NZ627012B2 - Pharmaceutical compositions for the treatment of tumours that express egfr and ganglioside n-glycolyl gm3 (neugcgm3) - Google Patents
Pharmaceutical compositions for the treatment of tumours that express egfr and ganglioside n-glycolyl gm3 (neugcgm3) Download PDFInfo
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- NZ627012B2 NZ627012B2 NZ627012A NZ62701212A NZ627012B2 NZ 627012 B2 NZ627012 B2 NZ 627012B2 NZ 627012 A NZ627012 A NZ 627012A NZ 62701212 A NZ62701212 A NZ 62701212A NZ 627012 B2 NZ627012 B2 NZ 627012B2
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Abstract
Disclosed is a composition that comprises a compound against epidermal growth factor receptor (EGFR) and a vaccine against N-glycolyl GM3 ganglioside (NeuGcGM3) ganglioside for use in the treatment of cancer.
Description
PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF TUMOURS
THAT EXPRESS EGFR AND GANGLIOSIDE N-GLYCOLYL GM3 (NeuGcGM3)
TECHNICAL FIELD
This invention relates to the field of human medicine, particularly to the treatment of
tumors that overexpress EGFR and N-glycolyl ganglioside (NeuGcGM3).
PREVIOUS ART
Epidermal growth factor receptor (EGFR) is one of the molecular targets most used in
current clinical evaluation. This molecule is overexpressed in a variety of human
epithelial tissues (Yarden, Y., and Sliwkowski M. X., Nat. Rev. Mol. Cell Biol. 2001, 2:
127-137). Two treatments are most often used in therapies to inhibit the function of
EGF receptor: neutralization of monoclonal antibodies (MAbs) and the small
molecules that inhibit tyrosine kinase activity (TKI, tyrosine quinasa inhibitor)
(Ciardiello, F., and Tortora G., N. Engl. J. Med. 2008, 358: 1160–1174). Although it
also has been demonstrated that a vaccine with the extracellular domain of EGFR
when using the very small size particle (VSSP) as adjuvant generated an anti-
metastatic effect in the murine model of Lewis lung carcinoma (Sánchez Ramírez B.,
et al, Int. J. Cancer. 2006, 119: 2190-2199). Treatment with anti-EGFR monoclonal
antibodies mediate tumor regression by the interruption of oncogenic signals and the
induction of an innate immune response mechanism mediated by the Fc receptor
(Martinelli, E., et al, Clin. Exp. Immunol. 2009,158: 1–9).
Several human monoclonal antibodies against EGFR have been generated including:
Cetuximab (Garrett CR, and Eng C., Expert Opin Biol Ther. 2011; 11: 7, 937-49) and
Nimotuzumab (Mateo C, Immunotechnology 1997; 3:71-81). The antitumor effect of
Nimotuzumab in the therapy of different tumors that overexpress the EGFR has been
described (Crombet T, et al, Cancer Biol Therapy. 2006, 5:375–379) or in
combination with other therapies (Crombet T, et al, J Clin Oncol. 2004, 22:1646–
1654; Zhao KL, et al, Invest New Drugs. 2011 Pre published online September 8).
On the other hand, the 7A7 MAb
generated against murine EGFR demonstrated antitumor effect mediated by T
cells in the treatment of Lewis lung carcinoma (Garrido G., et al, Cancer
Immunol Immunother. 2007, 56: 1701–1710).
