WO2022254340A1 - Compositions and methods for treating with a combination of alternating electric fields and trastuzumab - Google Patents
Compositions and methods for treating with a combination of alternating electric fields and trastuzumab Download PDFInfo
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- WO2022254340A1 WO2022254340A1 PCT/IB2022/055092 IB2022055092W WO2022254340A1 WO 2022254340 A1 WO2022254340 A1 WO 2022254340A1 IB 2022055092 W IB2022055092 W IB 2022055092W WO 2022254340 A1 WO2022254340 A1 WO 2022254340A1
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- trastuzumab
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- alternating electric
- electric field
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/36002—Cancer treatment, e.g. tumour
Definitions
- This drug also targets the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway and RAS/RAF/MEK/MAP kinase (MAPK) pathways.
- PI3K phosphatidylinositol 3-kinase
- MAPK MAP kinase
- ADCC antibody-dependent cellular cytotoxicity
- TTF trastuzumab
- trastuzumab combined antitumor effects on HER2 -positive breast cancer representative cell lines alongside a tumor xenograft model was studied.
- the results showed that the TTF therapy can enhance significantly the growth inhibition induce by trastuzumab.
- one pair of electrodes is located to the left and right (LR) of the target site, and the other pair of electrodes is located anterior and posterior (AP) to the target site. Cycling the field between these two directions (i.e., LR and AP) ensures that a maximal range of cell orientations is targeted.
- the term “subject” refers to the target of administration, e.g. an animal.
- the subject of the disclosed methods can be a vertebrate, such as a mammal.
- the subject can be a human.
- the term does not denote a particular age or sex.
- Subject can be used interchangeably with “individual” or “patient.”
- the subject of administration can mean the recipient of the alternating electrical field.
- the subject of administration can be a subject with early and advanced HER2 -positive breast cancer.
- a preparation can be administered prophylactically; that is, administered for prevention of breast or stomach cancer.
- the skilled person can determine an efficacious dose, an efficacious schedule, or an efficacious route of administration so as to treat a subject.
- administering comprises exposing or applying.
- exposing a target site or subject to alternating electrical fields or applying alternating electrical fields to a target site or subject means administering alternating electrical fields to the target site or subject.
- the alternating electric fields can be applied for a variety of different intervals ranging from 0.5 hours to 72 hours. In some aspects, a different duration can be used (e.g., between 0.5 hours and 14 days). In some aspects, application of the alternating electric fields can be repeated periodically. For example, the alternating electric fields can be applied every day for a two hour duration.
- the disclosed methods comprising applying one or more alternating electric fields to a cell or to a subject.
- the alternating electric field is applied to a target site or tumor target site.
- this can often refer to applying alternating electric fields to a subject comprising a cell.
- applying alternating electric fields to a target site of a subject results in applying alternating electric fields to a cell.
- compositions comprising one or more trastuzumab antibodies.
- Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer’s dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti -oxidants, chelating agents, and inert gases and the like.
- the trastuzumab comprises a detectable agent.
- a detectable agent or label, is any molecule that can be associated with trastuzumab, directly or indirectly, and which results in a measurable, detectable signal, either directly or indirectly.
- Many such labels for conjugating or coupling to an antibody are known to those of skill in the art.
- detection agents can be, but are not limited to, radioactive isotopes, fluorescent molecules (fluorophore), phosphorescent molecules, enzymes, antibodies, and ligands.
- the frequency of the alternating electric field is any of those described herein. In some aspects, the frequency of the alternating electric field is between 100 and 500 kHz. For example, in some aspects, the frequency of the alternating electric field is 150 kHz.
- trastuzumab is administered intratumorally, intracranially, intraventricularly, intrathecally, epidurally, intradurally, intravascularly, intravenously (targeted or non-targeted), intraarterially, intramuscularly, subcutaneously, intraperitoneally, orally, intranasally, via intratumor injection (e.g. computed tomography-guided, during surgery or biopsy) or via inhalation.
- the trastuzumab is administered in a pharmaceutical composition.
- the pharmaceutical composition can be any of those described herein.
- the subject in need thereof has cancer.
- the cancer can be breast or stomach cancer.
- the cancer can be a HER2 positive cancer.
- a subject in need thereof comprising applying an alternating electric field, at a frequency for a period of time, to a target site of the subject in need thereof; administering trastuzumab to the target site of the subject in need thereof and further comprising administering a second therapeutic agent to the subject.
- the second therapeutic agent can be a chemotherapeutic agent.
- Chemotherapeutic agents can be, but are not limited to, alkylating agents, antimetabolites, anthracyclines, antitumor antibiotics, monoclonal antibodies, platinums, or plant alkaloids.
- the trastuzumab is administered in a therapeutically effective amount.
- the target site comprises a cell.
- the cell can be a cancer cell.
- a cancer cell can be, but is not limited to, a breast or stomach cancer cell or any Her2 positive cell.
- the trastuzumab comprises a detectable agent.
- a detectable agent or label, is any molecule that can be associated with trastuzumab, directly or indirectly, and which results in a measurable, detectable signal, either directly or indirectly.
- Many such labels for conjugating or coupling to an antibody are known to those of skill in the art.
- detection agents can be, but are not limited to, radioactive isotopes, fluorescent molecules (fluorophore), phosphorescent molecules, enzymes, antibodies, and ligands.
