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WO1998008100A1 - Internalisation, dependante des agonistes, des recepteurs de la somatostatine humaine de type 1-5 - Google Patents

Internalisation, dependante des agonistes, des recepteurs de la somatostatine humaine de type 1-5 Download PDF

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Publication number
WO1998008100A1
WO1998008100A1 PCT/CA1997/000592 CA9700592W WO9808100A1 WO 1998008100 A1 WO1998008100 A1 WO 1998008100A1 CA 9700592 W CA9700592 W CA 9700592W WO 9808100 A1 WO9808100 A1 WO 9808100A1
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Prior art keywords
hsstrl
cells
sst
subtypes
agonist
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PCT/CA1997/000592
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English (en)
Inventor
Yogesh C. Patel
Nedim Hukovic
Rosemarie Panetta
Ujendra Kumar
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Patel, Cell & Receptor Technologies Inc.
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Priority to CA002264007A priority Critical patent/CA2264007A1/fr
Priority to EP97937370A priority patent/EP0925506A1/fr
Priority to AU40056/97A priority patent/AU4005697A/en
Publication of WO1998008100A1 publication Critical patent/WO1998008100A1/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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57415—Specifically defined cancers of breast
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
    • G01N2333/726—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH

Definitions

  • the invention relates to the uses of human soma- tostatin receptors types 1-5 in the diagnosis and/or treatment of diseases and more particularly to tumor cells and in cases of Alzheimer's.
  • Somatostatin occurs naturally as 2 bioac- tive peptides, SST-14 and SST-28, which exert potent effects on multiple targets including the brain, gut, pituitary, endocrine and exocrine pancreas, adrenal, thyroid, kidneys, and immune cells (Patel YC, 1992, In : The role of somatostatin : basic and clinical aspects of neuroscience series, Muller EE et al. (eds), Vol. 4, pp 1-16, Springer-Verlag, Berlin).
  • SST The cellular actions of SST include the inhibition of hormone and exocrine secretion, as well as modulation of neurotransmission and cell proliferation, and are mediated by a family of G protein coupled receptors (GPCR) termed SSTR1-5 (Patel YC et al . , 1995, Life Sci . , 57:1249-1265; Reisine T et al., 1995, Endocrinol ogy, 16:427-442).
  • SSTR1-4 display weak selectivity for SST-14 binding whereas SSTR5 is SST-28 selective (Patel YC et al., 1995, Life Sci . , 57:1249-1265).
  • SST analogs such as the octa-peptide SMS201-995 (SMS, octreotide) or the hexapeptide MK678 used clinically for diagnosis and treatment of neuroendocrine tumors bind to 3 of the SSTR subtypes 2,3, and 5 (Patel YC et al., 1995, Life Sci . , 57:1249-1265; Reisine T et al., 1995, Endocrinology, 16:427-442).
  • SST-14 or SMS produces a diverse range of bio- logical effects, the initial effects diminish with continued exposure to the peptides due to the development of tolerance (Lamberts S J et al., 1996, N. Engl . J.
  • hSSTRl-5 5 somatostatin receptors in humans termed hSSTRl-5 that have now been identified by molecular cloning.
  • SST agonists which bind and activate these receptors and which are currently available for diagnosis or treatment, consist of the natural lig- and SST-14 which binds to all 5 hSSTRs, and octapeptide analogs such as Octreotide which bind to the subtypes 2, 3 and 5.
  • hSSTR4 and hSSTR2 are also internalized but to a lesser extent (29% and 20% respectively).
  • hSSTRl is not internalized.
  • hSSTRl is upregulated at the cell surface by 110%.
  • hSSTR2 and 4 are weakly upregulated by 26% and 22% respectively whereas the levels of hSSTR3 and 5 do not change at the membrane .
