Note: Descriptions are shown in the official language in which they were submitted.
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aromatase inhibitors and monoclonal anti-her2 antibodies as antitumors agents
The present invention concerns the treatment of hormone
dependent disorders characterized by the overexpression of
HER2. More specifically, the invention concerns the
treatment of a human being susceptible to or diagnosed
with a disorder characterized by the overexpression of
HER2 with a combination of an anti-HER2 antibody and an
aromatase inhibitor.
Proto-oncogens that encode growth factors and growth
factors receptors have been identified to play important
roles in the pathogenesis of various malignancies,
including breast cancer. In particular numerous studies
have demonstrated the prognostic relevance of p185(HER2),
which is overexpressed in 10% to 400 of human breast
tumors. Moreover a recombinant humanized anti-HER2
monoclonal antibody (a humanized version of the murine
anti-HER-2 antibody 4D5, referred to as Herceptin~) has
been found clinically active in patients with HER2-
overexpressing breast cancer (J. Clin. Oncol. 14:737-744,
1996). Also the utility of aromatase inhibitors is well
acknowledged in anticancer therapy. However, it is also
well known in the art that administration to a patient of
therapeutically effective amounts of aromatase inhibitors
can. cause considerable side effects. The major toxicities
are for instance lethargy, hot flashes, rash, transient
leukopenia, dizzines, nausea, constipation and vomiting.
On the other hand, also administration to a patient of
therapeutically effective amounts of an antibody against
HER2 can similarly cause considerable side effects, e.g.
hypersensitivity, alterations of renal function,
myocardial lesions and cardiotoxicity in general.
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The inventors of the present invention have found that a
combination therapy of an hormone dependent disorder
characterized by the overexpression of HER2, comprising a
therapeutically effective amount of an aromatase inhibitor
and a therapeutically effective amount of an antibody
against HER2, can produce a therapeutic effect which is
greater than that obtainable by single administration of a
therapeutically effective amount of either a sole
aromatase inhibitor or a sole antibody against HER2.
Similarly they have found that a combination therapy of an
hormone dependent disorder characterized by the
overexpression of HER2, comprising a therapeutically sub-
effective amount of an aromatase inhibitor and a
therapeutically sub-effective amount of an antibody
against HER2, can produce substantially the same
therapeutic effect, which is obtainable by single
administration of a therapeutically effective amount of
either an aromatase inhibitor or an antibody against HER2.
The most important, they have found that such newly
obtained therapeutic effect is not paralleled by the toxic
effects, otherwise caused by single administrations of
either therapeutically effective amounts of an aromatase
inhibitor or therapeutically effective amounts of an anti-
HER2 antibody.
In view of the above, the effectiveness of an aromatase
inhibitor and an antibody against HER2 is significantly
increased without a parallel increased toxicity. In other
words, the combined. therapy of the present invention
enhances the therapeutic effects of the aromatase
inhibitor and the antibody against HER2 and thus yields
more effective and less toxic treatment for h.ormone-
dependent disorders.
Accordingly, the present invention provides a new and
valuable tool in the therapy of hormone dependent
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disorders characterized by the overexpression of HER2. The
advantages provided by the present invention can be
appreciated by their preferred features, described
herebelow.
Examples of such disorders are cancers, e.g. breast,
cervical, ovarian and endometrial cancers, and
endometriosis. However such disorder is preferably breast
cancer in a human being, in particular a female,
Accordingly, the present invention provides, as a first
object, a pharmaceutical composition comprising an
aromatase inhibitor and an antibody against HER2, having a
synergistic or superadditive therapeutic activity against
an hormone-dependent disorder characterized by the
overexpression of HER2.
The present invention also provides the use of an
aromatase inhibitor in the manufacture of a pharmaceutical
composition for treatment of an hormone-dependent disorder
characterized by the overexpression of HER2, the treatment
additionally comprising the administration of a
composition comprising an antibody against HER2, in
amounts effective to produce a superadditive effect.
Examples of aromatase inhibitors according to the
invention are exemestane, aminoglutethimide, roglethimide,
pyridoglutethimide, anastrazole, trilostane, testolactone,
formestane, atamestane, 1-methyl-1,4-androstadiene-3,17
dione (MAD), ketokonazole, fadrozole, letrozole, vorozole
and anastrozole.
Preferred examples of aromatase inhibitors according to
the invention are exemestane, anastrozole and letrozole,
in particular exemestane.
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The aromatase inhibitors cited herein are well known
products, which are cited for instance in Cancer-Treat-
Res.: 94, 231-254, 1998 and WO 99/30708.
Unless otherwise indicated, the terms "HER2" and ErbB2"
when used herein refer to the human protein and are used
interchangeably.
An antibody against HER2, according to the invention, can
be either and "intact" antibody or a fragment thereof.
The term "antibody" is used in the broadest sense and
specifically covers intact monoclonal antibodies,
polyclonal antibodies, multispecific antibodies (e. g.
bispecific antibodies) formed from at least two intact
antibodies, and antibody fragments so long as they exhibit
the desired biological activity. "Antibody fragments"
l5 comprise a portion of an intact antibody, preferably the
antigen binding or variable region of the intact antibody.
Examples of antibody fragments include Fab, Fab', F(ab')2,
and Fv fragments; diabodies; linear antibodies; single
chain antbody molecules; and multispecific antibodies
formed from antibody fragments.
A preferred example of an antibody against HER2 is
trastuzumab.
The recombinant humanized monoclonal antibody anti-HER2
trastuzumab (Herceptin°) is described in various
scientific publications, for example Cancer Res., 1998,
58: 2825-2831.
The present invention also provides a product comprising
an aromatase inhibitor and an antibody against HER2, as
combined preparation for simultaneous, separate or
sequential administration, in amounts to produce a
synergistic or superadditive therapeutic activity against
an hormone-dependent disorder characterized by the
overexpression of HER2.