- Preferred fluorescent labels for combinatorial multicolor coding are FITC and the cyanine dyes Cy3, Cy3.5, Cy5, Cy5.5 and Cy7.
- the absorption and emission maxima, respectively, for these fluors are: FITC (490 nm; 520 nm), Cy3 (554 nm; 568 nm), Cy3.5 (581 nm; 588 nm), Cy5 (652 nm: 672 nm), Cy5.5 (682 nm; 703 nm) and Cy7 (755 nm; 778 nm), thus allowing their simultaneous detection.
- the fluorescent labels can be obtained from a variety of commercial sources, including Molecular Probes, Eugene, OR and Research Organics, Cleveland, Ohio.
- one or more of pAKT, pERK, and pHER2 expression is reduced as a result of the increased accumulation of trastuzumab at the target site.
- a target site of a subject in need thereof comprising applying an alternating electric field, at a frequency for a period of time, to a target site of the subject in need thereof; administering trastuzumab to the target site of the subject in need thereof, wherein cancer cell proliferation is inhibited; and further comprising administering a second therapeutic agent to the subject.
- the second therapeutic agent can be a chemotherapeutic agent.
- Chemotherapeutic agents can be, but are not limited to, alkylating agents, antimetabolites, anthracyclines, antitumor antibiotics, monoclonal antibodies, platinums, or plant alkaloids.
- fluorescent labels include, but are not limited to, fluorescein (FITC), 5,6-carboxymethyl fluorescein, Texas red, nitrobenz-2-oxa-l,3-diazol-4-yl (NBD), coumarin, dansyl chloride, rhodamine, 4'-6-diamidino-2-phenylinodole (DAPI), and the cyanine dyes Cy3, Cy3.5, Cy5, Cy5.5 and Cy7.
- Preferred fluorescent labels are fluorescein (5-carboxyfluorescein-N- hydroxysuccinimide ester) and rhodamine (5,6-tetramethyl rhodamine).
- CFA Colony Formation Assay
- Alexa 488-NHS Ester (Invitrogen, Waltham, MA, USA) was prepared using DMSO. It contained 1% acetic acid was dissolved in 500 pL TRZ (10 mg/mL) in 1 M sodium bicarbonate solution with pH of 8.4. The obtained reaction was incubated at room temperature for 1 hour after which it was purified through size exclusion PD-10 column (GE Healthcare Bio-Sciences AB, Uppsala, Sweden) and connected with an ultra-violet/visible detector, which was set at 517-nm maximum wavelength.
- Jimtl cells was treated with fixed dose of trastuzumab to evaluate its effects on breast cancer cells in cell morphology and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and colony forming assay (FIG. 2A-2C).
- Jimtl cells were treated with TTFs (0.9 V/cm), TRZ, or a combination of the two and the changes related to morphology were observed using a phase -contrast microscope in combined treatment group.
- the cell growth was noted to be significantly inhibited after a 48-hour treatment at 100 pg trastuzumab.
- TTF tumor necrosis factor
- Numerous in vivo experiments have pointed towards the promising results of TTF’s in executing anti-tumor activities. Further, TTF’s are also capable of impeding the human lung tumor as demonstrated in the xenograft models and, GBM or GBM patient-derived stem cell tumor bearing models [22,23]
Abstract
Description
Claims
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CN202280039734.3A CN117425515A (en) | 2021-06-01 | 2022-05-31 | Compositions and methods for treatment with a combination of alternating electric field and trastuzumab |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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US7565205B2 (en) | 2000-02-17 | 2009-07-21 | Standen Ltd. | Treating a tumor or the like with electric fields at different orientations |
US20200269041A1 (en) * | 2019-02-22 | 2020-08-27 | Novocure Gmbh | Treating Gastric Cancer Using TTFields Combined with XELOX, FOLFOX or the Individual Constituents Thereof |
US20200297286A1 (en) * | 2017-10-13 | 2020-09-24 | Autem Medical, Llc | System for characterization, diagnosis, and treatment of a health condition of a patient and microtubule conductivity, and methods of using same |
US20200330758A1 (en) * | 2019-04-22 | 2020-10-22 | Boston Scientific Scimed, Inc. | Combination electrical and chemotherapeutic treatment of cancer |
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2022
- 2022-05-31 EP EP22744509.5A patent/EP4346998A1/en active Pending
- 2022-05-31 CN CN202280039734.3A patent/CN117425515A/en active Pending
- 2022-05-31 WO PCT/IB2022/055092 patent/WO2022254340A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7565205B2 (en) | 2000-02-17 | 2009-07-21 | Standen Ltd. | Treating a tumor or the like with electric fields at different orientations |
US20200297286A1 (en) * | 2017-10-13 | 2020-09-24 | Autem Medical, Llc | System for characterization, diagnosis, and treatment of a health condition of a patient and microtubule conductivity, and methods of using same |
US20200269041A1 (en) * | 2019-02-22 | 2020-08-27 | Novocure Gmbh | Treating Gastric Cancer Using TTFields Combined with XELOX, FOLFOX or the Individual Constituents Thereof |
US20200330758A1 (en) * | 2019-04-22 | 2020-10-22 | Boston Scientific Scimed, Inc. | Combination electrical and chemotherapeutic treatment of cancer |
Non-Patent Citations (1)
Title |
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