Another of the most studied targets is gangliosides, which are
glycosphingolipids that contain sialic acid in their structure. These molecules
are present in normal tissues and over-expressed in tumor tissues (Zhang S, et
al. Int J Cancer 73:42-49, 1997). There are two forms of sialic acid: N-
acetylated and N-glycolylated, the latter described in human tumors (Malykh Y
N., et al, Biochimie. 2001, 83:7 623–634), both as gangliosides (Kawai T. et al,
1991 Cancer. Res. (51) 1242-1246) and N-glycolylated glycoproteins (Devine
P.L., et al, Cancer Research, 1991, 51: 21, 5826–5836). For this reason these
molecules have been identified in many malignant tumors making them
attractive targets for cancer therapy. Particularly, NeuGcGM3 ganglioside is
specifically recognized by 14F7 MAb (Carr A. et al, Hybridoma, 2000, 19: 3,
241–247). This ganglioside has been identified in different tumors by various
methods (Blanco R., et al, ISRN Pathology. 2011, Article ID 953803, 10 pag.,
Marquina et al, Cancer Research. 1996, 56: 22, 5165–5171)
Active immunotherapy against NeuGcGM3 in tumors has been published using
NeuGcGM3/VSSP molecular vaccine (Estevez F., et al, Vaccine. 1999, 18:190-
197) which has demonstrated its immunogenicity and its safety in advanced
breast cancer patients (Carr A., et al, JCO. 2003, 21:1015-1021). Furthermore,
it has been demonstrated in the preclinical stage that its potent antitumor effect
(anti-metastatic), is mediated by a mechanism of cellular response of NK and
CD8+ cells (Labrada M., et al, Expert Opin. Biol. Ther. 2010, 10:2,153-162). At
the same time, an anti-tumor effect has been generated in patients with non
small cell lung cancer immunized with the anti-idiotypic vaccine (1E10 anti-
idiotypic monoclonal antibody, Racotumumab, which mimics N-glycolylated
gangliosides (Alfonso S., et al, Cancer Biology & Therapy. 2007, 6:12, 1847-
1852). Published results with this vaccine show its immunogenicity and safety
(Alfonso M., et al, Journal of Immunology. 2002, 168: 2523-2529).
The EGFR in membrane microdomains plays an essential role in controlling the
growth of tumor cells. It has been demonstrated that GM3 ganglioside inhibits
EGFR-dependent proliferation in a great variety of cell lines, both in vivo and in
vitro. GM3 inhibits EGFR kinase activity (EGFR autophosphorylation). GM3
ganglioside inhibits the autophosphorylation of the kinase domain of EGFR.
GM3 has the potential capacity of allosterically regulate structural transition of
the inactive form to signaling by the EGFR dimer in order to prevent the
autophosphorylation of the kinase intracellular domain to the ligand binding site
(Coskun Ü., et al, PNAS. 2011, 108: 22, 9044–9048). Changes in the
composition of gangliosides in the membrane are important in the regulation of
the EGFR signal transduction (Zurita AR., et al, Biochem. J. 2001, 35: 465-472).
Promising results are expected in the medical practice of simultaneous or
alternate anti-tumor therapies (Takeda K. et al, Cancer Sci., 2007; 98: 9, 1297–
1302). But not all schemes of applying anti-tumor therapies give positive and
synergistic results in practice. In a Phase III clinical study in metastatic
colorectal cancer, where the anti-EGFR MAb (Cetuximab) and anti-vascular
endothelial growth factor MAb (Bevacizumab) were used, together with a potent
chemotherapeutic drug regimen there was a worsening of the evolution of
cancer, which also caused serious adverse events as compared with patients
who received Bevacizumab plus chemotherapy only (Tol J., et al, N Engl J Med.
2009; 360:6,563-72). The successful implementation of various therapies in a
patient is the result of the specific functional relationships between selected
targets for these therapies, tumor localization, as well as the nature of the
therapies applied in each case (antibodies, vaccines or others).
Today there is evidence in the literature of a structural and functional
relationship between gangliosides and EGFR in tumor cells. However, the
practical implication of this relationship in the successful application in the same
patient of therapies against EGFR and gangliosides targets has not been
addressed either in clinical or preclinical studies. The novelty of the present
invention lies in the preclinical and clinical demonstration for the first time of the
synergistic potentiation of the antitumor activity derived from applying anti-
EGFR therapies and anti-NeuGcGM3 vaccines, in tumors co-expressing these
targets.
DESCRIPTION OF THE INVENTION
In one aspect the present invention provides a composition comprising a compound
against epidermal growth factor receptor (EGFR) and a vaccine against N-glycolyl
GM3 ganglioside (NeuGcGM3) ganglioside for use in the treatment of cancer.
The present invention relates to a composition that comprises a compound against
EGF receptor and a compound against the NeuGcGM3 ganglioside for the
manufacture of a medicament for the treatment of cancer.
The present invention further relates to use of a compound against EGFR and a
compound against NeuGcGM3 ganglioside for the preparation of a medicament for
retarding tumor growth in a patient, wherein the medicament is formulated for
administration according to the treatment regimen involving:
(a) a first administration to the patient the medicament comprising the
compound against the EGFR and,
(b) a subsequent administration to the same patient of the medicament
comprising the compound against the NeuGcGM3 ganglioside.
The present invention further relates to use of a compound against the EGFR and a
compound against NeuGcGM3 ganglioside for the preparation of a medicament for
retarding tumor growth in a patient, wherein the medicament is formulated for
administration according to the treatment regimen involving:
(a) a first administration to the patient the medicament comprising the
compound against NeuGcGM3 ganglioside and,
(b) a subsequently administration to the same patient of the medicament
comprising the compound against EGFR.