  • One aim of the present invention is to provide the characterization of agonist-induced receptor inter- nalization or upregulation of the 5 human (h) SSTR subtypes individually expressed in stable CH0-K1 cells and their respective uses thereof for the diagnosis and/or treatment of tumor cells.
  • Another aim of the present invention is to pro- vide the use of the internalization property of hSSTR subtypes to target tumors for selective targeted destruction.
  • subtypes such as hSSTR3 and 5 which are extensively internalized could be targeted with a cytotoxic agent in addition to selective ⁇ or ⁇ emitting SST radioligands for radiotherapy of, for example, breast cancers which display a rich concentration of these receptors.
  • Another aim of the present invention is to exploit the ability of hSSTRl (in particular) and hSSTRs 2 and 4 (to a lesser extent) to be upregulated at the cell surface upon prolonged treatment with agonist, as a mechanism for increasing the sensitivity of receptor scans for detection and diagnosis of tumors and inflammatory conditions.
  • treatment of patients suspected of having a tumor which is SSTRl positive (e.g. breast or prostate cancer) for 24 h with an agonist for hSSTRl (e.g. SST-14) should increase the number of surface receptors on the tumors for visualization by subsequent receptor scan with a labeled hSSTRl agonist.
  • SSTRl e.g. breast or prostate cancer
  • an agonist for hSSTRl e.g. SST-14
  • the same principle could also be used for recruiting hSSTR2 receptors to the cell surface (e.g.
  • Another aim of the present invention is to use the differential ability of the hSSTR subtypes to be upregulated or downregulated as a means for producing enhanced images in receptor scans by subtraction analy- sis to recruit e.g. SSTRl selectively to the membrane whilst internalizing others e.g. SSTRs 3, 4, 5.
  • a pituitary tumor expressing predominantly the hSSTRl subtype surrounded by normal pituitary tissue expressing several hSSTR subtypes e.g.
  • Another aim of the present invention is to provide for the long-term administration of somatostatin analogs that are selectively targeted on receptors that are expected to be upregulated due to reduced produc- tion of somatostatin as a result of disease.
  • a well known biochemical marker of Alzheimer's Disease is a profound reduction in the production of somatostatin by neurons in the deeper layers of the cerebral cortex. Since occupancy of hSSTRs 3, 4 and 5 leads to their immediate internalization, a deficiency of endogenous SST ligand would produce a state of chronic upregulation of these hSSTR subtypes. Since it is very likely that a disturbance of somatostatin production and the associated changes in its receptors plays a major role in producing symptoms (e.g.
  • somatostatin analogs could be targeted towards subtypes such as 3, 4 and 5 in order to normalize their function.
  • recombinant host cells individually expressing the hSSTRl-5 receptor subtypes.
  • These recombinant host cells may be used in a method for quantifying the amount of hSSTRl-5 receptors present on the cells, which comprises the steps of: a) incubating membrane fractions from host cells expressing one of the five hSSTRs with saturating concentrations of a cytotoxic agent in addi- tion to a radioligand; and b) determining the amount of hSSTRl-5 receptors present on the cell fractions of step a) in a saturation analysis.
  • this method is carried out as follows: incubating membrane fractions from host cells (e.g. CH0-K1 cells) expressing one of the five hSSTRs with saturating concentrations of a cytotoxic agent (e.g. methotrexate or doxorubicin) in addition to a radioligand (e.g. [ 125 I] Leu 8 , D-Trp 22 , Tyr 25 SST-28) in a saturation analysis.
  • a cytotoxic agent e.g. methotrexate or doxorubicin
  • radioligand e.g. [ 125 I] Leu 8 , D-Trp 22 , Tyr 25 SST-28
  • These recombinant host cells may be used in a method for determining their potency for binding to SST agonists and antagonists by competition analysis by displacement of membrane bound radioligand (e.g. [ 12 ⁇ ] LTT SST-28) with known amounts of SST-14, SST-28 or other SST agonists.
