WO1998024481A2 - Ligand radiomarque servant a introduire selectivement un radionucleide emetteur d'electrons auger dans le noyau d'une cellule cancereuse - Google Patents

Ligand radiomarque servant a introduire selectivement un radionucleide emetteur d'electrons auger dans le noyau d'une cellule cancereuse Download PDF

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Publication number
WO1998024481A2
WO1998024481A2 PCT/CA1997/000909 CA9700909W WO9824481A2 WO 1998024481 A2 WO1998024481 A2 WO 1998024481A2 CA 9700909 W CA9700909 W CA 9700909W WO 9824481 A2 WO9824481 A2 WO 9824481A2
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cell
ligand
hegf
cells
radiolabelled
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PCT/CA1997/000909
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WO1998024481A3 (fr
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Raymond M. Reilly
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Reilly Raymond M
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Priority to CA002273946A priority Critical patent/CA2273946A1/fr
Priority to AU51131/98A priority patent/AU5113198A/en
Publication of WO1998024481A2 publication Critical patent/WO1998024481A2/fr
Publication of WO1998024481A3 publication Critical patent/WO1998024481A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins

Definitions

  • the invention is a radiolabelled ligand for selectively introducing an Auger electron emitting radionuclide into the nucleus of a cancer cell.
  • the invention allows for the selective killing of cancer cells using Auger electrons while not affecting normal cells to which the fusion protein is not bound and internalized.
  • a strategy for treatment of cancer is to identify cell surface markers which are unique to the cancer or which are overexpressed as compared to normal cells so that a therapeutic agent can be targeted to such markers of cancer cells. It is known, for example, that certain cancers possess an overexpression of oncogene-encoded growth factor receptors on their cell surfaces . Growth factors are internalized after binding to their receptors and in certain cases are translocated to the cell nucleus .
  • a growth factor receptor which is frequently overexpressed in breast cancer is the epidermal growth factor receptor (EGFR) .
  • the polypeptide ligand, epidermal growth factor (EGF) may constitute the basis for constructing a polypeptide labelled with an Auger electron emitting radionuclide for use in treatment of this type of cancer.
  • the invention provides a radiolabelled ligand having the requisite characteristics for a cancer therapeutic composition, and as such, overcomes various shortcomings of prior art targeting vehicles employing Auger emitting radionuclides for cancer treatment .
  • the present invention will be described in relation to its application to breast cancer in which EGFR is overexpressed. The skilled person will appreciate that the invention has a broader scope than the specific embodiments described herein.
  • Radiopharmaceuticals of the invention constitute a new addition to the catalog of agents useful for the systemic treatment of this and other cancers.
  • the excess energy released causes a cascade of electrons from higher shells to fill vacancies in lower shells with release of 10-20 low energy electrons per decay for 125 I and 8 electrons for llx In.
  • This cascade of electrons was named after Pierre Auger who first reported it in 1925. Auger electrons have a very limited range in tissue of ⁇ 1 cell diameter, but their high rate of energy deposition over very short distances causes ionization tracks comparable or exceeding those of high linear energy transfer radiation such as ⁇ -particles.
  • chromosomal DNA is the radiosensitive target in the cell for Auger electrons.
  • K-shell Auger electrons of 125 I and 11:l In have sufficient range (8-14 ⁇ m) to deposit energy in the nucleus from decays on the cell membrane, the subcellular range of most Auger electrons requires that the radionuclide be internalized to exert its full effect.
