature proteases. Human IgAl antibodies are the only known substrate for these proteases. Fig.
  • Fig. 1 shows the primary structure of the so-called “hinge region" of the heavy amino acid chain of human IgAl (SEQ ID NO: 1) and the most common allotype of IgA2 (SEQ ID NO: 2) .
  • the I markers indicate 0-1inked oligosaccharides.
  • the residue numbers are based on P.N.A.S. , U.S.A. , 16:1104-08 (1979) .
  • Fig. 1 also shows the cleavage points along the IgA chain of IgA proteases produced by a variety of bacteria.
  • a non-human mammal e.g., a cow
  • a non-human mammal e.g., a cow
  • bovine immunization to obtain milk containing antibodies is preferably performed as follows.
  • the cow transfers a very large amount of circulating, plasma IgG into its udder.
  • a parenteral (subcutaneous, intramuscular, etc.) injection of an IgA protease is preferably made during this period to stimulate high levels of circulating (plasma) antibody that eventually are transferred to the colostrum.
  • This colostrum is then processed by conventional methods to produce the infant formula or formula additive.
  • a newborn human infant drinks the formula containing the antibody, it protects the infant's mucosa in all of the areas where the milk normally contacts the mucosa, i.e., the oral cavity, nasopharynx, bronchial passages, and intestine.
  • Example 1
  • Pregnant cows were injected three times with IgA proteases mixed with one mg of the adjuvant Quil A. Injections were given approximately 30, 14 and 7 days before expected calving.
  • the maternal colostrum (approximately nine liters) was collected (bovine colostral whey proteins typically consist of 40% immunoglobulins, 35% beta-lactoglobulin, 15% lactalbumin and small amounts of albumin and other proteins) .
  • the colostrum was centrifuged at 12,000xG at a temperature of 4°C for 30 minutes to remove the fat (which floats to the top) . The colostrum can be frozen at this point. The colostrum is further processed to remove casein.
  • the fluid was 3-fold diluted with normal sterile saline, and the casein was precipitated by adjusting the pH to 4.75 with concentrated HCl.
  • the material was centrifuged again for 25 minutes at 12,000xG in the cold to sediment the casein.
  • the supernatant fluid containing the antibody proteins of the colostrum can be frozen at this point also.
  • the fluid is passed through a 100,000 MW cutoff membrane using a Millipore Pelicon System.
  • the antibody is retained, and volume is reduced 10-fold. No preservatives need to be added.
  • Monoclonal antibodies directed against bacterial IgA proteases also can be used according to the invention. These antibodies or antibody fragments can be added to infant formulas in the same way as the bovine antibodies or bovine antibody containing colostrum described above.
  • Monoclonal antibodies useful in the invention can be made by immunizing mice with an IgA protease, fusing the murine splenocytes with appropriate myeloma cells, and screening the antibodies produced by the resultant hybridoma lines for the requisite IgA protease binding properties by means of an ELISA assay. A subsequent screening may be necessary to select binding antibodies that also inhibit or remove the protease.
  • Antibody production and screening can be performed according to Uchiyama et al. (J . Immunol . 126:1393, 1981) .
  • useful antibodies may be isolated from a combinatorial library produced by the method of Huse et al. ⁇ Science 246:1275, 1989) .
  • the invention can employ not only intact polyclonal or monoclonal antibodies, but also an immunologically-active antibody fragment, for example, a Fab or (Fab) 2 fragment; an antibody heavy chain, an antibody light chain; a genetically engineered single- chain Fv molecule (Ladner et al., U.S. Patent No. 4,946,778); or a chimeric antibody, for example, an antibody that contains the binding specificity of a murine or bovine antibody, but in which the remaining portions are of human origin.
  • IgA Protease Inhibition Assay A suitable enzyme assay uses human myeloma IgAl imm noglobulin trace labelled with 125 I as a substrate. Fragmentation products of the IgAl heavy chain are measured by first separating these fragments on PAGE gels. Introduction of an inhibitor blocks the IgAl cleavage by the protease.