  • membrane bound radioligand e.g. [ 12 ⁇ ] LTT SST-28
  • recombinant host cells may be used in a method for determining the ability of the expressed hSSTRl-5 to be internalized which comprises the steps of: a) culturing cells individually expressing SSTR1-5 to about 90% confluency; b) washing the cultured cells and incubating overnight at 4°C with a binding buffer containing [ 125 I] LTT SST-28; c) washing the cells of step b) with binding buffer and warming to 37 °C to initiate internalization ; d) removing surface-bound radioligand with acid wash; and e) the internalized radioligand is measured as acid resistant counts in NaOH extracts of acid washed cells and the radioactive fractions are counted in a ⁇ -spectrometer .
  • this method is carried out as follows: culturing CH0-K1 cells individually expressing SSTR1-5 in 6 well plates ( ⁇ 1.5xl0 6 cells/well) to ⁇ 90% confluency. Cells are then washed two times with PBS and incubated overnight at 4°C in 1 X binding buffer (50 mM Hepes, pH 7.5, 2mM CaCl , 5 M MgCl2, 5% Ficoll 0.5% BSA, 0.02% PMSF, and 0.02% Bacitracin) with [ 125 I] LTT SST-28 (200,000 cpm ) with or without 100 nm SST-14, SST-28, or other SST ligands.
  • 1 X binding buffer 50 mM Hepes, pH 7.5, 2mM CaCl , 5 M MgCl2, 5% Ficoll 0.5% BSA, 0.02% PMSF, and 0.02% Bacitracin
  • Radioligand can be measured as acid resistant counts in 0.1 N NaOH extracts of acid washed cells and the radioactive fractions are counted in a LKB gamma counter.
  • These recombinant host cells may be used in a method for determining their ability to be upregulated in response to chronic agonist exposure, which comprises the steps of: a) determining upregulation of hSSTRs of cells expressing hSSTRl-5 by culturing in a medium with SST agonist; b) the cells are subjected to acid wash for to remove surface-bound SST; and c) whole cell binding assay is carried out with a SST radioligand to determine total and nonspe- cific binding.
  • this method is carried out as follows: determining upregulation of SSTRs, CHO-Kl cells expressing hSSTRl-5 by culturing in F10 medium without fetal calf serum with 10 ⁇ 7 M SST-14, SST-28, or other SST agonists for 1, 13, 16, 19 and 22 h. Media are then removed and the cells subjected to acid wash for 15 min. at 37 °C to remove surface-bound SST. Cells are then washed with 1 X binding buffer and whole cell binding assays are carried out with [ 125 I] LTT SST-28 radioligand for 30 min. at 25°C with or without 10 -7 M SST-14, SST-28 (to determine total and nonspecific binding) .
  • a method of targeted treatment of tumors based on the use of the internalization property of hSSTR3 and hSSTR5 subtypes which comprises the use of ⁇ - or ⁇ -emitting SST radioligands for radiotherapy of tumors expressing a rich concentration of the hSSTR3 and hSSTR5 subtypes.
  • the tumors targeted for the treatment are breast cancer tumors or other tumors expressing hSSTR3 and hSSTR5.
  • a method for increasing the sensitivity of receptors scans for the detection and diagnosis of tumors and inflammatory conditions in a patient based on the use of the upregulation property of hSSTRl, hSSTR2 and hSSTR4 subtypes which comprises the steps of: a) prolonged treatment of a patient with an agonist of hSSTRl to increase the number of hSSTRl, hSSTR2 and hSSTR4 subtypes on the tumor and inflammatory conditions of the patient; and b) visualization of the tumors and inflammatory conditions of step a) by administering a labeled hSSTRl agonist.
  • the agonist used is preferably SST-14.
  • a method for producing enhanced images in receptors scans by subtraction analysis for the detection and diagnosis of a tumor essentially expressing hSSTRl in a patient based on the use of the upregulation property of hSSTRl and the internalization property of hSSTR3, hSSTR4 and hSSTR5 subtypes which comprises the steps of: a) prolonged treatment of a patient with a hSSTRl agonist to increase the number of hSSTRl on the tumor of the patient; b) administering agonist of hSSTR3, hSSTR4 and hSSTR5 subtypes for the internalization of hSSTR3, hSSTR4 and hSSTR5 subtypes expressed in tissues surrounding the tumor; and b) visualization of the tumor by administering a labeled hSSTRl agonist.
