Treatment of intestinal luminal immunoglobulin deficiency with semisynthetic polyclonal human secretory immunoglobulin A

Abstract

A method for suppressing or correcting symptoms of gastrointestinal antibody deficiency in a subject is provided, comprising orally administering to the subject human polyclonal secretory IgA formed by conjugating human recombinant secretory component with dimeric and polymeric forms derived from pooled polyclonal human plasma, which, when administered in a therapeutic amount, suppresses or prevents symptoms of intestinal luminal antibody deficiency in the subject.

Description

[Technical Field]

[0001] [Government support] This invention was made with government support under Grant 1R44DK130749-01A1 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0002] [Technical field] The present invention relates to a method for the prevention, treatment, or correction of intestinal luminal antibody deficiency in a subject suffering from or susceptible to the same using orally administered human secretory IgA, which is administered in the form of an oral pharmaceutical composition. [Background technology]

[0003] Intestinal antibody deficiency is caused by multiple diseases. The cause of antibody deficiency can be hereditary or acquired. It can occur as a symptom of many primary immunodeficiencies characterized by defective humoral immunity (Agarwal and Cunningham-Rundles 2019). IgA deficiency and common variable immunodeficiency (CVID) are the most common of these conditions. The prevalence of selective IgA deficiency ranges from 1:100 to 1:1000 (Agarwal and Cunningham-Rundles 2019). The associated risk of gastrointestinal infection and inflammation is increased 10-20-fold. Infections most commonly involve Giardia lamblia, and the inflammatory disease manifests as nodular lymphoid hyperplasia. The latter regresses after successful treatment of Giardia infection (Agarwal and Cunningham-Rundles 2019). Both infection and inflammation can occur in CVID. Gastrointestinal infections include Giardia, Salmonella, Campylobacter, and cytomegalovirus (Oksenhendler 2008). Inflammatory changes in the intestinal tissue also include nodular lymphoid hyperplasia and a decrease in plasma cells with an increase in intraepithelial lymphocytes (Khan R et al. 2020). The prevalence of intestinal antibody deficiency is 1 in 30,000 (Weifenbach 2020) (Khan R et al. 2020).

[0004] The etiology of intestinal antibody deficiency has no clear association with other conditions of enteritis, namely celiac disease, C. difficile infection, food intolerance, and food allergy. The mainstay of medical treatment for CVID is immunoglobulin replacement therapy (AAAAI Guidelines). This treatment involves intravenous infusion of IgG (IVIg) or subcutaneous administration of IgG. However, supplemental gastrointestinal polyclonal human secretory IgA has not been explored as a therapeutic platform.

[0005] The art remains focused on injections, excluding consideration of oral administration of IgA.

[0006] Thus, there is a need for human polyclonal secretory IgA therapeutics for the treatment of antibody deficiency diseases, and there is also a need to provide such therapeutics in dosage forms that are well suited for treating affected infants. Summary of the Invention

[0007] A method for suppressing or correcting symptoms of intestinal luminal antibody deficiency (particularly selective IgA deficiency and CVID) in a subject suffering from or susceptible to it is provided, comprising orally administering to the subject polyclonal human semisynthetic secretory IgA. When administered in a therapeutic amount based on the subject's characteristics and the type of IgA, symptoms of intestinal luminal antibody deficiency in the subject are suppressed. The administered immunoglobulin is easily formed from a polyclonal source. The present invention identifies an industrial method for producing polyclonal human secretory IgA that is not otherwise obtainable in quantities suitable for pharmaceutical use. The IgA is easily administered in a dimeric or polymeric form (semisynthetic secretory IgA) containing recombinant human secretory components. DETAILED DESCRIPTION OF THE INVENTION

[0008] The present invention is useful for preventing, treating, or correcting infection and inflammation caused by intestinal antibody deficiency by utilizing human polyclonal secretory IgA. This is easily prepared by the addition of recombinant human secretory components (semi-synthetic secretory IgA), making it a particularly promising pharmaceutical for treating gastrointestinal complications of antibody deficiency disorders. Methods of treatment or prevention include treatment with dimeric or polymeric polyclonal secretory IgA. Polyclonal dimeric or polymeric IgA can be recovered from Cohn Fraction III precipitates or equivalents, which are waste products of plasma fractionation (Simon, et al. 2014). It can also be recovered from ion exchange plasma fractionation processes used to recover other plasma proteins (U.S. Patent Nos. 9,828,418 B2, 10,385,117 B2, and 9,828,418 B2).