  • the reaction mixture has a volume of 75 ⁇ L, consisting of 25 ⁇ L stock substrate solution (IgAl) , 25 ⁇ L inhibitor, e.g., a colostrum dilution containing the IgA protease antibody (or a buffer control) , and 25 ⁇ L active IgA protease (Hemophilus. Neisseria or Streptococcal species, but any IgA protease can be used) . After the enzyme and inhibitor were preincubated for 30 minutes at 37°C to allow them to interact, the IgAl substrate was added, and "incubation continued at the same temperature.
  • IgAl stock substrate solution
  • inhibitor e.g., a colostrum dilution containing the IgA protease antibody (or a buffer control)
  • active IgA protease Hemophilus. Neisseria or Streptococcal species, but any IgA protease can be used
  • the developed autoradiograph was used as a template for cutting the stained and dried gel into segments consisting of 1) any uncleaved IgA heavy chain and 2) the Fd alpha fragment representing that portion of the heavy chain within the Fab fragment digestion product. Radioactivity in the uncleaved heavy chain and in its Fd product were counted on a Beckman Biogamma Counter, background counts from control digests were subtracted from each value, and quantitation of IgA protease activity was expressed as a percentage of the heavy chain that has been cleaved using the formula:
  • a typical inhibition assay from the colostrum of one cow is shown below. This cow was immunized with non- encapsulated Hemophilus influenzae type 1 protease, and inhibitory titers were done against this enzyme:
  • Neisseria gonorrhoeae type 2 2,500
  • Hemophilus influenzae serotype E type 2....5, 000
  • Hemophilus influenzae serotype B type 1 0 Streptococcus sanquis 0
  • IgA protease the lack of an antibody to the Hemophilus serotype B strain IgA protease was a chance occurrence, i.e., the cow did not . respond with antibody formation.
  • S ⁇ _ san ⁇ uis there is a possibility that it is an inherently non-antigenic enzyme.
  • Inhibition of enzymes other than the one used for immunization is generally at least one order of magnitude lower; that is, there is little cross-reactivity. Consequently, to produce an antibody effective to block a number of IgA proteases, each of those IgA proteases will have to be used for immunization, either as part of an antigenic mixture, or individually. These proteases are known and are publicly available. In the event that antigenic mixtures in the same cow do not yield sufficiently high titers, antibodies to each protease raised in individual cows can be combined for addition to the infant formula.
  • bovine colostral antibodies of the invention differ in inhibiting titre against various IgA proteases.
  • Fig. 2 shows that enzymes from strains sharing the same serogroup with that of the source of the immunizing enzyme are better inhibited.
  • Fig. 3 shows that enzymes having the same cleavage type as that of the im unogen are better inhibited.
  • a number of enzymes may have to be used to immunize each cow to assure that all, e.g., Haemophilus, proteases are fully blocked.
  • antibodies may be combined from cows immunized with each protease for addition to infant formula.
  • Fig. 2 shows the results of an experiment with cow # 1 which was immunized with Haemophilus influenzae type 1 IgA protease from strain Rd-.
  • the enzymes studied were all from Haemophilus strains designated Hi; serogroup B (HiB) , C (HiC) , E (HiE) , F (HiF) , and two serogroup D strains (HiD2 and HiD3) , in addition to the Rd- strain (HiRd-) .
  • the number in parentheses (1 or 2) describes the enzyme type, that is, which peptide bond the enzyme attacks in the IgAl heavy chain.
  • IgA protease activity (ordinate) as a function of the dilution of cow colostrum antibody to which it was added.
  • the protease used for immunization (curve starred *) retained about 50% activity in colostrum diluted to 1:2,100.
  • the protease in Haemophilus influenzae serogroup F (open squares) is much less inhibited, retaining about 50% activity at a colostral dilution of 1:100.
  • Fig. 3 is generally the same as Fig. 2, but shows the results for an experiment in which cow # 236 was immunized with a type 2 enzyme from serogroup HiE (curve starred *) .
  • the three proteases having type 2 specificity were inhibited to a greater extent than the three proteases having type 1 specificity.
  • These curves in Fig. 3 show that in addition to serogroup specificity as shown in Fig. 2, certain of the bovine antibodies of the invention also show more specificity for enzymes of the correct cleavage type. Characterization of Bovine IgA Protease Antibody
  • IgA protease antibody in bovine colostrum is IgG. This was done by .exposing enzymes on Western blots to the colostral preparations as a first antibody, and examining the isotype of the binding antibody by various antibodies against cow serum. Furthermore, chromatography of the inhibiting colostrum on Biogel P200 columns shows that the ability to inhibit co-elutes precisely with the IgG peak.