  • the tumor may be of pituitary origin.
  • Fig. 1 illustrates the time course of internalization of 125 I-LTT SST-28 by CHO-Kl cells expressing hSSTRl-5.
  • Fig. 2 illustrates the effect of chronic SST treatment of CHO-Kl cells expressing hSSTRl-5 on membrane SSTRs;
  • Fig. 3 illustrates the confocal immunohisto- chemical localization of hSSTRl by rhodamine fluores- cence of stable hSSTRl CHO-Kl cells treated with SST-14 (10 M) for different times;
  • Fig. 4 illustrates the comparison of the internalization (short term agonist exposure) and upregula- tion (chronic agonist exposure) profiles of hSSTRl-5 from Figs. 1 and 2.
  • SSTRs somatostatin receptors
  • hSSTRl was upregulated at the membrane by 110%, hSSTR2 and hSSTR4 by 26% and 22% respectively, whereas hSSTR3 and hSSTR5 showed little change.
  • Agonist- induced recruitment of hSSTRl to the membrane was confirmed by immunocytochemistry with hSSTRl antibodies.
  • Peptides were obtained as follows: SST-14 (Ayerst Laboratories, Montreal); SST-28 and Leu 8 D-Trp 22 Tyr 25 SST-28 (LTT SST-28) (Bachem, Marina Del Ray, CA).
  • Stable CHO-Kl transfectants expressing full length genomic sequences of hSSTRl, 3, 4, and 5 or hSSTR2A cDNA each in the expression vector pRc/CMV (Invitrogen) were prepared and characterized as previously reported (Patel YC et al . , 1994, Biochem . Biophys . Res . Commun . , 198:605-612).
  • Neomycin resistant clones were selected and maintained in Ham's F12 medium containing 10% fetal calf serum and 400 ug/ml G418.
  • CHO-Kl cells individually expressing hSSTRl-5 were cultured in 6 well plates and studied at ⁇ 90% con- fluency ( ⁇ 1.5 x 10° cells/well). On the day of study, medium was removed, the cells washed 2 times with PBS and incubated overnight at 4°C in 1 X binding buffer (50 mM Hepes, pH 7.5, 2 mM CaCl2, 5 mM MgCl2, 5% Ficoll 0.5% BSA, 0.02% PMSF, and 0.02% Bacitracin) with [ 125 I] LTT SST-28 (200,000 cpm) with or without 100 nM SST-14 (for hSSTRl-4) or SST-28 (for hSSTR5).
  • 1 X binding buffer 50 mM Hepes, pH 7.5, 2 mM CaCl2, 5 mM MgCl2, 5% Ficoll 0.5% BSA, 0.02% PMSF, and 0.02% Bacitracin
  • CHO-Kl cells expressing hSSTRl-5 were cultured in F10 medium without fetal calf serum with 10 ⁇ 7 M SST- 14 (hSSTRl-4) or SST-28 (hSSTR5) for 1, 13, 16, 19, and 22 h.
  • Control cells were cultured without SST pep- tides.
  • media were removed and the cells subjected to acid wash for 15 min. at 37°C to remove surface-bound SST.
  • Cells were then washed with 1 X binding buffer and whole cell binding assays were carried out with 1 5 ⁇ LTT SST-28 radioligand for 30 min at 25°C with or without 10 ⁇ 7 M SST-14 or SST-28 (to determine total and nonspecific binding). Residual surface binding was calculated as the difference in specific binding between control and experimental groups. Each experiment was repeated 3 times in triplicate and the data were analyzed and plotted using the Inplot ProgramTM (Graph Pad).
  • Fig. 1 shows a comparison of the internalization profiles of radioligand bound to the 5 hSSTR subtypes.
  • the maximum percent internalization by each hSSTR is shown in brackets (representative of 3 complete experiments).
  • Four of the subtypes 2, 3, 4 and 5 displayed agonist-dependent internalization of radioligand in a time- and temperature-dependent manner. Internalization of these 4 subtypes occurred at markedly different rates. Maximum internalization of radi- oligand (78%) occurred in the case of hSSTR3 , followed by hSSTR5 (66%) and hSSTR4 (29%).
  • hSSTR2 was weakly internalized to 20% at 60 min whereas hSSTRl displayed minimal (4%) internalization.
  • Fig. 1 shows a comparison of the internalization profiles of radioligand bound to the 5 hSSTR subtypes.