[0009] Due to its resistance to degradation in the gastrointestinal tract, secretory IgA (US9932392B2) can be administered orally. Because allogeneic immunoglobulins are naturally present in the gastrointestinal tract, direct administration to the gastrointestinal tract causes minimal side effects. The dimeric and polymeric IgA of the present invention are conjugated to recombinant human secretory component to mimic the subject's naturally secreted intestinal secretory IgA. Administration of semisynthetic secretory IgA compensates for the lack of naturally secreted secretory IgA in the gastrointestinal tract.

[0010] As used herein, a "subject" is defined as a human.

[0011] As used herein, "dimeric and polymeric IgA" is defined as a construct comprising two or more IgA monomers and a J chain.

[0012] As used herein, "disease correction" is defined as a state in which a subject is free from further symptoms of a disease after previously exhibiting symptoms.

[0013] The present invention uses immunoglobulins rather than metabolic or immunological inhibitors, and therefore provides effective treatment or prevention without interfering with metabolism in the body.

[0014] The preferred embodiment(s) described below are merely exemplary in nature and are in no way intended to limit the invention, its application, or uses.

[0015] Secretory IgA molecules are polyclonal and dimeric or polymeric; and are all known in the art, as supported by, for example, the references incorporated herein.

[0016] In a specific embodiment of the invention, the present invention provides a method for human medical treatment involving oral administration of secretory IgA, which can be derived from multiple sources. One such source of IgA is pooled human plasma following Cohn's cold ethanol fractionation method to produce a fraction III precipitate, as performed by those skilled in the art of protein separation (Cohn 1946). The IgA by-product can be further purified by adsorption to jack bean lectin (jacalin) or to ion exchange media under neutral or slightly acidic conditions, as performed by those skilled in the art of protein purification (Kabir S, 1998; and U.S. Patent No. 9,828,418 B2).

[0017] A more detailed description of the isolation of IgA components as a by-product from pooled human plasma or pooled hyperimmune human plasma follows. Ethanol fractionation of pooled human plasma is a well-known method for preparing immunoglobulin G. Pooled human plasma is first obtained from licensed plasmapheresis centers in the United States and tested for various pathogens, including HIV. The initial manufacturing step in most commercially available immunoglobulin G preparations involves a modified cold ethanol fractionation according to the Cohn method to produce Cohn Fraction II. In this fractionation method, many infectious viruses are removed from the pooled human plasma. After fractionation, Cohn Fraction II undergoes adsorption to an ion exchange medium. This step can selectively reduce the IgA concentration to less than 0.1%. Such a step is important for producing immunoglobulin G for intravenous infusion in humans. The modified low-temperature ethanol fractionation method according to the Cohn method is a series of fractionations using varying levels of ethanol, pH, and temperature to produce Fraction II, which is further processed to produce the immunoglobulins described above. In this fractionation method, pooled human plasma is first processed to produce cryoprecipitate and cryosupernatant. The cryosupernatant undergoes a first ethanol fractionation to obtain Supernatant I. Supernatant I undergoes a second ethanol fractionation to obtain Fraction II+III. Fraction II+III undergoes a third ethanol fractionation step to obtain Supernatant III and Fraction III precipitate.

[0018] The IgA-enriched Fraction III precipitate is typically discarded as an unwanted by-product. According to the present invention, this unwanted IgA, after affinity chromatography purification, is further treated by incubation with immobilized hydrolytic enzymes to inactivate viruses and vasoactive substances. Such treatment has been demonstrated to remove many tested viruses, including HIV, Sindbis virus, and vaccinia virus. Other antiviral treatments known to those skilled in the art may also be used, consisting of solvent / detergent treatment, nanofiltration, and / or heat inactivation. Typically, three antiviral steps are performed. After incubation to remove viruses, the concentration of the active ingredient is adjusted with sterile saline or buffer solution to achieve a fixed amount of active ingredient per milliliter of reconstituted product. Finally, the solution containing the fixed amount of reconstituted product is sterilized by filtration before use.

