WO2001002022A9 - New melanotropin analogs for potential radiopharmaceuticals for diagnosis and treatment of melanoma - Google Patents
New melanotropin analogs for potential radiopharmaceuticals for diagnosis and treatment of melanomaInfo
- Publication number
- WO2001002022A9 WO2001002022A9 PCT/US2000/011672 US0011672W WO0102022A9 WO 2001002022 A9 WO2001002022 A9 WO 2001002022A9 US 0011672 W US0011672 W US 0011672W WO 0102022 A9 WO0102022 A9 WO 0102022A9
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cys
- compound
- radionuclide
- analog
- msh
- Prior art date
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Classifications
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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
-
- 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
- A61K51/086—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being alphaMSH, alpha melanocyte stimulating hormone
Definitions
- Metal ions often play critical roles in protein structure and function.
- Engineered metal-binding sites in peptides and proteins have been widely used to enhance structural integrity, stabilize biologically active conformations, and confer novel enzymatic activities (Iverson, B.L., 1990; Regan, L., 1993; Kellis, J.T. Jr., 1991).
- Biochemical and structural analyses of transition metal coordination by proteins and peptides have traditionally focused on zinc, copper, manganese, and iron due to their roles in important biological processes (Klemba, M., 1995; Kruck, T.P.A., 1976; Lau, S., 1989; Franco, R., 1995).
- Other transition metals not found in natural proteins, have coordination, isotopic, and chemical properties which make them attractive for peptide and protein engineering.
- Rhenium (Re) and Technetium (Tc) are group VIIB transition metals which share similar coordination geometries and form stable complexes with amine and amide nitrogens, carboxylate oxygens, and thiolate and thioether sulfurs, with a strong preference for thiolate sulfurs (Vanbilloen, H. P., 1995). Radioactive isotopes of Re and Tc have significant medical applications due to the nature of their associated radiation and physical half-life properties.
- radiolabeled antibodies, peptides, and steroid hormones as in vivo tumor imaging and therapeutic agents are active areas of cancer research today. These molecules specifically target tumor cells by virtue of their high specificities for receptors and antigens present on the surfaces of these cells.
- metallic radionuclides such as 186 Re, 188 Re, and 99m Tc are appended to the tumor targeting molecule through bifunctional chelate groups which consist of a metal chelate and an activatable crosslinker (Bakker, W. H., 1991 ; Fritzberg, A. R., 1988; Liu, S., 1996).
- the resulting radiolabeled proteins, peptides, and small molecules are decorated with one or more chelating groups.
- the presence of bulky metal chelating groups and their associated crosslinkers may affect receptor affinity and biodistribution in vivo (Krenning, E. P., 1992; Wraight, E. P., 1992).
- Alpha melanocyte stimulating hormone is a tridecapeptide [Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH 2 ] that regulates skin pigmentation in most vertebrates (Hruby, V. J., 1993).
- the core ⁇ -MSH sequence His-Phe-Arg-Trp conserved in a number of species, has been found to be sufficient for receptor recognition (Hruby, V. J., 1993).
- ⁇ - melanotropin is a naturally occurring tridecapeptide that specifically recognizes melanotropin receptors.
- Radiolabeled ⁇ -MSH analog has been reported as a targeting agent of the radionuclide lndium-111.
- This analog consists of two des-acetyl- MSH molecules crosslinked through the chelating group DPTA. In vivo work on this analog was carried out under Home Office project license number PPL 70/00499, and was reported in Bard, D.R. et al. No studies have been reported which attach medically important radionuclides to ⁇ -MSH via peptide chelating groups.
- a compound for use as a diagnostic or therapeutic pharmaceutical consisting essentially of an alpha-melanotropin stimulating hormone analog which has integrally located a radionuclide.
- the radiolabeled alpha-melanotropin is administered to the body in an amount sufficient to allow uptake and retention by the tumor cells.
- Figure 1 depicts the chemical structure of the alpha-meloantropin hormone stimulating analogs
- Figure 3 is an image of a melanoma tumor in a mouse injected with TcCCMSH; the ⁇ -camera image of the melanoma bearing mouse being acquired 30 minutes post injection and the lateral image of the mouse with a 400 milligram tumor shows a high degree of radioactivity localized in the tumor (b) with lesser amounts present in the kidneys (a), bladder (C), and tail vein injection site (d); the intensity of the ⁇ -emission being color coded high to low, ranging from white-yellow through orange, with dark red representing lowest values.
