Patent Application
20200353081
This invention relates to the treatment of allergic disease. In particular, this invention relates to the use of pooled immunoglobulin in combination with antigen-specific polyclonal immunoglobulin in the prevention or treatment of allergic diseases.
Allergic diseases afflict a significant fraction of the human population and of the population of pets. Allergen immunotherapy can sometimes be used to build up an individual's tolerance to allergens. In the therapy, allergen injections are given in two phases: a build-up phase and a maintenance phase. The build-up phase can involve injections with increasing amounts of allergens about one to three times per week for three to six months. Once an effective dose is reached, the maintenance phase begins with further injections about once every two to four weeks for several years. Both the build-up phase and maintenance phase are therefore quite onerous.
It is an object of this invention to provide improved pharmaceutical compositions and methods for the treatment or prevention of allergic diseases.
This and other objects of the invention will be better understood by reference to the detailed description of the preferred embodiment which follows. Note that the object referred to above is a statement of what motivated the invention rather than promises. Not all the objects are necessarily met by all embodiments of the invention described below or by the invention defined by each of the claims.
According to one aspect of the invention, a combination of plasma immunoglobulin and antigen-specific immunoglobulin may be used for the treatment or prevention of allergic disease.
In another aspect, the invention comprises the use of a combination of plasma immunoglobulin and antigen-specific immunoglobulin for the treatment or prevention of allergic disease.
In another aspect, the invention is a pharmaceutical composition for the treatment or prevention of allergic disease. The pharmaceutical composition comprises plasma immunoglobulin and antigen-specific immunoglobulin.
In a further aspect, the plasma immunoglobulin is intramuscular immunoglobulin.
In a further aspect, the intramuscular immunoglobulin is human intramuscular immunoglobulin.
In a further aspect, the plasma immunoglobulin is human plasma immunoglobulin.
In a further aspect, the plasma immunoglobulin is from a non-human species.
In a further aspect, the plasma immunoglobulin and the antigen-specific immunoglobulin are from the same species.
In another aspect, the antigen-specific immunoglobulin is selected from the group consisting of polyclonal anti-Tetanus toxoid immunoglobulin, polyclonal anti-Rh immunoglobulin, polyclonal anti-hepatitis B immunoglobulin, polyclonal anti-rabies immunoglobulin, and polyclonal anti-varicella immunoglobulin.
In another aspect, the plasma immunoglobulin is greater than 50 mg per kg body weight.
In a further aspect, the invention is a method of treating or preventing allergic disease comprising administering injections of plasma immunoglobulin and antigen-specific immunoglobulin.
In a further aspect, the invention is a kit comprising aliquots of plasma immunoglobulin, aliquots of antigen-specific immunoglobulin, and instructions associated with the kit directing use of the aliquots of plasma immunoglobulin and the aliquots of antigen-specific immunoglobulin for the treatment or prevention of allergic disease.
In a further aspect, the invention is a kit comprising aliquots of mixtures of plasma immunoglobulin and antigen-specific immunoglobulin, and instructions associated with the kit directing use of the aliquots of mixtures of plasma immunoglobulin and antigen-specific immunoglobulin for the treatment or prevention of allergic disease.
The foregoing may cover only some of the aspects of the invention. Other aspects of the invention may be appreciated by reference to the following description of at least one preferred mode for carrying out the invention in terms of one or more examples. The following mode(s) for carrying out the invention is not a definition of the invention itself, but is only an example that embodies the inventive features of the invention.
At least one mode of carrying out the invention in terms of several examples will be described by reference to the drawings below in which:
The pharmaceutical compositions of the present invention are a combination of pooled plasma immunoglobulin and antigen-specific polyclonal immunoglobulin.
Plasma immunoglobulin is typically prepared from the serum of at least 1000 donors and has been used to treat patients with primary immunodeficiency diseases. Depending on how the plasma immunoglobulin is formulated and administered, it may be referred to as intramuscular immunoglobulin (“IMIG”), intravenous immunoglobulin (“IVIG”), subcutaneous immunoglobulin (“SCIG”), or intraperitoneal immunoglobulin (“IPIG”).