  • the highest radiotoxicity is observed for the thymidine analog 125 I-iododeoxyuridine ( 125 IUdR) which is incorporated into DNA (1) .
  • Chan et al . (2) showed that ⁇ 3 pCi of 125 IUdR/cell reduced the survival of Chinese hamster V79 fibroblasts to 1%.
  • the survival curve had no shoulder, characteristic of high linear energy transfer radiation.
  • Kassis (3) showed that rhodamine-123 (a mitochondrial dye) labelled with 125 I was also radiotoxic to V79 cells but 80-fold less potent than 12S IUdR.
  • 125 IUdR has limitations as a radiotherapeutic agent due to its lack of specificity, targeting cells only in S-phase and being subject to extensive deiodination by the liver (1) . Nevertheless, 125 IUdR is being studied for treatment of bladder cancer (4) , gliomas (5) and hepatic metastases (6, 7) where normal tissue uptake can be minimized by local administration.
  • Radiopharmaceuticals for the delivery of Auger electron emitters to cancer cells has been recognized to be desirable (8) .
  • 125 I labelled targeting vehicles such as monoclonal antibodies (9, 10), oligonucleotides complementary to certain genes (11) , or estradiol (12-14) have been investigated. All of these radiopharmaceuticals reported to date, however, suffer from various shortcomings as therapeutic agents. Nucleotides cannot be specifically targeted in vivo. Monoclonal antibodies have so far been disappointing as therapeutic agents in a large part because they are themselves immunogenic.
  • Radiolabelled estradiol may be useful in treatment of some breast cancers where there is an overexpression of the estradiol receptor, but the action of estradiol depends on a passive diffusion of the compound across the cell membrane to the receptor which is located inside the cell. This need for passive diffusion across the cell membrane essentially limits the use of Auger electron emitters to 12S I .
  • the use of 125 I as the radionuclide source of Auger electrons has some disadvantages, as discussed below.
  • the present invention focuses on the hitherto unexplored utilization of overexpressed or uniquely expressed oncogene-encoded cell surface receptors to ' provide a means for targeting cancer cells for the delivery of Auger emitting radionuclides.
  • growth factor receptors present particularly favorable candidates for targeting (15, 16).
  • the growth factors which are polypeptides, are internalized after binding to their cell surface receptors, and in certain cases are translocated to the cell nucleus (17) .
  • the invention provides a radiolabelled ligand which selectively binds a cell surface receptor for introducing an Auger electron emitting radionuclide into a cancer cell.
  • the ligand binds a cell surface receptor that is unique to a cancer cell or that is overexpressed on a cancer cell.
  • An Auger electron emitting radionuclide is bonded to the ligand by, for example, a chelator.
  • the radiolabelled ligand is internalized by the cancer cell after binding to the cell surface receptor in the same fashion as is the naked ligand itself.
  • Figure 1 is a chromatogram showing the purification Of ⁇ In-DTPA-hEGF.
  • Figure 2 is a chromatogram showing the radiochemical purity of 11:L In-DTPA-hEGF.
  • Figure 3 is a graph showing total binding, non-specific binding and specific binding of llx In-DTPA-hEGF to MDA-MB-468 breast cancer cells.
  • Figure 4 is a graph showing the kinetics of binding and retention of 11:L In-DTPA-hEGF and 125 I-hEGF to MDA-MB-468 breast cancer cells.
  • Figure 5 is a graph showing the inhibition of the growth of MDA-MB-468 breast cancer cells by internalizing ni j n ra ⁇ :i 0 p armaceuticals.
  • Figure 6 is a graph showing the radiotoxicity of internalized 1:L1 In-hEGF for MDA-MB-468 breast cancer cells using a colony forming assay.