- Alpha melanocyte stimulating hormone is a tridecapeptide [Ac-Ser-Tyr-Ser- Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH 2 ] that regulates skin pigmentation in most vertebrates (Hruby, V. J., 1993).
- the core ⁇ -MSH sequence His-Phe- Arg-Trp conserved in a number of species, has been found to be sufficient for receptor recognition (Hruby, V. J., 1993).
- ⁇ -MSH receptors on both murine and human melanoma cells (Tatro, J. B., 1989; Siegrist, W., 1989) suggests that ⁇ -MSH analogs might be developed into targeted imaging or therapeutic agents.
- Several analogs of ⁇ -MSH have been radiolabeled either with halogens or with transition metal radionuclides coordinated by bifunctional chelates (Bard, D. R., 1990; Bagutti, C, 1994; Garg, P. K., 1996; Vaidyanathan, G., 1997).
- the present invention provides 188 Re or 99m Tc radiolabeled ⁇ -MSH analogs in which metal coordination is an integral part of the molecules' structure. It was hypothesized that cyclic ⁇ -MSH analogs, engineered to incorporate radionuclides directly into their structures, would display exceptional stability, biodistribution, and tumor targeting properties. Rhenium bound ⁇ -MSH analogs were synthesized and characterized to determine if different metal incorporation strategies resulted in molecules with varying structural stabilities and bioactivities. Incorporation of Re into an initial ⁇ -MSH analog resulted in decreased stability and receptor affinity. Structural characterization of the Re bound ⁇ -MSH complex indicated that metal coordination dramatically altered the core receptor binding sequence.
- X any amino acid
- n 1 to 1000
- E radioelement which binds with at least two of the Cys-SH groups, depending upon the radioelement used;
- Radioelements include ytrium(Y), bismuth(Bi), and any radiometal with an affinity for sulfhydral groups (the cysteine/SH groups). More specifically, certain radiometals are preferred, such as Tc-99M, Re-186, Re-188, Rh-105, Au-199, Cu-64, Cu-67, Ga-68, ln-111 , Bi-212, Bi-213, Y-90, and any radiolanthanides.
- the compound is of the general formula:
- X any amino acid
- n 1 to 1000
- E radioelement which is bonded to at least two of the Dys-SH groups, depending upon the radioelement which is used;
- the present invention compounds contain at least one peptide analog which is cyclysed by coordination between two adjacent cysteines and at least one member of the group containing non-contiguous cysteine, an amide or an amine.
- the radionuclide bound ⁇ -MSH complex is administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, patient age, sex, body weight and other factors known to medical practitioners.
- the pharmaceutically "effective amount" for purposes herein is thus determined by such considerations as are known in the art. The amount must be effective to achieve improvement including but not limited to elimination of all cancer cells and to improved survival rate or more rapid recovery, or improvement or elimination of symptoms and other indicators as are selected as appropriate measures by those skilled in the art.
- the radionuclide bound ⁇ - MSH complex can be administered in various ways. It should be noted that the radionuclide bound ⁇ -MSH complex can be administered as the compound or as pharmaceutically acceptable salt and can be administered alone or as an active ingredient in combination with pharmaceutically acceptable carriers, diluents, adjuvants and vehicles.
- the compounds can be administered orally, subcutaneously or parenterally including intravenous, intraarterial, intramuscular, intraperitoneally, as well as intrathecal and through infusion techniques. Implants of the compounds are also useful. The patient being treated is a warm-blooded animal and, in particular, mammals including man.
- the pharmaceutically acceptable carriers, diluents, adjuvants and vehicles as well as implant carriers generally refer to inert, non-toxic solid or liquid fillers, diluents or encapsulating material not reacting with the active ingredients of the invention. It is noted that humans are treated generally longer than the mice exemplified herein which treatment has a length proportional to the length of the disease process and drug effectiveness. The doses may be single doses or multiple doses over a period of several days. The treatment generally has a length proportional to the length of the disease process and drug effectiveness and the patient species being treated. Optimal dosing schedules may be calculated using measurements of drug accumulation in the body. Practitioners of ordinary skill in the art can readily determine optimum dosages, dosing methodologies, and repetition rates. Optimum dosages may vary depending on the relative potency of radionuclide bound ⁇ -MSH complex, and can generally be determined based on ED 50 values in in vitro and in vivo animal studies and clinical trials.