Antigen-specific polyclonal immunoglobulin is immunoglobulin prepared with a high antibody count against a specific pathogen, such as Varicella-zoster virus, or against a specific antigen, such as Tetanus toxoid.
The inventors have found that the combination of pooled plasma immunoglobulin and antigen-specific polyclonal immunoglobulin is useful for the treatment or prevention of allergic diseases.
As will be described in detail below, the inventors conducted experiments using various antigen-specific immunoglobulins against various antigens. In view of the significant differences in preparation and chemical composition between the antigen-specific immunoglobulins used (polyclonal anti-Tetanus immunoglobulin, polyclonal anti-Rabies immunoglobulin, and polyclonal anti-Varicella immunoglobulin), the combination of plasma immunoglobulin with any antigen-specific immunoglobulin (including but not limited to polyclonal anti-Rh immunoglobulin and polyclonal anti-hepatitis B immunoglobulin) is predicted to result in a similar modification of the immune system of the treated human or animal and to similarly prevent and/or treat allergic diseases.
For the treatment and prevention of allergic diseases in humans and pets, the plasma immunoglobulin component of the combination may be plasma immunoglobulin approved for use in humans such as, but not limited to, Gamunex™ and Hizentra™.
The plasma immunoglobulin and antigen-specific polyclonal immunoglobulin may be administered in any suitable manner. For example, the antibodies may be administered in a non-immunogenic form, that is without an adjuvant, in a non-immunogenic amount, for example intramuscularly, intravenously, subcutaneously, or intraperitoneally. A pharmaceutical composition comprising the combination of plasma immunoglobulin and antigen-specific polyclonal immunoglobulin may include a pharmaceutically acceptable carrier, such as buffered saline, phosphate buffered saline, or phosphate buffered saline at neutral pH.
Another aspect of the invention is a kit comprising aliquots of plasma immunoglobulin, aliquots of polyclonal antigen-specific immunoglobulin, and instructions directing use of such two different aliquots for the treatment or prevention of allergic disease.
Another aspect of the invention is a kit comprising aliquots of a mixture of plasma immunoglobulin and polyclonal antigen-specific immunoglobulin and instructions directing use of such aliquots for the treatment or prevention of allergic disease.
The antibodies may be administered at any suitable site and time. However, the antibodies are preferably administered contemporaneously or substantially contemporaneously. The antibodies may be administered in separate compositions sequentially or contemporaneously or together as a mixture.
Allergy Experiment Protocol with Polyclonal Human IMIG and Polyclonal Human Anti-Tetanus Ig
Five BALB/c mice (8 weeks of age at initiation of study) were used per group. All mice except a control group (Group 1—see below) received ovalbumin (10 μg OVA plus Al(OH)3) intraperitoneally in 0.3 ml phosphate buffered saline (“PBS”) on day 0 and day 14 with a further boost on day 56. All mice received egg white solution (filtered 20% (w/v) EWS) in their drinking water from day 14.
Mice receiving intramuscular immunoglobulin (Gamunex™ 25 μg: Grifols) were given intramuscular injections in 0.05 ml PBS in the left gluteus muscle at days −2, 7, 14, 21, 28, 35, and 42. Animals receiving Anti-Tetanus immune Ig (HyperTET™ 25 μg: Grifols) were given intramuscular injections in 0.05 ml PBS in the right deltoid muscle at days −2, 7, 14, 21, 28, 35, and 42. In some cases IMIG or Anti-Tetanus was absorbed with Tetanus toxoid (×3) before use. The control groups received PBS only in the same sites.
The following groups were used.
All mice were sacrificed at day 63 of the study. On sacrifice, serum IgE to OVA obtained by cardiac puncture was measured by ELISA using plates coated with 100 ng/well of OVA and developed with HRP-anti-mouse IgE and appropriate substrate.
In addition, 5×106 splenocytes from individual animals were challenged in vitro in 2 ml medium with 1 μg/ml OVA for 72 hr and IL-2/IL-4 measured in culture supernatants using commercial ELISA Kits (eBIOSciences).