  • Figures 7 A-C are fluorescent micrographs showing the rapid binding and internalization of fluorescein-hEGF with MDA-MB-468 breast cancer cells.
  • 11:L In is radiotoxic to cells when it is internalized.
  • Studies using 11:L In-oxine which is a lipophilic complex that internalizes nonspecifically into cells, show toxicity due to chromosomal damage in lymphocytes (18) , hematopoietic stem cells (19) , fibroblasts (20, 21) , sperm heads (22), and tumour cells (23, 24) .
  • 1:L1 In-oxine cannot be used as a radiotherapeutic agent because of its lack of specificity, but the present invention overcomes this problem by providing a vehicle for preferentially delivering an Auger electron emitting radionuclide to a cancer cell .
  • EGFR epidermal growth factor receptor
  • Other growth factor receptors which may be overexpressed in cancer cells include nerve growth factor and platelet-derived growth factor receptors .
  • EGFR overexpression As a means for targeting cancer cells.
  • Several investigators have reported that a proportion of internalized EGF molecules are translocated to the cell nucleus (17, 26, 27) .
  • Overexpression of the EGFR occurs in up to 60% of breast cancers and is inversely correlated with estrogen receptor expression (28-36) .
  • EGFR expression in breast cancer biopsies has ranged from 1-1200 fmol/mg membrane protein (approx. 600-700,000 receptors/cell) with overexpression considered to be >10 fmol/mg (37) . Elevated EGFR expression is associated with a high relapse rate and poor long term survival .
  • Normal epithelial cells express ⁇ 10 4 receptors/cell.
  • HBL-100 8000 EGFR/cell has been reported (29) .
  • the expression of EGFR in breast cancer cell lines has a reported range of 800 EGFR/cell for MCF-7 cells to 10 6 EGFR/cell for MDA-MB-468 cells (25, 29, 38) .
  • the liver is the only normal tissue exhibiting moderate high levels of EGFR (8 X 10 4 - 3 X 10 5 receptors/cell) likely reflecting its role in the elimination of EGF from the blood (39-41) .
  • hEGF Human epidermal growth factor
  • DTPA Human epidermal growth factor
  • 11:L In-DTPA-hEGF exhibits an affinity identical to 15 I-hEGF for binding to EGFR on MDA-MB-468 breast cancer cells (Ka of 7 X 10 8 L/mol) .
  • 11:L In-DTPA-hEGF detected different levels of EGFR on breast cancer cell lines in vitro.
  • Fluore ⁇ cein has also been conjugated with hEGF (fsc-hEGF) .
  • Fluorescence microscopy of MDA-MB-468 breast cancer cells incubated with fsc-hEGF for 1 hour showed membrane staining (Fig. 7A) , but at 5 hours, there was almost complete internalization into cytoplasmic vesicles with some nuclear localization (Fig. 7B) .
  • the kinetics of binding and internalization of 11:1 In-DTPA-hEGF with MDA-MB-468 cells have been examined.
  • 1:L1 In-DTPA-hEGF bound rapidly to the cells, was internalized and in contrast to 12S I-hEGF remained in the cell.
  • the proportion of 11:1 In-DTPA-hEGF internalized increased from 70% at 0.25 hours to >95% at 24 hours.
  • hEGF Lyophilized human epidermal growth factor
  • hEGF Lyophilized human epidermal growth factor
  • DTPA diethylenetriamine-pentaacetic acid
  • the DTPA-conjugated hEGF was purified from excess DTPA by size-exclusion chromatography on a P-2 mini-column (BioRad) eluted with 50 mM sodium bicarbonate in 150 mM sodium chloride buffer pH 7.5. The absorbance of fractions was measured at 280 nm.
  • Purified DTPA-hEGF was radiolabelled with 11:I In to a specific activity of 100-400 mCi/mg by incubation with llx In chloride mixed 1:1
  • ⁇ In-DTPA-hEGF (0.25-80 ng) was incubated with 1.5 X 10 s MDA-MB-468 cells in 1 mL of 0.1% human serum albumin in 35 mm multiwell culture dishes at 37°C for 30 minutes. The cells were transferred to a centrifuge tube and centrifuged. The cell pellet was separated from the supernatant and counted in a g-scintillation counter to determine bound (B) and free (F) radioactivity. Non-specific binding was determined by conducting the assay in 100 nM hEGF51. The affinity constant (Ka) and number of receptors/cell were determined from Scatchard plots of B/F versus B.