- the radionuclide bound ⁇ -MSH complex When administering the radionuclide bound ⁇ -MSH complex parenterally, the radionuclide bound ⁇ -MSH complex will generally be formulated in a unit dosage injectable form (solution, suspension, emulsion).
- the pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- the carrier can be a solvent or dispersing medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
- Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- Nonaqueous vehicles such as cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil and esters, such as isopropyl myristate, may also be used as solvent systems for compound compositions.
- various additives which enhance the stability, sterility, and isotonicity of the compositions including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added.
- antibacterial and antifungal agents for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
- isotonic agents for example, sugars, sodium chloride, and the like.
- Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin, ccording to the present invention, however, any vehicle, diluent, or additive used would have to be compatible with the compounds.
- Sterile injectable solutions can be prepared by incorporating the compounds utilized in practicing the present invention in the required amount of the appropriate solvent with various of the other ingredients, as desired.
- a pharmacological formulation of the radionuclide bound ⁇ -MSH complex can be administered to the patient in an injectable formulation containing any compatible carrier, such as various vehicle, adjuvants, additives, and diluents; or the compounds utilized in the present invention can be administered parenterally to the patient in the form of slow-release subcutaneous implants or targeted delivery systems such as monoclonal antibodies, vectored delivery, iontophoretic, polymer matrices, liposomes, and microspheres. Examples of delivery systems useful in the present invention include: U.S.
- Many other such implants, delivery systems, and modules are well known to those skilled in the art.
- a pharmacological formulation of the radionuclide bound ⁇ -MSH complex utilized in the present invention can be administered orally to the patient.
- intrathecal delivery can be used with for example an Ommaya reservoir.
- United States Patent 5,455,044 provides for use of a dispersion system for CNS delivery or see United States Patent 5,558,852 for a discussion of CNS delivery.
- pharmacological formulations that cross the blood-brain barrier can be administered. [Betz et al., 1994; Brem et al., 1993] Such formulations can take advantage of methods now available to produce chimeric peptides in which the present invention is coupled to a brain transport vector allowing transportation across the barrier [Pardridge, et al., 1992; Pardridge, 1992; Bickel, et al., 1993]. Further, in appropriate cases blood-brain barrier disruption can be utilized [Neuwelt et al., 1980].
- the radionuclide bound ⁇ -MSH complex can be administered initially by intravenous injection to bring blood levels of radionuclide bound ⁇ -MSH complex to a suitable level.
- the patient's radionuclide bound ⁇ - MSH complex levels are then maintained by an oral dosage form, although other forms of administration, dependent upon the patient's condition and as indicated above, can be used.
- the quantity of radionuclide bound ⁇ -MSH complex to be administered will vary for the patient being treated and will vary from about 100 ng/kg of body weight to 100 mg/kg of body weight per day and preferably will be from 10 mg/kg to 10 mg/kg per day.
- 99m Tc0 4 " was obtained from a 99 Mo/" m Tc generator produced by Mallinckrodt, Inc.
- 188 Re was obtained from a 188 W/ 188 Re generator produced by the University of Missouri research reactor.
- Radiolabeled peptides were prepared by substitution onto either 99m Tc- or 188 Re- glucoheptonate.
- 500 ⁇ L of generator eluant was added to a tube containing 50 mg Na-giucoheptonate and 10 mg SnCI 2 *2H 2 O dissolved in 200 ⁇ L N 2 -purged 5% disodium-EDTA and heated at 70-80°C for 0.5 hour.
- NMR data collection and processing NMR data were collected on a 500-MHz Bruker AMX or DMX spectrometer and processed on a Silicon Graphics Inc. (SGI) XZ4000 workstation using the SYBYL program (Tripos, Inc.).
- the 1 H data were collected in 90%H 2 O/10%D 2 O at concentrations ranging from 4-10 mg/mL. All spectra were recorded using the time-proportional phase incrementation (TPPI) method. In most cases, the spectral width was 6000 Hz.
- TPPI time-proportional phase incrementation
- the spectral width was 6000 Hz.
- the data set size was 2048(t 2 ) x 256(t,) blocks with between 16-64 scans/fid.
- TOCSY spectra were collected using an 80 ms mixing time; the NOESY and ROESY mixing time was 200 ms.