  • the inhibiting property of bovine colostral IgG is localized in the Fab fragment (as anticipated for an antibody) .
  • Papain enzyme/protein ratio of 1/100 w/w
  • the Fab fragments were isolated by column chromatography on Biogel P100, and identified by their reduced molecular weight (changed elution position) and light chain content as determined by appropriate antisera.
  • This Fab fragment material- was tested as an IgA protease inhibitor, and found to be 2-3 fold less effective than the starting material before proteolysis. Thus, the entire IgG antibody molecule is not required for IgA protease inhibition, although some inhibiting power could be lost by isolation of the monovalent Fab region of the antibody.
  • Non-human antibodies to bacterial ' IgA proteases can be. added to bovine milk-based infant formulas. Like human milk, such formulas will inhibit IgA proteases in the fluids bathing the nasopharynx and upper respiratory passages of the infant. The advantage of such inhibition is that, in general, the child's own IgA will be protected from cleavage by the IgA proteases. Thus, all IgAl antibodies will benefit, not only those directed against the IgA protease producing bacteria themselves.
  • the processed colostrum containing the IgA protease antibodies can be diluted or concentrated and used as an infant formula additive.
  • Standard infant formulas include the Similac® line, of formulas (Ross Laboratories, Columbus, Ohio) and the SMA® line of formulas (Wyeth Laboratories, Philadelphia, Pennsylvania) .
  • the colostrum also can be used undiluted as an infant formula, with or without added nutrients.
  • the bovine antibodies to bacterial IgA proteases can also be purified from the colostrum and added to infant formula directly.
  • Figs. 4A and 4B are autoradiographs of polyacrylamide electrophoresis gels of 125 I-IgAl substrate subjected to IgA protease. These autoradiographs show uncleaved (IgA heavy chain) substrate, and fragments arising from proteolysis (Fab) . In all cases the protease assay was for 30 minutes.
  • Fig. 4A shows that IgA protease is active when added to five commercial infant formulas
  • Fig. 4B shows that the IgA protease is inactive when added to formula supplemented with the inhibiting bovine antibodies of the invention.
  • Fig. 4A shows the gel resulting from Haemophilus influenzae type 1 IgA protease added to a number of commercial infant formulas, along with trace amounts of 125 I-IgA substrate.
  • the top two lanes are controls: the top is substrate without protease, which resulted in no cleavage products; the second lane is substrate and protease in buffer (not formula) to show the basic activity of the protease we added to formula products.
  • the subsequent five lanes show that unmodified formulas cannot affect activity of IgA protease; the Fab fragment is the cleavage product.
  • Fig. 4B shows that the Haemophilus influenzae IgA protease used above in the gel of Fig. 4A is inactive in infant formula (here Nutramigen®) supplemented by an ariti-IgA protease from immune cow colostrum.
  • infant formula here Nutramigen®
  • the bottom two lanes are substrate and enzyme controls.
  • the top four lanes are Nutramigen® formula containing varying amounts of cow # 1 immune colostrum: from top to bottom, the ratio of colostrum:formula (vol:vol) is 1:640, 1:1280,- 1:2560, and 1:5120.
  • the enzyme added to all these dilutions is inactive, as shown by the inability to fragment any 125 I-IgA substrate during 30 minutes.
  • the bovine antibodies of the invention should be fed to an infant, preferably as a formula supplement, at a dosage of about 1.0 to 2.0 grams of inhibitor peptide or bovine colostral antibody protein/kg/day, equally distributed over all feedings.
  • This dosage must be adjusted dependent on the titer of the antibodies in the particular colostral preparation used as the infant formula additive, because different colostrum preparations have different percentages of-the IgA protease antibodies compared to total antibodies in the preparation.
  • Other Embodiments Further embodiments are within the following claims.