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In a further aspect, the present invention provides a kit
comprising, in a suitable container means, a
pharmaceutical composition containing an aromatase
inhibitor, as an active agent, and an antibody against
5 HER2, as a further active agent, in amounts to produce a
synergistic or superadditive therapeutic activity against
hormone-dependent disorder characterized by the
overexpression of HER2.
A further aspect of the present invention is to provide a
method of treating a human being, particularly a female,
suffering from an hormone-dependent disorder characterized
by the overexpression of HER2 comprising administering to
said human being an aromatase inhibitor and an antibody
against HER2, in amounts effective to produce a
superadditive or synergistic therapeutic effect.
A still further aspect of the present invention is to
provide a method for lowering the side effects (adverse
reactions) caused by antitumor therapy with an aromatase
inhibitor in a human being, particularly a female,
suffering from an hormone-dependent tumor overexpressing
HER2, the method comprising administering to said human
being a combined preparation comprising an aromatase
inhibitor and an antibody against HER2, in amounts
effective to produce a superadditive or synergistic
antitumor effect.
A still further aspect of the present invention is to
provide a method for lowering the side effects (adverse
reactions) caused by antitumor therapy with an antibody
against HER2 in a human being, particularly a female,
suffering from an hormone-dependent tumor overexpressing
HER2, the method comprising administering to said human
being a combined preparation comprising an antibody
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against HER2 and an aromatase inhibitor, in amounts
effective to produce a superadditive or synergistic
antitumor effect.
By the term "a superadditive or synergistic antitumor
effect" as used herein is meant the inhibition of the
growth tumor, preferably the complete regression of the
tumor, by administering a combination of an aromatase
inhibitor, as defined above, and an antibody against a
HER2, to a human being, particularly a human female.
Said preparation having therefore a potentiated antitumor
(superadditive) activity with respect to products
containing either an aromatase inhibitor or an antibody
against HER2.
By the term "administered" or "administering" as used
herein is meant any acceptable manner of~administering a
drug to a patient which is medically acceptable including
parenteral and oral administration.
By "parenteral" is meant intravenous, subcutaneous,
intradermal or intramuscular administration.
Oral administration includes administering the costituents
of the combined preparation in a suitable oral form such
as, e.g., tablets, capsules, suspensions, solutions,
emulsions, powders, syrups and the like.
Parenteral administration includes administering the
constituents of the combined preparation by subcutaneous,
subcutaneous, intravenous or intramuscular injections.
The actual preferred method and order of administration of
the combined preparations of the invention may vary
according to, inter alia, the particular pharmaceutical
formulation of the aromatase inhibitor being utilized, the
particular pharmaceutical formulation of the antibody
against the growth factor receptor being utilized, the
particular cancer being treated and the particular patient
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being treated.
The dosage ranges for the administration of the combined
preparation may vary with the age, condition and extent of
the disease in the patient and can be determined by one of
skill in the art.
The dosage regimen must therefore be tailored to the
particular of the patient's conditions, response and
associate treatments in a manner which is conventional for
any therapy, and may need to be adjusted in response to
changes in conditions and/or in light of other clinical
conditions.
In the combined method of treatment according to the
subject invention, the aromatase inhibitor may be
administered simultaneously with the antibody against HER2
or the compounds may be administered sequentially, in
either order.
An effective amount of an aromatase inhibitor antitumor
agent may vary from about 0.5 to about 500 mg pro dose 1-2
times a day. Exemestane, for example, may be administered
orally in a dosage range varying from about 5 to about 200
mg, and particularly, from about 10 to about 25 mg, or
parenterally from about 50 to about 500 mg, in particular
from about 100 to about 250 mg.
Fadrozole, for example, may be administered orally in a
dosage range varying from about 0.5 to about 10 mg, and
particularly, from about 1 to about 2 mg.
Letrozole, for example, may be administered orally in a
dosage range varying from about 0.5 to about 10 mg, and
particularly, from about 1 to about 2.5 mg.
Formestane, for example, may be administered parenterally
in a dosage range varying from about 250 to about 500 mg,
and particularly, from about 250 to about 300 mg.
Anastrozole, for example, may be administered orally in a
dosage range varying from about 0.5 to about 10 mg, and
particularly, from about 1 to about 2 mg.
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In the method of the subject invention, for example for
the administration of the recombinant humanized monoclonal
antibody anti-HER2 trastuzumab, the course of therapy
generally employed is from about 1 to about 1000 mg/m2 of
body surface area. More preferably, the course therapy
employed is from about 50 to about 500 mg/m2 of body
surface area.
The therapy method according to the present invention is,
in particular, suitable for treating a human being
suffering from hormone dependent disorders, characterized
by the overexpression of HER2. Typical examples of such
disorders are endometriosis and tumors, like ovarian,
cervical and endometrial cancers in a human female or
breast cancer in a human being, in particular a female.
More in particular, the combined use of an aromatase
inhibitor, according to the invention, preferably
exemestane, and a recombinant humanized anti-HER2
antibody, for example the recombinant humanized monoclonal
antibody anti-HER2 trastuzumab, can be suitable for the
treatment of patients with cancers over-expressing the
HER2 protein, for example, for patient with breast cancer,
in particular with metastatic breast cancer, over-
expressing the HER2 protein.
Suitable modifications and adaptations of a variety of
conditions and parameters normally encountered in clinical
therapy which are obvious to those skilled in the art are
within the scope of this invention.
A pharmaceutically composition containing an aromatase
inhibitor and/or an antibody against HER2 can be prepared
according to well known techniques to those skilled in the
art. For instance a pharmaceutical composition containing
exemestane can be prepared according to US 4,808,616.
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