The present invention further relates to use of a compound against NeuGcGM3
ganglioside, and a compound against the EGFR, for the preparation of a medicament
for retarding tumor growth in a patient, wherein said patient suffers from lung, breast,
digestive system, urogenital system and sarcoma tumors derived of neuroectodermic
tissue and lymphoproliferative disorders.
A kit of reagents for tumor therapy in which EGFR and NeuGcGM3 ganglioside
targets are co-expressed, wherein said reagent kit is formulated for simultaneous,
staggered or alternate administration of:
(a): Compound against EGFR; and
(b): Compound against NeuGcGM3 ganglioside
The present invention relates to pharmaceutical cancer compositions aimed
specifically at EGFR and GM3 N-glycolyl ganglioside targets with the purpose of
enhancing the therapeutic effect produced by therapies against those targets
separately. In one embodiment, the invention comprises vaccines which target GM3
N glycolyl and antibodies against EGFR. In another embodiment, the invention
comprises vaccines which target N glycolyl GM3 and vaccines which target the
EGFR. In other embodiments of the invention, the vaccine against the ganglioside
target comprises vaccines such as: NeuGcGM3/VSSP vaccine and/or anti-idiotype
vaccine (Racotumumab MAb adjuvated in alumina). In another embodiment the
invention comprises anti-EGFR therapies such as Nimotuzumab MAb and/or EGFR
vaccine.
In another embodiment the invention encompasses a composition comprising a
compound against EGF receptor and a compound against the NeuGcGM3
ganglioside for use in cancer treatment.
In another aspect, the invention provides a pharmaceutical composition that
comprises any of the compounds described above, mixed with a pharmaceutically
acceptable excipient.
The compounds of the invention are useful as medicaments, and are useful for the
manufacture of medicaments, including medicaments for the treatment of conditions
such as cancer.
In another embodiment the therapeutic compositions of the present invention are
useful in cancer treatment, particularly in human tumors of different localizations.
Preferably the therapeutic compositions of the present invention are used for
treatment of those tumors that express simultaneously EGFR and the N-glycolylated
variant of gangliosides. Most preferably used to treat lung, breast, digestive system,
urogenital system and sarcoma tumors derived of neuroectodermic tissue and
lymphoproliferative disorders.
Any suitable formulation of a compound described above may be prepared for
administration by methods known in the art. The selection of useful excipients or
carriers can be achieved without undue experimentation, based on the
intended route of administration and the physical properties of the compound
being administered.
Any suitable route of administration may be used, according to the doctor
treating the patient criterion, including but not limited to: parenteral, intravenous,
intramuscular, transdermal, topical and subcutaneous. The preparation of the
suitable formulations for each route of administration is known in the art.
Formulation of each substance often includes a diluent and, in some cases,
adjuvants, buffers, preservatives, etc. These compounds may also be
administered in liposomes or microemulsions compositions.
For injection, formulations can be prepared in conventional forms such as: liquid
solutions or suspensions or solid forms suitable for the solution or suspension in
liquid prior to injection. Suitable excipients include, for example: water, saline,
dextrose and similar compounds.
The compounds of the invention may be used alone or in combination with
another therapeutic agent. In particular embodiments the invention refers to the
combination with conventional chemotherapy and/or radiation used for the type
of tumor being treated.
In another embodiment the present invention also relates to the simultaneous,
staggered or alternate use of therapies directed against EGFR and GM3 N-
glycolyl ganglioside targets in cancer treatment.
The compound against EGFR and the compound/s against GM3 N-glycolyl
ganglioside target are administered separately, even at different times and with
different frequencies. Both compounds may be administered by any known
route, such as: subcutaneous, intravenous, intradermal, intramuscular or
intraperitoneal, and the like. In many embodiments, at least one and optionally
two therapeutic agents can be administered parenterally.
When a compound or a composition of the invention are used in combination
with another anticancer agent, the present invention provides, for example,
simultaneous, staggered or alternate treatment. Thus, the compound/s of the
invention may be administered simultaneously in separate pharmaceutical
compositions, and wherein a compound of the invention can be administered
before or after the other anticancer agent with a difference of seconds, minutes,
hours, days or weeks.