  • the maximum percent internalization by each hSSTR is shown in brackets (representative of 3 complete experiments).
  • Four of the subtypes 2, 3, 4 and 5 displayed
  • FIG. 2 depicts the effect of chronic agonist exposure on surface bound radioactivity.
  • the hSSTRs display differential subtype selective upregulation. Numbers in brackets indicate maximum percent increase in membrane binding (representative of 3 complete experiments).
  • Agonist treatment for 22 h led to an upregulation of some of the SSTR subtypes. As in the case of internalization, this process was also subtype-selective.
  • SSTRl was upregulated by 110%
  • SSTR2 and SSTR4 were also weakly upregulated by 26% and 22% respectively whereas SSTR3 and SSTR5 showed little change.
  • Fig. 3 illustrates specific SSTRl immunofluorescence in cells after 0, 13 h, 19 h and 22 h of agonist treatment.
  • Fig. 3 illustrates specific SSTRl immunofluorescence in cells after 0, 13 h, 19 h and 22 h of agonist treatment.
  • Control cells exhibit weak expression of hSSTRl immunofluorescence at the cell surface (arrow). There is marked increase in labeling at 13 h and 22 h. Specificity of the fluorescence images was determined with preimmune serum, antigen absorbed antibody, and nontransfected CHO-Kl cells. Most cells displayed weak labeling at 0 and 1 h. At 13 h there was noticeably greater expression of hSSTRl immunoreactivity in the majority of cells. The immunofluorescent labeling increased further at 22 h exhibiting intense labeling of most cells.
  • hSSTRs undergo agonist-dependent internalization in a time-, temperature-, and subtype-selective manner with the following rank order hSSTR3 > 5, > 4, > 2, > 1.
  • hSSTRs are also differentially upregulated by chronic agonist exposure in a subtype-selective manner. Sub- type selectivity for internalization and upregulation is inversely related.
  • G protein coupled receptors are internalized both via the classical endocytic pathway involving clathrin-coated vesicles as well as through several other mechanisms such as nonclathrin-coated vesicles (Roettger BF et al . , 1995, J. CelJ Biol . , 128:1029-1041).
  • the clathrin-dependent pathway may be preferentially used for targeting receptors to lysosomes for degradation whereas the nonclathrin vesicles may be more involved in resensitization by recy- cling the receptor to the membrane following dephos- phorylation.
  • All 5 hSSTRs feature the sequence NPXXY at the junction of the 7th TMD and cytoplasmic tail similar to the NPXY internalization motif that has been implicated in mediating the internalization of a number of GPCRs through clathrin-coated pits (Trowbridge IS et al., 1993, Annu . Rev. Cell Biol . , 9:129-161).
  • the 5 hSSTRs feature a number of phosphorylation sites on serine and threonine residues in the C-tail and cytoplasmic loops that are believed to play a role in receptor sequestration (Patel YC et al., 1995, Life Sci . , 57:1249-1265).
  • hSSTRl would be expected to be upregulated in the somatostatinoma syndrome but not by SMS which does not interact with this subtype.
  • hSSTRl signals through G proteins as well as via G protein- independent pathways and further studies will be necessary to determine the functional state of this receptor and of the other subtypes that are recruited to the membrane by agonist exposure.
  • SSTRs in tumors behave differently due to a loss of normal receptor regulatory function, or to an alteration in the pattern and composition of the various subtypes expressed, or because of abnormal receptor signaling.
  • the ability of SST to regulate SSTRs may provide a mechanism for targeting selective subtypes for diagnosis and therapy. For instance, upregulation of hSSTRl and 2 by appropriate agonist treatment could be used for enhancing SSTR expression for receptor scans.
  • Subtypes such as hSSTR3 and 5 which are extensively internalized could be targeted with selective ⁇ - or ⁇ -emitting SST radioligands for radiotherapy of cer- tain SSTR positive human cancers.