[0019] Ethanol fractionation according to the Cohn method is well known in the art and is described in Cohn et al., 1946, and more specifically in the Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 3, second edition (1963), pp. 576-602. Alternatively, ion exchange chromatography can be used to obtain dimeric and polymeric IgA by-products during the production of intravenous immunoglobulin. Dimeric and polymeric IgA account for 4% to 22% of plasma IgA (Delacroix et al., 1981; Delacroix et al., 1983). The resulting dimeric and polymeric IgA are purified. In addition to the IgA component, the compositions of the present invention contain recombinant human secretory component. Human secretory component can be produced by recombinant techniques, such as those described in Crottet et al., 1999. The resulting dimeric IgA is further conjugated to recombinant human secretory component. In a preferred embodiment, conjugation is achieved by disulfide bond formation under mildly oxidizing conditions (Jones, 1998). Dimeric secretory IgA, containing both J chain and secretory component, is repurified by ion exchange and size exclusion chromatography and / or ultrafiltration, as described in Lullau et al., 1996; Corthesy, 1997; and Crottet et al., 1999; and performed by those skilled in the art of protein purification. Purified dimeric and polymeric secretory IgA, containing recombinant human secretory component, may be stabilized, for example, by the addition of human serum albumin to a final concentration of 5%. The presence of human secretory component in the compositions of the invention provides a physiologically effective dose of immunoglobulin A, whereas compositions lacking secretory component do not. Furthermore, the present invention identifies an industrial method for producing polyclonal human secretory IgA, composed of recombinant human secretory components and IgA dimers and higher order polymers derived from natural human plasma, which cannot otherwise be obtained in sufficient quantities for commercial medical use.

[0020] In yet other embodiments, IgA is combined with pasteurized human breast milk or with human breast milk prepared in a bioreactor (Deng M, 2022).

[0021] Secretory IgA antibodies can be administered alone or in combination with various pharmaceutical adjuvants.

[0022] These compositions may contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, etc. Prolonged retention of IgA in the intestinal lumen can be achieved by the use of absorption delaying agents, for example, aluminum monostearate and gelatin.

[0023] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert conventional excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) fillers or extenders (e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid), (b) binders (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia), (c) humectants (e.g., glycerol), (d) disintegrants (e.g., agar, , calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate), (e) solution retarders (e.g., paraffin), (f) absorption enhancers (e.g., quaternary ammonium compounds), (g) wetting agents (e.g., cetyl alcohol and glycerol monostearate), (h) adsorbents (e.g., kaolin and bentonite), and (i) lubricants (e.g., calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof). In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0024] Solid compositions of a similar type may also be employed as fillers in soft and hard capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0025] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art; these are detailed, for example, in U.S. Pat. Nos. 4,017,647; 4,385,078; 4,518,433; and 4,556,552.

[0026] Such solid preparations may contain opacifying agents, and may be of such composition that they release the active ingredient(s) in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.

[0027] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain the following: inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, specifically cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures of these substances.

[0028] Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0029] Suspensions may contain, in addition to the active ingredient, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium or other metal hydroxides, bentonite, agar-agar and tragacanth, or mixtures of these substances.

[0030] Because the effectiveness of IgA antibodies depends on their reaching the small intestine, preferred tablets or capsules are enteric coated. Alternatively, the active IgA antibodies themselves may be microencapsulated prior to formulation. Preparation of IgA antibody microcapsules and enteric-coated tablets or capsules can be achieved by conventional methods as detailed above.

[0031] It is understood that the therapeutic amount of IgA depends on its form, with forms that are susceptible to degradation in the gastrointestinal tract requiring larger doses. Typical human subject doses of IgA range from about 0.005 mg to 50 g per day, preferably 1 mg to 40 g per day. Generally, secretory IgA is effective as a sole therapeutic when administered to a patient at about 10 g per day. Forms of IgA that are easily degraded in the gastrointestinal tract are typically effective at doses at least 80% greater than the secretory form. For example, about 5 g of secretory IgA can be administered to a subject in a single dose once daily or in divided doses three to four times daily. Preferably, multiple doses are administered with meals that may contain food allergens. It is understood that a physician can easily adjust the dose of IgA to be administered based on the subject's response to treatment. Many factors are taken into consideration when adjusting the dose. However, it should be understood that the dose can be easily adjusted to provide an appropriate amount of IgA antibodies.