  • the kinetics of binding was determined by incubating 1 ng of 1:L1 In-DTPA-hEGF or 125 I-hEGF with 3 X 10 6 MDA-MB-468 breast cancer cells at 37°C and determining the proportion of radioactivity bound to the cells at various times up to 24 hours.
  • the internalized fraction was measured by determining the proportion of radioactivity which could not be displaced from the cell surface by 100 nM hEGF.
  • MDA-MB-468 breast cancer cells expressing approximately 10 6 epidermal growth factor receptors/cell were incubated with ⁇ In-DTPA-hEGF, unlabelled hEGF or 1:L1 In-oxine, centrifuged to remove free ligand, then assayed and seeded (10 6 cells/dish) into 35 mm culture dishes. Growth medium was added and the cells were cultured at 37°C/5% C0 2 for 4 days. The cells were then recovered by trypsinization and counted in a hemocytometer . Control dishes contained cells cultured in growth medium containing X11 ln-DTPA or growth medium alone . Cytotoxicity Assay of lxl In-DTPA-hEGF against MDA-MB-468 Cells
  • MDA-MB-468 breast cancer cells expressing approximately 10 6 epidermal growth factor receptors/cell were incubated with increasing amounts 1:L1 In-DTPA-hEGF or 11:L In-oxine, centrifuged to remove free ligand, assayed and then seeded into 50 mm culture dishes. The number of cells seeded was varied from 3 X 10 4 to 3 X 10 6 cells to obtain approximately 300 viable colonies/dish taking into account the plating efficiency and the expected level of cytotoxicity .
  • Control dishes contained MDA-MB-468 breast cancer cells which were incubated with normal saline. Growth medium was added and the cells were cultured at 37°C/5% C0 2 for 14 days.
  • the growth medium was removed and the colonies were stained with methylene blue (1% in a 1:1 mixture of ethanol and water) then washed twice with normal saline. The number of colonies per dish was counted using a manual colony counter (Manostat Corp.) . The plating efficiency was calculated by dividing the number of colonies observed by the number of cells seeded in each dish. The surviving fraction at increasing amounts of 1:11 In-DTPA-hEGF or 1:11 In-oxine was calculated by dividing the plating efficiency for dishes containing treated cells with that observed for control dishes.
  • hEGF Lyophilized hEGF was dissolved in 100 mM sodium bicarbonate buffer pH 9 to a concentration of 10 mg/mL. hEGF was then reacted with fluorescein isothiocyanate (FITC, Pierce) at a molar ratio of 12:1 (FITC:hEGF) at room temperature in the dark for 1 hour.
  • FITC fluorescein isothiocyanate
  • the fluorescein-conjugated hEGF was purified from excess fluorescein by size-exclusion chromatography on a P-2 mini-column (BioRad) eluted with normal saline. The absorbance of fractions was measured at 495 nm. Purified fluorescein-hEGF was stored in light-resistant polypropylene tubes at -10°C.
  • hEGF Human epidermal growth factor
  • DTPA-hEGF was radiolabelled with llx In acetate to a specific activity of 100-400 mCi/mg and purified on a P-2 size-exclusion mini-column.
  • a representative chromatogram is shown in Fig. 1.
  • the radiochemical purity of 1:ll In-DTPA-hEGF was >99% by instant thin layer chromatography in 100 mM sodium citrate pH 5.
  • the affinity constant for binding of 11:L In-DTPA-hEGF to MDA-MB-468 cells was 7 X 10 s L/mol and the number of binding sites was 1.3 X 10 6 .
  • a typical binding curve showing total binding (TB) , non-specific binding (NSB) and specific binding (SB) is shown in Fig. 3.
  • the kinetics of binding of 1:L1 In-DTPA-hEGF to MDA-MB-468 human breast cancer cells is shown in Fig. 4.
  • 1:L1 In-DTPA-hEGF was rapidly bound by the breast cancer cells and was retained for at least 24 hours. Over a 24 hour period at 37°C, ⁇ 8% of 11:L In radioactivity was lost from the cells in-vitro.