The present invention provides methods for controlling and/or inhibiting tumor
growth, comprising administration of the combination of the compounds
described herein to a subject in need thereof in an amount effective to control or
reduce tumor proliferation. In certain embodiments, tumor proliferation is
associated to a tumor in different clinical stages, provided that tumors co-
express the EGFR and N-glycolyl GM3. In a particular embodiment the present
invention relates lung, breast, digestive system, urogenital system and sarcoma
tumors derived of neuroectodermic tissue and lymphoproliferative disorders.
The invention also includes methods for treating cancer in a subject in need of
such treatments which comprise methods for: administering to the subject a
therapeutically effective amount of a compound against EGFR, useful for
treating of such disorder and administering to the subject a NeuGcGM3 vaccine
or anti-idiotypic vaccine in an amount effective to enhance the desired effect.
Improve according to the present invention relates to partial or complete
regression or stabilization of the clinical symptoms of the disease. In another
embodiment of the present invention improving means decrease tumor size
and/or induce an increased survival on the subject.
In a certain embodiment the invention includes a method comprising a first
induction phase and a second maintenance phase. In a particular embodiment,
the induction phase comprises administering to the patient the anti-EGFR
vaccine in a dose in the range of approximately 0.1 to 2 mg, for a time period of
approximately 7 to 14 days for approximately 8 to 14 weeks. During that period,
patients will be administered NeuGcGM3 anti-ganglioside therapy which
comprises a NeuGcGM3 vaccine or an anti-idiotypic vaccine at a dose in the
range of approximately 0.1 to 2 mg at intervals of approximately 7 to 14 days.
The invention includes a method comprising administering to the patient
passive therapy with anti-EGFR at a dose in the range of approximately 100 to
400 mg during a time interval from approximately 6 to 10 weeks. In another
embodiment the anti-EGFR therapy comprises administration of a vaccine
against EGFR, in doses ranging from approximately 0.1 to 2 mg at time
intervals of approximately 7 to 14 days. During that period, patients will
additionally receive the NeuGcGM3 vaccine or an anti-idiotypic vaccine at
doses in the range from approximately 0.1 to 2 mg at time intervals of
approximately 7 to 14 days.
In another embodiment, the second phase of the invention treatment method
comprises a treatment schedule designed to be administered as maintenance
therapy while no toxicity and/or clinical symptoms of the disease appear. In the
maintenance phase, vaccines are preferably administered at the doses
described above and at a time interval of approximately 1 to 3 months. In
another embodiment, passive therapies are administered in an interval from
approximately 14 days to 3 months. The therapy scheme can be administered
in a time period from approximately 1 to 5 years.
In some embodiments, the therapeutic agent directed to EGFR and the
NeuGcGM3 vaccine or anti-idiotypic vaccine are administered simultaneously.
The therapeutic agent directed to EGFR and NeuGcGM3 vaccine or anti-
idiotype vaccine are sometimes used at the same time on the subject.
In some embodiments the NeuGcGM3 anti-ganglioside therapy can be
administered by: subcutaneous, intravenous, intradermal, intramuscular or
intraperitoneal injections, while the anti-EGFR therapy can be administered by
subcutaneous, intravenous, or intramuscular routes. In other embodiments the
administration site is determined by the presence of afferent lymph nodes.
In another embodiment, during the application of therapies, certain biochemical
and imaging parameters of patients are recorded. Cellular and humoral
immunity is preferably analyzed using the blood of patients. Blood tests are
performed at a frequency ranging from weekly to every six months.
"Co-expression" as used in the present invention means that both targets are
expressed but may or may not have a close structural relationship, the
operational criterium for this definition is by determination of EGFR and N-
glycolylated ganglioside (NeuGcGM3) expression by double staining, using a
fluorescent microscope and a processor that allow the superposition of images.
"Co-localization" as used in the present invention refers to both targets being
structurally close, the operational criterium for this determination is by definition
of EGFR and N-glycolylated ganglioside (NeuGcGM3) expression by double
staining using a confocal microscope.
In a further embodiment the present invention encompasses the use of a
compound against EGFR and a compound against NeuGcGM3 ganglioside, for
the preparation of a medicament for retarding tumor growth in a patient
according to the treatment regimen that involves:
(a) first administering to the patient the medicament comprising the
compound against the EGF receptor and,
(b) subsequently administering to the same patient the medicament
comprising the compound against NeuGcGM3 ganglioside.
Administration can be in this order or in reverse order, that is, first administering
to the patient the medicament comprising the compound against NeuGcGM3
ganglioside and subsequently administering to the same patient the
medicament comprising the compound against EGF receptor.