[0032] The present invention is further described with reference to the following detailed examples, and exemplary process procedures are described below. These examples are not meant to limit the scope of the invention set forth in the foregoing description. Variations within the spirit of the invention will be apparent to those skilled in the art.

[0033] The present invention is distinguished from the prior art in that its dimeric and polymeric IgA components are derived from pooled healthy human plasma. The present invention is further distinguished in that the dimeric and polymeric IgA components are conjugated to recombinant human secretory components necessary for their normal activity in the intestine. Importantly, the present invention identifies an industrial method for producing polyclonal semisynthetic human secretory IgA that is not otherwise obtainable in quantities suitable for widespread medical use. [Example]

[0034] [Example 1] Dimeric IgA is obtained by affinity purification from pooled healthy human plasma and conjugated with recombinant human secretory component to form secretory IgA. Secretory IgA is stabilized by the addition of human serum albumin to a final concentration of 5%. The final solution is adjusted to a therapeutic dose of 10 g of secretory IgA per day. Secretory IgA is administered once daily to individuals with intestinal antibody deficiency. One week after initiating treatment, patients with intestinal antibody deficiency demonstrate a reduction in their physiological abnormalities.

[0035] [Example 2] The method of Example 1 is repeated with enteric-coated secretory IgA administered at a higher dose of 20 g per day to achieve similar results.

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[0077] The patent applications and publications mentioned in this specification are indicative of the levels of those skilled in the art to which this invention pertains and are hereby incorporated by reference to the same extent as if each individual application or publication was specifically and individually incorporated by reference.

[0078] The above description illustrates specific embodiments of the present invention, but is not meant to limit its practice. The following claims, including all equivalents thereof, are intended to define the scope of the present invention.

Claims

1. 1. A method for suppressing symptoms of intestinal luminal antibody deficiency in a subject suffering therefrom, comprising: The method comprises: orally administering to said subject suffering from intestinal antibody deficiency purified polymeric secretory IgA comprising recombinant human secretory component and human plasma-derived IgA dimers and higher polymers; and allowing a sufficient time for the purified high molecular weight secretory IgA to suppress the symptoms of luminal intestinal antibody deficiency in the subject; Including, method.

2. 2. The method of claim 1, and further comprising the step of microencapsulating the purified high molecular weight secretory IgA prior to said administration. method.

3. 2. The method of claim 1, The human plasma-derived IgA dimers are stabilized by the addition of human serum albumin prior to or in conjunction with the administration. method.

4. 2. The method of claim 1, The purified high molecular weight secretory IgA is stabilized by delivery with an antacid. method.

5. 2. The method of claim 1, The purified high molecular weight secretory IgA is produced by an industrial method. method.

6. The method according to any one of claims 1 to 5, the subject is a human. method.

7. The method according to any one of claims 1 to 5, Intestinal antibody deficiency is caused by selective IgA deficiency. method.

8. The method according to any one of claims 1 to 5, Intestinal antibody deficiency is caused by common variable immunodeficiency syndrome (CVID). method.

9. The method according to any one of claims 1 to 5, wherein the administration is prophylactic. method.

10. 1. A method for correcting intestinal luminal antibody deficiency in a subject, comprising: The method comprises: orally administering to the subject purified high molecular weight secretory IgA comprising recombinant human secretory component and IgA dimers and higher polymers derived from human plasma; and allowing a sufficient time for the purified high molecular weight secretory IgA to suppress the symptoms of luminal intestinal antibody deficiency in the subject; Including, method.

11. 11. The method of claim 10, further comprising the step of obviating further symptoms of said intestinal luminal antibody deficiency. method.

12. 11. The method of claim 10, and further comprising the step of microencapsulating the purified high molecular weight secretory IgA prior to said administration. method.

13. 11. The method of claim 10, The human plasma-derived IgA dimers are stabilized by the addition of human serum albumin prior to or in conjunction with the administration. method.

14. The method according to any one of claims 10 to 13, The purified high molecular weight secretory IgA is stabilized by delivery with an antacid. method.

15. The method according to any one of claims 10 to 13, The purified high molecular weight secretory IgA is produced by an industrial method. method.

16. The method according to any one of claims 10 to 13, the subject is a human. method.

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