- H 2 0 suppression was carried out using the WATERGATE pulse sequence (Piotto, M., 1992). A 1-1 jump return sequence was used in some 1 D experiments for H 2 0 suppression. Data sets were multiplied by a 0-90° shifted sinebell squared transformation function and zerofilled to 1024k in t, prior to Fourier transformation. 2D spectra for the peptide-metal complexes were collected at 298K. For APOMSH, additional 2D spectra were collected at 278K. 3 J ⁇ NH data were gathered from resolution enhanced 1 D spectra for each compound. Temperature gradient studies spanned 278K-308K for each compound.
- Bioactivity and receptor binding assays Peptide bioactivity was determined by measuring melanin released into cell culture media in an in vitro assay using B16F1 murine melanoma cells (Siegrist, W., 1986). Cells were incubated with various concentrations of peptide and assayed for melanin production by measuring the absorbance of the culture media at 405 nm. Absorbance values were compared to a standard curve obtained using synthetic melanin from Sigma. The standard curve was linear over the experimental range of absorbance values.
- mice Six week old C57BIJ6 mice (Harlan, Sprague, Dawley, Inc.) were injected in the right flank with 1 x 10 6 B16-F1 mouse melanoma cells. Tumors, approximately 200-400 mgs, appeared 10 days post injection. Each mouse was given 25 ⁇ Ci of 99 ⁇ r TcCCMSH by tail vein injection. The mice were sacrificed thirty minutes post injection and the images were acquired by a Prism XP3000 triple head ⁇ camera (Picker, Inc.) equipped with a low-energy high resolution parallel collimator. The images were collected on a 512 matrix with 3.999 magnification.
- Biodistributions The biodistribution and pharmacokinetics of the 99m Tc and 188 Re labeled cyclic ⁇ -MSH peptide analogue (CCMSH) were examined in a C57BIJ6 murine melanoma animal model. 1 x 10 6 B16-F1 melanoma cells were injected subcutaneously to induce tumor formation. Tumors, 200-400 milligrams in weight, appeared approximately 10 days post injection. Normal and tumor bearing mice were injected with 2-3 ⁇ Ci of 99m Tc or 188 Re labeled CCMSH. At various times post-injection the mice were sacrificed and the individual tissues were counted.
- CCMSH cyclic ⁇ -MSH peptide analogue
- Metal-binding site design Molecular modeling was used to design and evaluate cyclic ⁇ -MSH analogs for their potential to incorporate Re or Tc into their structures. Several different factors were taken into account in the design of rhenium- and technetium-binding sites, including metal coordination geometry, donor atom selection, and peptide conformation. Both Tc and Re, when in the +5 oxidation state, prefer a square pyramidal coordination geometry. Structural studies of small organic complexes of these metals have shown that donor atoms are located at the corners of a square plane, with a monooxo group of located above, at the apex of a square pyramid (Grummon, G., 1995; Hansen, L, 1992; Rao, T. N., 1991).
- Cys 4,10 , D-Phe 7 - ⁇ -MSH 4.13 retains a core sequence of residues, His- D-Phe-Arg-Trp, which has been found to be sufficient for the bioactivity of a ⁇ -MSH (Hruby, V. J., 1993).
- APOMSH D-Phe 7 - ⁇ -MSH 4.13
- NOESY spectra of both APOMSH and ReMSH were examined and sequential and nonsequential NOE's were identified.
- NOE derived distance restraints were grouped into either strong, medium, or weak categories based on their intensities. These restraints were then applied to randomly generated starting structures within SYBYL.
- geometrical restraints range, angle, and torsion
- the geometric restraints were optimized to maintain a square planar array of donor atoms in a model rhenium-peptide compound (Cys-Gly-Cys).
- ReMSH molecule For the ReMSH molecule, 20 cycles of MD/annealing/minimization converged to a single family of structures, with backbone RMSD's ranging between 0.86-1.26 A. Compared with the APOMSH structures, the ReMSH NMR structures converged to a much more tightly defined family which included a reverse turn centered on residues Glu5-His6. The higher degree of definition was due to a cross ring NOE between Cys4NH and Arg ⁇ H not present in APOMSH and the smaller ring size of ReMSH. As with APOMSH, high values for temperature dependencies of amide 1 H chemical shifts indicated that no intramolecular hydrogen bonds were present to stabilize the turn.
