Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,...
Reexamination Certificate
1993-05-04
2001-05-15
Spector, Lorraine (Department: 1647)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
C424S156100, C530S388100, C530S388900
Reexamination Certificate
active
06231855
ABSTRACT:
BACKGROUND OF THE INVENTION
Anthracycline antibiotics are a widely investigated class of compounds having antitumor activity. Particularly, doxorubicin (DXR) has been used for a long time in antitumor chemotherapy protocols.
The clinical usefulness of anthracycline antibiotics is limited by serious side effects such as cardiomyopathy, bone-marrow depression, gastrointestinal tract mucositis and, if there is drug leakage at the injection site, local tissue necrosis.
Particularly, local side effects are represented by sloughing ulcerations and occur when the drug is inadvertently extravasated during administration or oozes out through compromised vein walls. Damage from extravasation is not immediately apparent, but comes out days later and slowly progresses to involve superficial and deep structures, such as soft tissues and nerves and tendons as well. The severe course of this type of lesions, which can be experimentally reproduced in animal models (see Balsari A., et al, Chemotherapy 5: 324-329, 1989), is due to the long term persistence of residual active drug at the extravasation sites.
Another peculiar side effect consists in alopecia, which is due to the inhibiting activity exerted by anthracyclines on the continuously growing cells of hair roots. Alopecia occurs in almost the totality of the patients treated with anthracycline drug. Such effect is not life endangering per se, but severely harasses the patient and deteriorates the quality of life.
Many attempts have been made to reduce the toxicity of anthracycline antibiotics, while retaining substantially unaffected the antitumor activity thereof. For this purpose, two main approaches have been taken: (a) synthesis of DXR analogues and derivatives; and (b) combination with substances which are thought likely to interfere with factors claimed to be responsible for the toxic effects of these drugs, such as vitamin E, ubiquinone, chelating agents and the like.
However, no efficient method of treatment has been so far described for the above-mentioned highly distressing tissue lesions. In a number of cases surgical intervention is considered for wide removal of the lesions in the attempt of salvaging structures and retain function. In some cases, limb amputation and/or skin grafting may be necessary. Local infiltration at extravasation sites with sodium bicarbonate or hyaluronidase or saline solution is of limited usefulness, if any.
Many approaches have been suggested to reduce alopecia incidence and extent by decreasing the scalp blood flow with the use of tourniquets, tight refrigerated caps, etc.
So far, the above-described problems have not satisfactorily been solved.
BRIEF SUMMARY OF THE INVENTION
Now it has surprisingly been found the MAbs anti-anthracycline can reduce the toxicity of these drugs, while substantially retaining the antitumor efficacy. In fact, a higher detoxifying affect of monoclonal antibodies in normal cells or tissues than in tumor cells or tissues has been evidenced from both in vitro and in vivo tests. This is particularly surprising in that previous reports on the detoxifying activity of anti-drug MAbs, such as those against digoxin (Hunter, et al, J. Immunol., 129, 1165-1172, 1982) evidenced no tissue or organ specificity. In those cases, detoxication has been assigned to an inactivation of the drug.
Previous research on anti-DXR polyclonal antibodies (Chien, et al, Immunochemistry, 12, 291-296 1975; Savaray, et al, Res. Comm. Chem. Pathol. Pharmacal., 29, 549-559, 1980 e Proc. AACR-ASCO, 21, Abst. 1020, p. 254, 1980) evidenced potential antagonist properties on DXR cardiotoxicity, but no selective affect has been reported.
According to the present invention, anti-anthracycline MAbs are prepared as described in EP-A 03416776 and Int. J. Cancer 42, 798-802, 1988 and Anticancer Res. 10, 129-132, 1990, from the hybridoma deposited at ECACC under No. 90011003 on Jan. 12, 1990. Briefly, such hybridomas are obtained by fusing splenocytes of BALB/c mice subjected to an unrelated antigenic stimulus and treated for a short period of time with the specific antigen, as disclosed in U. S. Pat. No. 5,177,016. Monoclonal antibodies obtained according to such procedure are able to react with different epitopes of the anthracycline glycosides molecules. It has now been surprisingly found that these antibodies possess the property of modulating at a different degree the multifactorial type of interaction occurring between anthracycline drug molecules and cell populations. The point is of utmost relevance owing to the fact that in the case of administration of cytotoxic agents (such as anthracycline derivatives) the outcome of positive or negative biologic action, i.e. the onset of either therapeutic or toxic affects, depends on the characteristics of the interaction.
In operative conditions, advantage can be taken from this novel anti-anthracycline MAb property to improve the otherwise narrow therapeutic index of anthracycline drugs. Indeed, such monoclonal antibodies can be administered to animals, e.g. human patients, affected by tumors which are sensitive to treatment with anthracyclines, preferably before the anthracycline antibiotic treatment, or after, in case of extravasation lesions.
Thus, the invention includes a composition useful for cytostatic therapy comprising anthracycline antibiotic and an antidotal effective amount of an anti-anthracycline antibiotic monoclonal antibody produced from a hybridoma deposited at ECACC under No. 90011003 on Jan. 12, 1990. However, the invention also included composition useful for decreasing the toxic affect in animals caused by the administration of anthracycline antibiotics for cytostatic therapy wherein the composition comprises an antidotal effective amount of the anti-anthracycline antibiotic monoclonal antibody. Further, the invention includes a method of cytostatic therapy in animals, e.g. humans, comprising administering to an animal in need of such therapy an anthracycline antibiotic and an antidotal effective amount of the anti-anthracycline antibiotic monoclonal antibody. Finally, the invention includes a topical pharmaceutical composition useful for decreasing the toxic affect in animals caused by the administration of an anthracycline antibiotic comprising an antidotal effective amount of the anti-anthracycline antibiotic monoclonal antibody.
All of the foregoing are directed to decreasing the toxic affect of administration of the anthracycline antibiotic, and an effective amount of the monoclonal antibody can vary considerably. The detoxifying effect is generally proportional to the amount of the antibody administered, and, hence, even a very small amount will produce some detoxifying effect. Hence, the amount administered is not critical to the effect produced and is only related to the degree of the effect produced. However, generally speaking, the amount of the antibody administered for essentially maximum effectiveness will be substantially equimolar with the amount of anthracycline antibiotic administered, although this amount can be up to twice or more that amount. For certain administrations of the antibody, certain dosages are preferred, as set forth below.
DESCRIPTION OF PREFERRED EMBODIMENTS
In a preferred embodiment, the present invention provides a pharmaceutical composition comprising:
a) an anthracycline drug, and
b) a monoclonal antibody specific against anthracyclines,
said compounds a) and b) may be formulated separately for prior, simultaneous, separate or sequential use in cytostatic therapy.
The formulation of the anthracycline drug can be carried out according to conventional techniques such as lyophilization of an active compound solution in vials, e.g. containing 5, 10 or 20 mg thereof, the 10 mg dosage having been found to be more suitable for use in clinical setting. The MAb preparation for human use should be purified by extended chromatographic procedures based on elution of the active fraction with salt solutions (such as elution buffer: 10 mM citric acid/sodium citrate at pH 5.5 or 3.5 depending on the IgG class). The elu
Balsari Andrea
Colnaghi Maria Ines
Ghione Mario
Birch & Stewart Kolasch & Birch, LLP
Istituto Nazionale Per Lo Studio E La Cura Dei Tumori
Spector Lorraine
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