Polyclonal antibody composition for treating allergy

Abstract

A pharmaceutical composition for treating allergy is described. The composition comprises as an active ingredient a recombinant polyclonal antibody or a mixture of different monoclonal antibodies capable of reacting with or binding to an allergen together with one or more pharmaceutically acceptable excipients. The composition may be used topically as a solution, dispersion, powder, or in the form of microspheres. The polyclonal antibody is preferably a recombinant polyclonal antibody produced by phage display technology. The pairing of specific immunoglobulin variable region light chain and heavy chain maintained from the original polyclonal immune response or selected by panning using the allergen in question is preferably maintained by bulk transfer of the pairs into an expression vector.

Description

FIELD OF INVENTION [0001] The present invention relates to a composition comprising a recombinant polyclonal antibody or a mixture of different monoclonal antibodies or an isolated or purified polyclonal antibody capable of reacting with or binding to an allergen, as well as the use of a polyclonal antibody capable of reacting with or binding to an allergen for the treatment of allergy. BACKGROUND OF THE INVENTION [0002] The protective effects of humoral immunity are known to be mediated by a family of structurally related glycoproteins called antibodies. Antibodies initiate their biological activity by binding to antigens. Antibody binding to antigens is generally specific for one antigen and the binding is usually of high affinity. Antibodies are produced by B-lymphocytes. Blood contains many different antibodies, each derived from a clone of B-cells and each having a distinct structure and specificity for antigen. Antibodies are present on the surface of B-lymphocytes, in the pla...

AI Technical Summary

Benefits of technology

[0024] In most embodiments, the pharmaceutical composition according to the invention is free of the allergen to which the recombinant polyclonal antibody or the mixture of different monoclonal antibodies or the isolated or purified polyclonal antibody bind or is reactive with. However, in special cases during so-called specific allergen immunotherapy to induce allergen tolerance in a patient, the allergen-specific polyclonal antibody may be administered to the patient in conjunction with an allergen preparation, in order to enable or enhance the efficacy of the tolerance induction procedure.

[0027] The use of a polyclonal antibody has potential clinical advantages compared with the use of a monoclonal antibody due to the presence of multiple reactivities in a polyclonal antibody against the allergen-target in question. There may be generated a polyclonal antibody which has reactivities against all epitopes on a complex allergen target. Due to the polyclonal nature of the composition, containing many epitope specificities, the functional antibody density which can be achieved on complex allergen antigens when using a polyclonal antibody is significantly higher, than with a monoclonal antibody. This results in more efficient blocking or clearance of the target allergen. Further, the polyclonal nature of the composition enables recognition of and blocking of epitopes on related, homologous allergen isotypes, due to broad reactivity with several epitopes shared in part between related allergens, something which is not enabled by a monoclonal antibody.

[0028] Further, it can be expected that treatment with allergen-specific polyclonal antibodies of the IgA or IgG isotype will have an immunomodulating effect by inducing tolerance to an allergen, and thus have a long term effect in curing the allergy or reducing the need for further treatment. Thus, a further aspect of the invention relates to the use of a pharmaceutical composition according to the invention for prophylactic treatment inducing tolerance to the allergen. This may even be used in patients where an allergic reaction has not yet been observed but which patients due to family history or genetic analysis are likely to develop allergy to an allergen.

[0029] Furthermore, contrary to a monoclonal antibody, a polyclonal antibody preparation comprises a mixture of specificities, and therefore any single and individual, cross-reacting specificity idiotype will be delivered at a very low concentration, thus reducing significantly the potential for harmful side-effects, due to cross-reactivity. In other words, the potential for deleterious side-effects due to unwanted tissue cross-reactivity is diluted out in the polyclonal antibody reagent. Further, any unwanted cross-reactivity of the polyclonal antibody preparation can be removed by adsorption. If a monoclonal antibody results in an unwanted cross-reactivity, it is inherent to the single antibody present and can of course not be removed without destroying the activity of the preparation.

[0030] Also, in analogy with the properties of polyclonal antibodies in terms of the diminished potential for cross-reactivity, polyclonal antibodies will also be much less likely than monoclonal antibodies to induce a neutralizing anti-idiotype immune response, since each single epitope-specific idiotype of the administered polyclonal antibody preparation is present in a very low quantity or concentration, being below the threshold for generation of an anti-idiotype response.

Problems solved by technology

Thus, allergens enter the respiratory tract through inhalation and get trapped on the mucosal surfaces of the nasal lining or the bronchial passages of the respiratory tract.

Desensitization immunotherapy is the most important novel therapy for severely affected patients, but the medical advances have been limited to refining the classification of the allergenic substances, improving diagnostic methods, and providing a better controlled and broader library of allergen extracts for immunotherapy.

Also, because monoclonal antibodies are directed against single antigenic determinants, the density of the antibody targets on e.g. allergens may not be high enough to mediate elimination of the allergen.

Thus, a single monoclonal antibody preparation cannot be expected to exhaustively cover more than a minority of the possible epitopes on an allergen, e.g. a pollen particle or proteins from cat dander.

This means that if the desired clinical effect of an antibody can be characterized as a complete blocking of the available antibody epitopes, then a single monoclonal antibody will not be sufficient.

Further, if an antibody preparation should preferably be developed against several homologous allergens from closely related allergens, e.g. pollens, or against several proteins from one allergen source e.g. animal dander, then a single monoclonal antibody will not meet the required efficacy.

However, it must be stressed that this allergen model is based on the induction of allergy-like symptoms using a single allergen, Amb a I. Thus, the study does not take into account that the vast majority of allergies are caused by reactions towards a number of allergen proteins and epitopes derived from a single allergen particle, which emphasizes the need for a polyclonal antibody mixture in this regime of treatment.

Furthermore, human allergy is profoundly more complex than the allergy-like symptoms induced in an inbred mouse strain (Inhal. Toxicol., Vol 12, pp.

Consequently, the potential usefulness of monoclonal antibodies as allergen blocking agents is limited.

Finally, monoclonal antibodies may display cross-reactivity to antigenic structures of host cell tissue resulting in potential unwanted side effects.

Therefore a large number of different monoclonal antibodies may need to be produced in order to generate the desired combination of antigen specificity and target selectivity, and even so there still remains a significant risk of cross-reactivity towards endogenous self-antigens in a proportion of patients.

A separate issue is the generation of human anti-mouse antibody responses (HAMA).

Conventional murine monoclonal antibodies are foreign proteins to the human recipient, and therefore a HAMA immune response is often elicited in the recipient, which may lead to unwanted side effects in addition to reduced treatment efficacy.

There are several drawbacks of using conventional polyclonal antibodies in the treatment of allergy.

First of all, polyclonal antibodies in the form of IgG purified from hyperimmune human serum is available in limited supply and in amounts insufficient for the treatment of allergic diseases and other common conditions.

Also, gamma globulin preparations are expensive to produce, and display low efficacy due to their mixed nature containing an overwhelming majority of non-specific human serum immunoglobulin reactivities.

Also, there exist a real risk of transmitting contaminating reagents, including infectious microorganisms (hepatitis virus, HIV, prions, others), or mitogens, cytokines and toxins.

Finally, the variability between preparations remains a major problem.

However, such compositions may result in the generation of potent anti-xenoantibody responses, and carries a real risk of serious side effects such as anaphylactic shock or serum sickness, as well as the transmission of xenotropic infections.