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Abstract

L'invention concerne les utilisations des récepteurs de la somatostatine humaine (hSSTR) de type 1-5 pour le diagnostic et/ou le traitement de certaines maladies, notamment les tumeurs, par exemple le cancer du sein, et la maladie d'Alzheimer. L'invention concerne (i) des cellules hôtes recombinantes (cellules CHO-K1) exprimant individuellement les 5 sous-types de hSSTR; (ii) l'utilisation de ces cellules comme instruments pour tester la capacité d'agonistes ou d'antagonistes synthétiques de la somatostatine (SST) à induire l'internalisation ou la régulation positive des récepteurs; et (iii) l'utilisation de la propriété d'internalisation des sous-types de hSSTR pour cibler des tumeurs en vue de leur destruction ciblée. Par exemple, des sous-types tels que les hSSTR3 et 5, qui sont largement internalisés, pourraient être ciblés avec des radioligands α ou β-émetteurs afin de traiter par radiothérapie, par exemple, les cancers du sein présentant une riche concentration en lesdits récepteurs; (iv) l'utilisation de la capacité du hSSTR1 (en particulier) et des hSSTR2 et 4 (dans une moindre mesure) à être régulés positivement à la surface cellulaire, après un traitement prolongé par l'agoniste, comme test permettant de d'augmenter la sensibilité des balayages des récepteurs afin de détecter et de diagnostiquer des tumeurs ou des états inflammatoires; (v) l'utilisation de la capacité différentielle des sous-types de hSSTR à être régulés positivement ou internalisés pour produire des images améliorées lors de balayages des récepteurs par analyse soustractive, afin de recruter, par exemple, le hSSTR1 sélectif de membrane tout en internalisant d'autres hSSTR comme les hSSTR3, 4 et 5.
PCT/CA1997/000592 1996-08-23 1997-08-20 Internalisation, dependante des agonistes, des recepteurs de la somatostatine humaine de type 1-5 WO1998008100A1 (fr)

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CA002264007A CA2264007A1 (fr) 1996-08-23 1997-08-20 Internalisation, dependante des agonistes, des recepteurs de la somatostatine humaine de type 1-5
EP97937370A EP0925506A1 (fr) 1996-08-23 1997-08-20 Internalisation, dependante des agonistes, des recepteurs de la somatostatine humaine de type 1-5
AU40056/97A AU4005697A (en) 1996-08-23 1997-08-20 Agonist-dependent internalization of human somatostatin receptors types 1-5

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US60/024,409 1996-08-23

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Cited By (2)

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SG122043A1 (en) * 2004-10-25 2006-05-26 Hoffmann La Roche Ligand-receptor tracking assays
EP2161037A2 (fr) 2003-04-22 2010-03-10 Ipsen Pharma Conjugués de Camptothecin-Somatostatin

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Publication number Priority date Publication date Assignee Title
US4727041A (en) * 1986-04-16 1988-02-23 Chaovanee Aroonsakul Method of diagnosing Alzheimer's disease
WO1994000489A2 (fr) * 1992-06-23 1994-01-06 Diatech, Inc. Peptides derives de la somatostatine et marques de maniere radioactive pour imagerie et utilisations therapeutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4727041A (en) * 1986-04-16 1988-02-23 Chaovanee Aroonsakul Method of diagnosing Alzheimer's disease
WO1994000489A2 (fr) * 1992-06-23 1994-01-06 Diatech, Inc. Peptides derives de la somatostatine et marques de maniere radioactive pour imagerie et utilisations therapeutiques

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
EP2161037A2 (fr) 2003-04-22 2010-03-10 Ipsen Pharma Conjugués de Camptothecin-Somatostatin
EP2662087A1 (fr) 2003-04-22 2013-11-13 Ipsen Pharma Vecteurs de somatostatine
SG122043A1 (en) * 2004-10-25 2006-05-26 Hoffmann La Roche Ligand-receptor tracking assays

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