Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2000-06-12
2003-01-07
Nolan, Patrick J. (Department: 1644)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C424S141100
Reexamination Certificate
active
06504013
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for decreasing IgE levels and for alleviating allergic symptoms in canines. The compositions comprise chimeric canine anti-IgE mAbs and the methods are useful for treating allergies in canines.
BACKGROUND ART
It is estimated that up to 30% of all dogs suffer from allergies or allergy-related skin disorders. Specifically, allergic dermatitis has been estimated to affect between 3% and 15% of the entire canine population. Given the prevalence of allergies in dogs, there is a need to develop methods and compositions to properly diagnose and treat, canine allergies.
The substances most likely to cause an allergic reaction vary from species to species. Common canine allergens include fleas, pollens, molds and dust. Allergy to fleas is believed to be the most common dog allergy. Typically, a flea's saliva is the allergen, and a single fleabite can cause substantial itching. An additional form of allergy in dogs is termed atopy. Atopy is a condition where a dog. is allergic to inhalants such as pollens, molds or microscopic mites found in house dust. Current treatments of canine allergies often focus on the use of steroids which cause undesirable side effects or allergen-mediated desensitization which requires a different treatment for each type of allergy.
In mammals, antibody molecules are classified into various isotypes referred to as IgA, IgD, IgE, IgG, and IgM. Antibody molecules consist of heavy and light chain components. The heavy chains of molecules of a given isotype have extensive regions of amino acid sequence homology, and conversely have regions of difference from antibodies belonging to other isotypes. The shared regions of the heavy chains provide members of each isotype with common abilities to bind to certain cell surface receptors or to other macromolecules such as complement, and therefore to activate particular immune effector functions. Accordingly, separation of antibody molecules into isotypes also serves to separate the antibodies according to a set of effector functions that they commonly activate. In humans and dogs, Immunoglobulin E (IgE) is involved in allergy, and recognizes antigen in immediate hypersensitivity reactions.
Furthermore, IgE is the antibody type that is understood to be an important mediator of allergic response in mammals, including Type I immediate hypersensitivity. IgE molecules bind to receptors on mediator cells such as mast cells. This binding occurs when the Fc region of the IgE molecule is bound to Fc receptors on the mast cells. When such cell-bound IgE antibodies then bind to an allergen, the allergen cross-links multiple IgE antibodies on the mast cell surface. This cross-linking mediates Type I immediate hypersensitivity reactions and causes release of histamines and other molecules that produce symptoms associated with allergy.
In humans the serum level of total IgE is diagnostic of allergic disease. To explore the possibility that the serum level of IgE might also be diagnostic of allergy in dogs, DeBoer and Hill performed additional studies. (Hill and DeBoer,
Am. J. Vet. Res.
55 (7):944-48 (1994)). They used monoclonal antibody (“mAb”) D9, in an ELISA assay with the following configuration: D9 was bound to a substrate, antibodies were captured by D9 and then D9 having a marker was used to flag the captured antibody.
The Hill and DeBoer ELISA was used to establish the total amount of IgE in canine serum in an effort to diagnose canine allergy. However, it was found that quantifying IgE was not useful for diagnosing allergy in dogs. (See, e.g., Abstract and Discussion sections of Hill and DeBoer.) This finding was in direct contrast to the situation in human immunology. This result points out the difficulty of any attempt to correlate data between animals of two different genera.
This difficulty is further exemplified by the fact that dogs can be allergic to a different set of antigens than humans are. Allergies to fleas, for instance, are a severe problem for dogs but not humans. Furthermore, in instances where dogs and humans appear to be allergic to the same allergen extract, studies by doctors Esch and Greer of Greer Laboratories (Lenoir, N.C.), have indicated that the specific allergens in an allergen extract which produce canine disease are not necessarily the same allergens that produce disease in humans. For example, it is known that the immunodominant components of dust mite extracts are different in dogs than in humans.
Adding to the difficulty of study across genera of allergic mechanisms and response is that allergies in dogs are primarily expressed in the skin, while humans primarily exhibit allergic symptoms in the respiratory system. Additionally, eosinophilia is correlated to allergies in humans, but not in dogs.
In considering the administration of a therapeutic composition to treat a physiological condition, when recombinant or chimeric molecules are administered in vivo to an animal, they may be quickly cleared from that animal. Recombinant IgG molecules have been used to increase the half-life of recombinant molecules when the recombinants are administered to an animal. E.g., Capon, D., Chamow, S., et al., “Designing CD4 immunoadhesins,”
Nature
337:525 (1989); Byrn, R., Mordenti, C., et al., “Biological Properties of a CD4 Immunoadhesin,”
Nature
344:667 (1990); Haak-Frendscho, M., Ridgway, J., et al., “Human IgE Receptor Alpha-Chain IgG Chimera Blocks Passive Cutaneous Anaphylaxis Reaction in vitro,”
Journal of Immunology
151:351-53 (1993); U.S. Pat. No. 5,116,964, issued May 26, 1992 to Capon, D. J., et al. entitled “Hybrid Immunoglobulins”.
It is generally accepted that in humans IgG is the immunoglobulin isotype with the longest serum half-life. In dogs, the isotype with the longest half-life is not known. Although the sequences that are believed to correspond to a portion of exon 1 and 3 of at least two and possibly all four heavy chain canine IgG immunoglobulin sequences have been reported in U.S. Pat. No. 5,593,861 to Maeda et al., it is not known which of these heavy chain sequences is part of the IgG structure with the longest half-life in dogs.
IgE levels are elevated in human patients experiencing allergic disease, and IgE is believed to mediate allergic symptoms. Although the levels of serum IgE may not correlate with allergic disease in dogs, it may nevertheless be desirable to decrease IgE levels as a mechanism for alleviating allergic symptoms.
Furthermore, there is a need for compositions and methods for treatment of canine allergies which avoid the disadvantages of the conventional compositions and methods, yet provide effective treatment for canine allergies.
One object of the present invention is to provide compositions and methods for treatment of canine allergies, with substantially less side effects than those experienced with steroid treatments.
Another object of the invention is to provide compositions and methods of treatment for alleviating canine allergy symptoms that are effective independent of the type of allergen, and compositions and methods where treatment is based on the presence of an allergic response rather than a specific allergen.
Another object of the present invention is to provide compositions and methods of treatment for alleviating canine allergy symptoms by targeting IgE synthesis.
These and other objects will be apparent to those skilled in the art from the following disclosure and appended claims.
SUMMARY OF THE INVENTION
The present invention concerns compositions and methods for treating allergy in dogs. More particularly, the invention provides methods and compositions for administration to dogs, which compositions actually bind the dog's immunoglobulin E molecules so that the binding of free, serum IgE will inhibit this IgE from binding to the high affinity IgE receptor on mast cells and basophils. The compositions and methods provided may eliminate or reduce levels of free serum IgE. Lower free serum IgE levels may down regulate the synthesis and expression of
Aiyappa Ashok P.
Guo Hongliang
Krah, III Eugene R.
Lawton Robert L.
Liu Wendy W.
Ewoldt Gerald R.
Idexx Laboratories Inc.
McDonnell & Boehnen Hulbert & Berghoff
Nolan Patrick J.
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