Results
Allergy Experiment Protocol with Polyclonal Human IMIG and Polyclonal Human Anti-Varicella Ig
Eight BALB/c mice (8 weeks of age at initiation of study) were used per group. All mice except a control group (Group 1—see below) received ovalbumin (10 μg OVA plus Al(OH)3) intraperitoneally in 0.3 ml PBS on day 0, day 14, and day 42. All mice received egg white solution (filtered 20% (w/v) EWS) in their drinking water from days 14-42.
IMIG (Gamunex™ 25 μg: Grifols) and anti-Varicella Ig (25 μg: Grifols) was infused weekly intravenously from days 7-35.
The following groups were used.
All mice were sacrificed at day 49 of the study. On sacrifice, serum IgE to OVA obtained by cardiac puncture was measured by ELISA using plates coated with 100 ng/well of OVA and developed with HRP-anti-mouse IgE and appropriate substrate.
In addition, 5×106 splenocytes from individual animals were challenged in vitro in 2 ml medium with 1 μg/ml OVA for 72 hr and IL-2/IL-4 measured in culture supernatants using commercial ELISA Kits (eBIOSciences).
Results
Allergy Experiment Protocol with Polyclonal Human IMIG and Polyclonal Human Anti-Tetanus Ig, or Polyclonal Dog Ig and Dog Anti-Rabies Ig, Using Beagle Dogs Sensitized to Peanut Butter
In a modification of the protocol in EXAMPLE 1 and EXAMPLE 2, the inventors considered whether they could attenuate allergic sensitization in large animals (Beagle dogs) where previous literature reports indicate a high prevalence (>80%) of induced allergic sensitization to peanut butter applied topically.
Animals received weekly topical exposure to peanut butter (abdomen) with the first exposure occurring 1 week before treatment. The next 5 exposures of peanut better were with 5 weekly treatments with combined dog Igs (IMIG and pooled dog anti-Rabies immune Ig) or with combined human Igs (IMIG and Anti-Tet Ig). After 5 weekly treatments all animals received a further 3 treatments given at 14 d intervals of the same Ig mixes. Finally, all dogs received an oral challenge with peanut butter, and serum IgG, serum IgE, and peanut butter induced IL-2/IL-4 production was measured.
Dogs receiving dog intramuscular immunoglobulin (Innovative Research, USA) were given 1 mg/kg intramuscular injections in 0.5 ml PBS in the gluteus muscle and dogs receiving pooled dog anti-Rabies immune Ig (prepared from pooled dogs re-immunized with rabies vaccine) were given 1 mg/kg intramuscular injections in 0.5 ml PBS in the opposite gluteus muscle.
Dogs receiving human intramuscular immunoglobulin (Gamunex™: Grifols) were given 1 mg/kg intramuscular injections in 0.5 ml PBS in the gluteus muscle and dogs receiving human Anti-Tetanus Ig (HyperTET™: Grifols) were given 1 mg/kg intramuscular injections in 0.5 ml PBS in the opposite gluteus muscle.
Results
Dose Response Study—Polyclonal Human IMIG and Polyclonal Human Anti-Tetanus Ig in Pre-Immune Mice
The inventors also conducted a dose response study using polyclonal human IMIG and polyclonal human anti-Tetanus Ig in pre-immune mice.
In the dose response study, all groups had five BALB/c mice each. Mice were approximately 25 grams. All mice received OVA (10 μg OVA plus Al(OH)3) on day 0 and day 14 with a boost on day 56. All mice received EWS (filtered 20% (w/v) egg white solution in their drinking bottle) from day 14.
Mice began treatment with immunoglobulin injections on days 56, 63, 70, 77, and 84.
The following groups were used:
A final boost with OVA was on day 90 and the mice were sacrificed on day 97.
Serum OVA-specific IgG/IgE was measured by ELISA. Additionally, 2×106 splenocytes were challenged in vitro in 2 ml medium with 1 μg/ml OVA for 72 hr and IL-2/IL-4 was measured in culture supernatants using commercial ELISA Kits (BioLegend).
Results
In the foregoing description, exemplary modes for carrying out the invention in terms of examples have been described. However, the scope of the claims should not be limited by those examples, but should be given the broadest interpretation consistent with the description as a whole. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CA2019/050013 | 1/4/2019 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62614131 | Jan 2018 | US |