In a particular embodiment the present invention encompasses a kit of reagents
for therapy of tumors which co-express EGFR and NeuGcGM3 ganglioside
targets, said kit comprises the simultaneous, staggered or alternate
administration of a compound against EGFR and another compound against
NeuGcGM3 ganglioside.
Determination of co-expression of EGFR and N-glycolylated ganglioside
(NeuGcGM3) in human tumors of different localizations.
Measuring the expression of EGFR and NeuGcGM3 therapeutic targets in
tumors can be performed using any of the methods described in the art for such
purposes. Such measurement is performed in tumors of different localizations
and origin, on tumor samples previously fixed in formol or on fresh tissue slices.
In a preferred embodiment, the detection is performed by employing
immunological techniques for EGFR and the GM3 N-glycolated variant
recognition. Particularly immunohistochemistry and brightfield microscopy can
be used separately for immunorecognition of both molecules or
immunofluorescence and fluorescence microscopy to determine the co-
expression or the immunofluorescence and confocal microscopy to determine
the co-localization.
In preferred embodiments of the present invention the EGFR can be detected
using ior egf/R3m MAb (5-20μg/ml), described in the EP 0586002B1 and
NeuGcGM3 can be detected using 14F7 MAb (5-25μg/ml), described in the US
6,429,295 or EP 0972782B1. In one embodiment of the present invention, for
immunorecognition by separate of both molecules (Simple staining) Dako,
LSAB Peroxidase System, DAB (Dako, Carpinteria, California, USA) can be
used as detection system.
Given that the EGFR is located on the cytoplasmic membrane of tumor cells
while the GM3 N-glycolyl is located in the membrane and intracytoplasmic,
immunorecognition is deemed to be positive when the intensity of the reaction is
equal or larger 20% positivity.
In a preferred embodiment, the co-expression of both molecules can be
detected using a double staining technique and analyzed by fluorescence
microscopy, only in those tumor samples where immunorecognition was
previously positive for both molecules separately. While the co-localization of
both molecules can be detected by using a double staining technique and
analyzed by confocal fluorescence microscopy. In a preferred embodiment
immunorecognition of the EGFR is performed by incubation with Ior egf/R3m
mAb (5-20μg/ml) for 1 hr, followed by an IgG antibody conjugated to rhodamine
(Dako, Carpinteria, California, USA). In another preferred embodiment,
NeuGcGM3 immunodetection is performed using biotinylated 14F7 mAb (5-
20μg/ml), 30 min. Followed by FITC-conjugated streptavidin (Dako, Carpinteria,
California, USA).
The following examples illustrate a preferred embodiment of the present
invention and therefore serve to illustrate it but in no case should they be
considered as a limitation.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1. The EGFR is co-localized with NeuGcGM3 ganglioside in different
murine tumors. Co-localization (C and F) of EGFR and NeuGcGM3 ganglioside
in the lung metastases induced in Lewis epidermoid carcinoma (A-C) and
murine myeloma P3-X63-Ag.8653 (D-F).
Figure 2. Anti-EGFR therapy (7A7 MAb) in combination with NeuGcGM3
(NeuGcGM3/VSSP) anti-ganglioside vaccine synergistically increases the
survival of C57BL/6 mice bearing Lewis lung carcinoma.
Figure 3. Objective response to passive therapy against EGFR (Nimotuzumab)
and NeuGcGM3 (Racotumumab/Alumina) anti-ganglioside vaccine in a patient
with a non-small cell lung carcinoma.
Figure 4. Surprising clinical response to anti-EGFR (Nimotuzumab) in
combination with NeuGcGM3 (NeuGcGM3/VSSP) ganglioside vaccine
therapies in a patient with retroperitoneal-peripancreatic hemangiopericytoma.
EXAMPLES
Example 1: Measuring EGFR and NeuGcGM3 ganglioside coexpression in
different human tumors.
The tumor samples were fixed in neutral buffered formalin and processed by
paraffin inclusion technique, which is known to those skilled in the art.
The tissue sections obtained which had a thickness of 5 microns were
maintained at 60 C for 30 min, deparaffinized and rehydrated in a series of
decreasing alcohols, kept in distilled water for 10 minutes and washed with TBS
for 5 minutes. The reactivity of total tissue protein was blocked with a
commercially available solution (Dako, Carpinteria, California, USA) for 30 min.