- the ReMSH model structures were strained due to the restraints imposed by Trp9N and Cys4S metal coordination. This increased strain was reflected experimentally in the low stability of the ReMSH molecule. As assessed by NMR, approximately 20% of the original ReMSH species had degraded after a 24 hour period. The decay of the ReMSH complex most likely represented a rearrangement of the donor atoms in the metal coordination sphere to relieve the strain introduced into the molecule by the Cys4 sulfur coordination. Release over time of the Cys4 sulfur as a free thiolate would be consistent with the Ellman's analysis of the ReMSH complex. The same trends in stability were observed at the tracer level. Synthesis of 99m Tc/ 188 ReMSH confirmed the relatively low stability of ReMSH.
- Table 2 shows that in competition with 10mM free cysteine, the 188 ReMSH complex has a t 1/2 of approximately 4 hours.
- the analogous 99m TcMSH complex had an even shorter half-life, with a t 1/2 of less than 2 hours, consistent with an increased lability of Tc to substitution reactions.
- the effect of metal incorporation on the bioactivity and receptor binding affinity of ReMSH is shown in Table 3.
- the bioactivities of APOMSH and the ReMSH complex were assayed by measuring stimulation of melanin production by B16-F1 murine melanoma cells.
- the EC 50 values for melanin synthesis by APOMSH and ReMSH were 2.6 x 10 '11 and 5.4 x 10 "10 , respectively.
- Incorporation of rhenium into ReMSH resulted in approximately a 20-fold decrease in the ability of the molecule to stimulate melanin production compared to APOMSH.
- Receptor binding assays were performed with APOMSH and ReMSH on B16-F1 murine melanoma cells.
- the compound was synthesized using the same conditions used for the synthesis of ReMSH and resulted in a complex which appeared by FAB-MS to contain 2 rhenium-oxo groups per peptide molecule.
- Receptor binding data on this 2:1 rhenium:peptide complex showed no increase in binding affinity over ReMSH (data not shown). That this dimeric complex was the major product of two separate syntheses suggested that there may be an entropic barrier to the cyclization of larger rings via an Re(V)0 core.
- the ReCCMSH analog exhibited a receptor binding affinity of 2.9 nM, which was approximately 25-fold higher than that of ReMSH (Table 3).
- Redesign of the Re coordination site in ReCCMSH appeared to relieve internal steric constraints within the core receptor binding sequence that resulted in greatly improved radiochemical stability and receptor affinity.
- the percent dose/gram tumor uptake of the 188 Re- CCMSH analogue was 10.89+ 2.27 at 0.5 hours, and 3.24 ⁇ 0.63 at 12 hours. By 24 hours the tumor dose/gram was 1.72 ⁇ 0.39 % with a tumor/blood ratio of 207.90.
- a ""relabeled bombesin peptide analog was also injected into a tumor-bearing mouse as a control for peptide targeting specificity.
- the radiolabeled bombesin analog did not display selective tumor uptake (data not shown).
- the data presented in this application results demonstrated that the redesigned 99 TcCCMSH molecule was capable of selectively targeting melanoma tumors in vivo. Detailed distribution studies are underway with the 99m Tc- and ⁇ Relabeled CCMSH analogs exhibit rapid tumor uptake, superior tumor residency and efficient whole body clearance.
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Abstract
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Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU48100/00A AU4810000A (en) | 1999-05-19 | 2000-05-01 | New melanotropin analogs for potential radiopharmaceuticals for diagnosis and treatment of melanoma |
Applications Claiming Priority (2)
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US31444499A | 1999-05-19 | 1999-05-19 | |
US09/314,444 | 1999-05-19 |
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WO2001002022A1 WO2001002022A1 (en) | 2001-01-11 |
WO2001002022A9 true WO2001002022A9 (en) | 2002-06-13 |
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PCT/US2000/011672 WO2001002022A1 (en) | 1999-05-19 | 2000-05-01 | New melanotropin analogs for potential radiopharmaceuticals for diagnosis and treatment of melanoma |
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AU (1) | AU4810000A (en) |
WO (1) | WO2001002022A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2005123761A1 (en) * | 2004-06-21 | 2005-12-29 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | GnRH ANALOGS BACKBONE CYCLIZED THROUGH METAL COMPLEXATION |
KR100999044B1 (en) | 2008-03-26 | 2010-12-09 | 한국원자력연구원 | Chelating agent-?MSH peptide derivates, preparation method thereof and composition for diagnosis or treatment of melanoma tumor containing the same as an active ingredient |
-
2000
- 2000-05-01 AU AU48100/00A patent/AU4810000A/en not_active Abandoned
- 2000-05-01 WO PCT/US2000/011672 patent/WO2001002022A1/en active Application Filing
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AU4810000A (en) | 2001-01-22 |
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