  • the proportion of 1:L1 In-EGF internalized i.e. not displaceable from the cell surface by 100 nM EGF
  • 1:11 In-hEGF (3.4 pCi/cell) achieved a 63% growth inhibition of the MDA-MB-468 cells compared to the medium control, whereas 11:L In-oxine (3.5 pCi/cell) resulted in 89% growth inhibition (Fig. 5) .
  • ⁇ In-DTPA which does not internalize, had no effect on growth.
  • hEGF Human epidermal growth factor
  • Fluorescence microscopy of MDA-MB-468 human breast cancer cells incubated with fluorescein-hEGF showed rapid binding to the cell surface followed by internalization into cytoplasmic vesicles and then nuclear localization (Fig. 7 A-C) .
  • the skilled person will appreciate the various advantages of radiolabelled ligands of the invention for use in cancer therapy. As seen from the foregoing data, radiolabelled hEGF is rapidly internalized by cancer cells after binding. In contrast with estradiol, for example, the internalization process for hEGF involves an active transport mechanism rather than simple diffusion across the cell membrane.
  • This active transport mechanism for hEGF also includes nuclear translocation which allows for a maximal radiation dose of Auger electrons to be delivered to the cell's DNA.
  • 1 E I-estradiol enters the cell by simple diffusion, the estradiol receptor being located inside the cell . Because diffusion of estradiol across the cell membrane is dependent on maintaining its lipid solubility, modifications to the molecule to allow radiolabelling may adversely affect the targetability of the molecule.
  • conjugation of estradiol with a chelating agent such as DTPA for labelling the molecule with X11 ln would decrease lipid solubility, and significantly impair the ability of the molecule to diffuse into the cell.
  • hEGF human polypeptide like hEGF.
  • hEGF being an endogenous polypeptide is not itself immunogenic in humans, and the conjugation of the molecule with DTPA for labelling with llx In should not increase its immunogenicity.
  • Clinical experience with the somatostatin peptide analog, octreotide conjugated with DTPA and labelled with 1:L1 In has shown very low immunogenicity in a study conducted on 1000 patients in Europe .
  • 11:L In has certain advantages as compared to, for example, 15 I.
  • the uptake of the radioligand can be monitored by external imaging because 11:L In also emits gamma radiation of sufficient energy to be detected outside the body using a gamma ray camera.
  • 1 B I does not emit gamma radiation of sufficient energy to be detected outside the body.
  • the invention comprising 11:L In labelled hEGF has been shown by the data presented to retain 11:L In within the cell. Over a 24 hour period at 37°C, ⁇ 8% of 1:L1 In radioactivity was lost from cells in vitro as compared to 77% loss for cells which internalized a 125 I labelled molecule. 125 I labelled peptides and proteins are catabolized in the cell to 125 I-iodotyrosine .
  • Dehalogenase enzymes then cleave the radioiodine from the iodotyrosine, and the free radioiodine diffuses away from the tumour.
  • the free radioiodine may then localize in other normal tissues such as the thyroid, potentially increasing toxicity to these tissues.
  • 11;L In labelled peptides and proteins are degraded in the cell to the terminal catabolite 1:L1 In-DTPA-lysine which is not exported from the cell. Retention of 1:L1 In in the cell maximizes the radiation dose (which is delivered over the lifetime of the radionuclide) and minimizes normal tissue toxicity.
  • Auger electron emitting radiopharmaceuticals such as iododeoxyuridine, iodoestradiol or internalizing monoclonal antibodies have used 125 I as the radiolabel; and therefore, suffer from intracellular catabolism and export of free 125 I from the cell.
  • a human breast cancer cell line with a high number of epidermal growth factor (EGF) receptors has an amplified EGF receptor gene and is growth inhibited by EGF. Biochem. Biophys . Res. Commun. 128 : 898-905, 1985.