The EGFR was immunodetected using the ior egf/R3m (20μg/ml) for 1 hr. The
immunorecognition of NeuGcGM3 was performed using 14F7 (MAb 20μg/ml)
for 30 min. After reaction of the primary antibodies, in both cases, the detection
system used was Dako, LSABR Peroxidase System, DAB (Dako, Carpinteria,
California, USA). Tissue sections were dehydrated and Mayer's hematoxylin
contrast was used (Dako, Carpinteria, California, USA). The negative control
was obtained by substituting the primary antibody (Ior egf/R3m MAb or 14F7
MAb) by TBS wash solution (1X) and breast ductal carcinoma was used as a
positive control.
The immunorecognition of the EGFR was located on the cytoplasmic
membrane of tumor cells and the NeuGcGM3 ganglioside was detected
intracytoplasmic and/or in the cytoplasmic membrane of cells.
Double staining: The EGFR was detected with Ior egf/R3m MAb (anti-EGFR)
and then incubated with FITC-conjugated streptavidin (Dako, Carpinteria,
California, USA). NeuGcGM3 was detected with biotinylated 14F7 MAb and
subsequently with anti-murine IgG antibody conjugated to rhodamine (Dako,
Carpinteria, California, USA). Co-expression of both molecules in tumor cells
were identified in yellow in the images. Tissue sections were digitized and
analyzed using a camera attached to an Olympus BX51 fluorescence
microscope (Olympus, Japan). For the analysis of the digitized images ImageJ
image processor version 1.43u was used.
Table 1 shows tumors from different localizations wherein EGFR and
NeuGcGM3 ganglioside are co-expressed.
Intensity: - negative + weak + + moderate, + + + intense.
EGFR NeuGcGM3 Double positive
Positive Intensity Positive Intensity Positive Intensity
Histological
cases Range cases Range cases Range
types
(%) (%) (%)
Respiratory
8/10(80) ++/+++ 6/10(60) +/+++ 6/10(60) +/+++
system
NSCLC
Digestive
2/3(66,6) ++/+++ 2/3 66,6) +/+++
3/3 (100)
++/+++
system
4/4 100) + /+++ 4/4(100) ++
4/4 (100)
+/+++
Stomach
2/4(50) ++/+++ 2/4(50) ++
3/4 (75)
++/+++
(ADC)
3/4(75) ++/+++ 3/4 (75) +/+++
4/4(100)
++/+++
Colorectal
(ADC)
Pancreas
(ADC)
Liver
Urogenital
2/2 (100) ++/+++ 1/2 (50) ++ 1/2 (50) ++
system
Bladder
Nervous
/5(100) +++ 3/5(60) ++ 3/5(60) ++
system
Glioblastoma
multiforme
2/3 (66,6) +/++ 1/3 (33,3) + 1/3(33,3) +
Sarcomas
Haemopoieti
c system
2/3(66,6) + 2/3 (66,6) + 2/3(66,6) +
Non-Hodgkin
lymphoma
Example 2. Coexpression and co-localization measurement of EGFR and
NeuGcGM3 ganglioside in murine tumor models
Murine tumor models used were Lewis lung carcinoma (3LL-D122), and
Myeloma P3-X63-Ag8.653 (X63).
Double staining was performed to determine the co-expression/co-localization.
The immunorecognition of EGFR was performed by incubation with 7A7 MAb
(20μg/ml), biotinylated, for 1 hr, followed by incubation with FITC-conjugated
Streptavidin (Dako, Carpinteria, California, USA). Immunostaining of
NeuGcGM3 was determined by incubation with 14F7 MAb (20μg/ml), for 30
min, followed by incubation with an anti-murine IgG antibody conjugated to
rhodamine (Dako, Carpinteria, California, USA). The negative control was
obtained by replacing the primary antibody (7A7 MAb or 14F7 MAb) by TBS
wash solution (1X). The co-expression was determined by using an Olympus
BX51 fluorescence microscope (Olympus, Japan) and analysis of the digitized
images using ImageJ image processor version 1.43u. The co-localization was
determined by confocal laser microscope Flouview FV500 (Olympus, Japan).
Figure 1 shows the co-localization of EGFR and NeuGcGM3 in tumor samples
from various murine models. The EGFR was identified with biotinylated 7A7
MAb followed by FITC-coupled streptavidin. The yellow color identifies the co-
localization (C and F) of both molecules in tumor cells of murine models by
color overlay.
Example 3. Measurement of survival of C57BL/6 mice bearing Lewis lung
carcinoma treated with NeuGcGM3/VSSP vaccine and 7A7 mAb.