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Abstract

Préparation lactée pour nouveau-nés et additif pour cette préparation, comprenant des inhibiteurs d'IgA protéase, par exemple des anticorps, qui protègent les nouveau-nés buvant cette préparation contre les infections provoquées par les bactéries et éventuellement par d'autres agents infectieux, par exemple les virus, dont l'élimination par réaction immunitaire au niveau des muqueuses dans les voies respiratoires supérieures peut dépendre de l'IgA.
PCT/US1992/010432 1991-12-04 1992-12-03 Preparation lactee pour nouveau-nes et additif pour cette preparation WO1993010818A1 (fr)

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US80233891A 1991-12-04 1991-12-04
US802,338 1991-12-04

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995008562A1 (fr) * 1993-09-20 1995-03-30 Anadis Ltd. Procede d'extraction d'immunoglobulines du colostrum et emploi de ces dernieres dans des preparations pharmaceutiques
WO1997005884A1 (fr) * 1995-08-07 1997-02-20 New England Medical Center Hospitals, Inc. Aliment lacte pour nourrissons et additifs correspondants
EP0859552A4 (fr) * 1995-11-08 1999-04-28 Northfield Lab Pty Ltd Colostrum liquide pour produits laitiers
WO1999015198A3 (fr) * 1997-09-23 1999-06-17 Max Planck Gesellschaft Agents pour lutter contre la meningite purulente
WO2006057551A1 (fr) * 2004-11-26 2006-06-01 N.V. Nutricia Aliment pour nourrisson contenant un inhibiteur de protease
GB2507641A (en) * 2012-09-11 2014-05-07 Al Urdonia Lemudaddat Al Ajsam Co Immunized camelid milk for the treatment of skin or mucous membrane infections

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
INFECTION AND IMMUNITY, Volume 57, No. 4, issued April 1989, M. BOESMAN-FINKELSTEIN et al., "Bovine Lactogenic Immunity Against Cholera Toxin-Related Enterotoxins and Vibrio Chlerae Outer Membranes", pages 1227-1234. *
MICROBIAL IMMUNOLOGY, Volume 31, No. 11, issued 1987, K. KOBAYASHI et al., "Resistance of Normal Serum IgA and Secretory IgA to Bacterial IgA Proteases: Evidence for the Presence of Enzyme-Neutralizing Antibodies in Both Serum and Secretory IgA, and Also in Serum IgG", pages 1097-1106. *
XXIII SYMPOSIUM OF THE SWEDISH NUTRITION FOUNDATION, Volume 13, issued 1987, H. HILPERT et al., "Bovine Milk Immunoglobulins (Ig), their Possible Utilization in Industrially Prepared Infant's Milk Formulae", pages 182-195. *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995008562A1 (fr) * 1993-09-20 1995-03-30 Anadis Ltd. Procede d'extraction d'immunoglobulines du colostrum et emploi de ces dernieres dans des preparations pharmaceutiques
US5780028A (en) * 1993-09-20 1998-07-14 Anadis Ltd. Method of obtaining immunoglobulins from colostrum and their use in pharmaceutical composition
WO1997005884A1 (fr) * 1995-08-07 1997-02-20 New England Medical Center Hospitals, Inc. Aliment lacte pour nourrissons et additifs correspondants
EP0859552A4 (fr) * 1995-11-08 1999-04-28 Northfield Lab Pty Ltd Colostrum liquide pour produits laitiers
US6202546B1 (en) 1995-11-08 2001-03-20 Northfield Laboratories Pty. Ltd Liquid colostrum for dairy products
US6248366B1 (en) 1995-11-08 2001-06-19 Northfield Laboratories Pty Ltd. Liquid colostrum for dairy products
WO1999015198A3 (fr) * 1997-09-23 1999-06-17 Max Planck Gesellschaft Agents pour lutter contre la meningite purulente
WO2006057551A1 (fr) * 2004-11-26 2006-06-01 N.V. Nutricia Aliment pour nourrisson contenant un inhibiteur de protease
GB2507641A (en) * 2012-09-11 2014-05-07 Al Urdonia Lemudaddat Al Ajsam Co Immunized camelid milk for the treatment of skin or mucous membrane infections
GB2507641B (en) * 2012-09-11 2017-08-30 Al-Urdonia Lemudaddat Al-Ajsam Co Camel Milk Based Pharmaceutical Composition

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