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Abstract

Cette invention se rapporte à un ligand radiomarqué qui permet d'introduire un radionucléide émetteur d'électrons Auger dans le noyau d'une cellule cancéreuse. Ce ligand se lie spécifiquement à un récepteur de surface cellulaire qui est unique à une cellule cancéreuse ou qui est surexprimé sur une cellule cancéreuse. Un radionucléide émetteur d'électrons Auger se lie au ligand soit directement soit par l'intermédiaire d'un chélateur. Le ligand radiomarqué est internalisé par la cellule lors de la liaison au récepteur, et une partie suffisante des ligands ainsi internalisés est transportée jusqu'au noyau, afin d'appliquer sur celui-ci une dose de rayonnement l'étale.
PCT/CA1997/000909 1996-12-02 1997-12-01 Ligand radiomarque servant a introduire selectivement un radionucleide emetteur d'electrons auger dans le noyau d'une cellule cancereuse WO1998024481A2 (fr)

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CA002273946A CA2273946A1 (fr) 1996-12-02 1997-12-01 Ligand radiomarque servant a introduire selectivement un radionucleide emetteur d'electrons auger dans le noyau d'une cellule cancereuse
AU51131/98A AU5113198A (en) 1996-12-02 1997-12-01 A radiolabelled ligand for selectively introducing an auger electron emitting radionuclide into the nucleus of a cancer cell

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US75928296A 1996-12-02 1996-12-02
US08/759,282 1996-12-02

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991001144A1 (fr) * 1989-07-20 1991-02-07 Sandoz Ltd Derives de polypeptide etiquetes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991001144A1 (fr) * 1989-07-20 1991-02-07 Sandoz Ltd Derives de polypeptide etiquetes

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
CAPALA J ET AL: "RADIOLABELING OF EPIDERMAL GROWTH FACTOR WITH 99MTC AND IN VIVO LOCALIZATION FOLLOWING INTRACEREBRAL INJECTION INTO NORMAL AND GLIOMA-BEARING RATS" BIOCONJUGATE CHEMISTRY, vol. 8, no. 3, May 1997, pages 289-295, XP000689386 *
DADPARVAR S ET AL: "Indium-111-labeled anti-EGFr-425 scintigraphy in the detection of malignant gliomas." CANCER, 1-2-1994, VOL. 73, NO. 3 SUPPL, PAGE(S) 884-9, XP002068413 *
DE JONG M ET AL: "HANDLING OF IODINE-125 TYR-3-OCTREOTIDE INDIUM-111 DTPA -D-PHE-1-OCTREOTIDE AND IODINE-125 EPIDERMAL GROWTH FACTOR EGF BY THE ISOLATED PERFUSED RAT LIVER" 39TH ANNUAL MEETING OF THE SOCIETY OF NUCLEAR MEDICINE, LOS ANGELES, CALIFORNIA, USA, JUNE 9-12, 1992., XP002068414 & J NUCL MED, 1992, VOL. 33, NO. 5, SUPPL., PAGE(S) 955, ABSTRACT NO. 548, *
DERUI L ET AL: "RADIOTOXICITY OF IODINE-125-LABELED MONOCLONAL ANTIBODY 425 AGAINST CANCER CELLS CONTAINING EPIDERMAL GROWTH FACTOR RECEPTOR" AM J CLIN ONCOL, 1992, VOL. 15, NO. 4, PAGE(S) 288-294., XP002068412 *
ENNIS B W ET AL: "THE EGF RECEPTOR SYSTEM AS A TARGET FOR ANTITUMOR THERAPY" CANCER INVESTIGATION, vol. 9, no. 5, 1991, pages 553-562, XP000619907 *
GOLDENBERG A ET AL: "Imaging of human tumor xenografts with an indium-111-labeled anti-epidermal growth factor receptor monoclonal antibody." J NATL CANCER INST, NOV 1 1989, VOL. 81, NO. 21, PAGE(S) 1616-25, XP002068410 *
SAGA T ET AL: "SCINTIGRAPHIC DETECTION OF OVEREXPRESSED C-ERB-B-2 PROTOONCOGENE PRODUCTS BY A CLASS-SWITCHED MURINE ANTI-C-ERB-B-2 PROTEIN MONOCLONAL ANTIBODY" CANCER RES, 1991, VOL. 51, NO. 3, PAGE(S) 990-994., XP002068411 *
SANDRINE REMY ET AL: "A NEW RADIOLIGAND FOR THE EPIDERMAL GROWTH FACTOR RECEPTOR: 111IN LABELED HUMAN EPIDERMAL GROWTH FACTOR DERIVATIZED WITH A BIFUNCTIONAL METAL-CHELATING PEPTIDE" BIOCONJUGATE CHEMISTRY, vol. 6, no. 6, 1 November 1995, pages 683-690, XP000542534 *

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AU5113198A (en) 1998-06-29
CA2273946A1 (fr) 1998-06-11

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