Spontaneous metastasis model.
The animals were inoculated in the right footpad with 2x10 cells of Lewis
epidermoid carcinoma (3LL-D122), in a volume of 0.05 ml, which corresponded
to day 0 of the experimental protocol. On day 3 of the experiment the animals
were randomized into four experimental groups of 10 animals each. On day 24,
when the tumor reached a volume of 8-9 mm primary tumor surgery was
performed. From day 48, observation of the clinical status of the animals began.
Survival data were analyzed using the Log-rank test, p <0.05, and displayed on
a Kaplan-Meier plot. The result includes three experiments performed on equal
conditions.
Experimental groups
Untreated control. (T)
Passive anti-EGFR therapy: 7A7 MAb, intravenously at a dose of 56μg in 200 l
of Saline Solution, on days 3, 5, 7, 9, 31, 33 and 35.
Active anti-NeuGcGM3 therapy: NeuGcGM3/VSSP vaccine, subcutaneously at
a dose of 200 μg in 200 l, on days 7, 21, 35 and 47.
Simultaneous administration of anti-EGFR and anti-NeuGcGM3 therapies as
described for groups 2 and 3.
Figure 2a shows that the simultaneous administration of anti-EGFR and anti-
NeuGcGM3 (group 4) therapies on the lung metastasis model induced with
Lewis lung carcinoma, increased survival of the animals by 60% compared with
the other experimental groups. Surviving animals (one in group 4) were
sacrificed one week after the end of the experiment and their lungs were
removed. Macroscopic analysis showed that only one animal showed two lung
metastases, noticing also that the rest the lungs of the animals were normal.
(Figure 2b). This result demonstrates a strong synergy of antitumor activity of
anti-EGFR and anti-NeuGcGM3 therapies studied in this murine tumor model
wherein EGFR and NeuGcGM3 are co-localizated (see Example 2)
Example 4. Measurement of survival of cancer patients undergoing therapy with
Nimotuzumab antibody and Racotumumab/Alumina vaccine.
Given the finding on the frequent co-localization/co-expression of therapeutic
targets EGFR and NeuGcGM3 ganglioside in samples of human lung tumor
(Example 1); and the preclinical evidence shown in Example 3, we proceeded
to study simultaneous treatment with anti-EGFR (Nimotuzumab antibody) and
anti-ganglioside (Racotumumab/Alumina anti-idiotypic vaccine) therapies in
lung cancer patients who had received the standard therapy for each tumor site
and who had already disease progression.
Table 2 shows the test results from expanded use program (compassionate) of
Racotumomab (1E10/Alumina) vaccine as single therapy or in combination with
Nimotuzumab. Survival of cancer patients with non-small cell lung cancer
(NSCLC) in advanced stages (Recurrent and/or Metastatic) is observed on it. It
should be noted that patients on this study had received all established
standard treatment lines and were only candidates for palliative, non onco-
specific, therapy and that at the time of inclusion in the trial they had disease
progression. In the group of patients that received therapy simultaneously
against both targets a significant increase in overall survival at two years of
treatment was observed, as compared with those who received only the
monotherapies.
Table 2. Increased survival of patients with non-small cell lung cancer treated
with anti-EGFR (Nimotuzumab antibody) and anti-ganglioside
(Racotumumab/Alumina anti-idiotypic vaccine) therapies at two years of
treatment.
Treatment Groups SV at 12 m SV at 24 m
(%) (%)
Racotumumab/Alumina 42.7 16.1
(n ₌86)
Nimotuzumab (n ₌165) 36 21.4
Racotumumab/Alumina + 40.7 37.7
Nimotuzumab (n ₌88)
Figure 3 shows the objective response to passive therapy against EGFR
(Nimotuzumab) and NeuGcGM3 anti-ganglioside vaccine (Racotumomab/
Alumina) in a patient with NSCLC that, as mentioned above, had received all
established standard treatments lines, which was candidate only for palliative,
non onco-specific, therapy and that at the time of inclusion in the trial had
disease progression. Figure 3A shows the localization and extent of the tumor
at the time of diagnosis. Figure 3B shows the results from Computed
Tomography (CT) at two years after treatment. In the latter figure only areas of
fibroblastic response with areas of increased transparency in relation with bullae
of emphysema that can be seen and no lung tumor lesion is observed. The
same radiographic image remains three years later. This result indicates a
surprising complete remission of a very advanced tumor as a result of therapy.
Example 5. Measurement of clinical response in a patient with retroperitoneal-
peripancreatic hemangiopericytoma treated with the Nimotuzumab antibody and
NeuGcGM3/VSSP vaccine.
Figure 4 shows a sequential computed tomography of the abdomen of a patient
with retroperitoneal-peripancreatic hemangiopericytoma (soft tissue tumor), with
no response to radiotherapy and chemotherapy. The patient received anti-
EGFR (Nimotuzumab) and anti-ganglioside (NeuGcGM3/VSSP vaccine)
therapies 18 months after the initial diagnosis. The patient had severe pain and
a throbbing tumor mass in the periumbilical region and weight loss of more than
kilos. Figures 4 A and B correspond to the start time of therapies; C and D
correspond to the evaluation after three years. Three years after application of
treatment a stabilization of the disease can be observed, as evidenced by both
images wherein the tumor size remains the same. Moreover, in the 72-month
evaluation, patient maintains an excellent quality of life and is able to continue
his working life. A tendency towards reduction of the tumor mass can also be
seen. In summary, there is a surprising clinical benefit as response to the treatment.
Cancer patients treated with anti-EGFR and anti-ganglioside immunotherapy, as
described in this invention, exhibit excellent tolerance (no significant toxicity) for long
periods of treatment. The therapy promotes stabilization of the disease, increasing the
quality of life, time to progression and overall survival of patients. The therapy
described above has a superior effect to that observed in patients receiving traditional
anti-EGFR or anti-ganglioside monotherapies.
The discussion of documents, acts, materials, devices, articles and the like is included
in this specification solely for the purpose of providing a context for the present
invention. It is not suggested or represented that any or all of these matters formed
part of the prior art base or were common general knowledge in the field relevant to
the present invention as it existed before the priority date of each claim of this
application.
Where the terms “comprise”, “comprises”, “comprised” or “comprising” are used in this
specification (including the claims) they are to be interpreted as specifying the
presence of the stated features, integers, steps or components, but not precluding the
presence of one or more other features, integers, steps or components, or group
thereof.
THE
Claims (12)
1. A composition that comprises a compound against epidermal growth factor receptor (EGFR) and a vaccine against N-glycolyl GM3 ganglioside (NeuGcGM3) ganglioside for use in the treatment of cancer. 5
2. The composition of claim 1 wherein the compound against the EGF receptor is humanized monoclonal antibody Nimotuzumab.
3. The composition of claim 1 wherein the compound against the EGF receptor is an anti-EGFR vaccine.
4. The composition of claim 1 wherein the vaccine has NeuGcGM3/very small 10 size particle (VSSP) as active principle.
5. The composition of claim 1 wherein the vaccine is Racotumumab anti-idiotypic vaccine adjuvated with alumina.
6. The composition of claim 1 wherein the cancer is a tumor that co-expresses EGFR and NeuGcGM3 ganglioside targets. 15
7. The composition of claim 6 wherein the tumor is a cancer selected from the group consisting of lung, breast, digestive system, urogenital system and sarcoma tumors derived of neuroectodermic tissue and lymphoproliferative disorders.
8. The composition of claim 2, wherein the dosage of the monoclonal antibody 20 against EGFR is in the range from approximately 100 to 400 mg.
9. The composition of claim 3, wherein the dose of the vaccine against EGFR is in the range from approximately 0.1 to 2 mg.
10. The composition of claim 4, wherein the dose of the NeuGcGM3 vaccine or the anti-idiotypic vaccine is in the range from approximately 0.1 to 2 mg. 25
11. The composition of claim 5, wherein the dose of the NeuGcGM3 vaccine or the anti-idiotypic vaccine is in the range from approximately 0.1 to 2 mg.
12. The composition according to claim 1, as herein describe with reference to the Examples and/or
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CU20110245A CU24070B1 (en) | 2011-12-27 | 2011-12-27 | PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF TUMORS EXPRESSING REGF AND GM3 N-GLYCOLLATED GANGLIOSIDS (NEUGCGM3) |
CUCU/P/2011/0245 | 2011-12-27 | ||
PCT/CU2012/000007 WO2013097834A1 (en) | 2011-12-27 | 2012-12-04 | Pharmaceutical compositions for the treatment of tumours that express egfr and ganglioside n-glycolyl gm3 (neugcgm3) |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ627012A NZ627012A (en) | 2016-01-29 |
NZ627012B2 true NZ627012B2 (en) | 2016-05-03 |
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