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WO1990000567A1 - Facteur stimulant la migration - Google Patents

Facteur stimulant la migration Download PDF

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Publication number
WO1990000567A1
WO1990000567A1 PCT/GB1989/000768 GB8900768W WO9000567A1 WO 1990000567 A1 WO1990000567 A1 WO 1990000567A1 GB 8900768 W GB8900768 W GB 8900768W WO 9000567 A1 WO9000567 A1 WO 9000567A1
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Prior art keywords
migration
fibroblasts
cells
fetal
msf
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PCT/GB1989/000768
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English (en)
Inventor
Seth Lawrence Schor
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Cancer Research Campaign Technology Ltd
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Cancer Research Campaign Technology Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel polypeptides hereinafter referred to as migration stimulating factors (MSF's), to processes for their production and use in diagnosis and therapy.
  • MSF's migration stimulating factors
  • MSF-1 migration stimulating factor-1
  • MSF-1 migration stimulating factor-1
  • MSF's further migration stimulating factors
  • MSF's affect matrix biosynthesis by fibroblasts particularly hyaluronic acid (HA) biosynthesis. This effect on HA biosynthesis is probably responsible for the observed effect of MSF's on fibroblast migration. It is also believed that the MSF's affect protein synthesis by human mammary epithelial cells.
  • SUBSTITUTE SHEET Other polypeptides which promote migratory activity of various cells have been described in the literature. These appear to differ from MSF as explained below: “Scatter Factor” [Stoker, M. and Penny an, M. , .. Cell Sci.. 77.. 209-224 (1986) and Stoker, M. , et al. , Nature. 327. 239-242 (1987) ] and “autocrine motility factor” (AMF) [Liotta, L. et. , Proc. Nat. Acad. sci..
  • HA stimulating factor is produced by foetal fibroblasts but not by adult fibroblasts but differs from MSF-1 in that MSF-1 is cationic whereas HASF is anionic.
  • MSF-1 is a polypeptide having a molecular weight of 70kD by polyacrylamide gel electrophoresis, and the following properties in solution;
  • MSF-1 is precipitated by ammonium sulphate at 10% saturation and binds to a heparin affinity column being eluted at 0.3 and 0.6 M sodium chloride. MSF-1 is believed to have a N-terminal sequence of Ala-Pro-Ile-Pro.
  • SUBSTITUTE SHEET MSF-2 and MSF-3 are anionic, being eluted from anion exchange resins with 0.3 or 3.0M sodium chloride; they do not bind to cationic exchange resins and precipitate from solution with 10 to 20% or 20 to 30% saturated ammonium sulphate.
  • the present invention therefore further provides a polypeptide capable of stimulating migration of normal adult fibroblasts which do not themselves produce the polypeptide, particularly adult skin fibroblasts, having an apparent molecular weight in the range 50-70 kD by gel filtration and having the solution properties set out above.
  • the polypeptides may be obtained by purification of suitable conditioned media or by synthetic or recombinant DNA techniques. They may be substantially identical to a MSF, a fragment thereof or homologues of a MSF or fragment thereof provided that the migration stimulating activity is retained. Such activity may be assayed readily by techniques described below.
  • the present invention further provides, in further aspects, (a) a MSF or a polypeptide as hereinbefore defined in solution, preferably at physiological pH and salt concentration, optionally in the presence of buffers, serum, nutrients and/or other components of a cell culture medium and (b) a MSF or a polypeptide as hereinbefore defined in pure, solid form or in solution substantially free of serum, and/or components of cell culture media.
  • a MSF or a polypeptide as hereinbefore defined in homogeneous form preferably at physiological pH and salt concentration
  • the most preferred embodiment of the invention is MSF-1.
  • the present invention further provides a MSF or a polypeptide as hereinbefore defined for use in a method of treatment of the human or animal body or a method of diagnosis performed on the human or animal body.
  • MSF's and polypeptides as hereinbefore defined have benefits in the diagnosis and treatment of cancer and in wound healing and other disorders involving alterations in fibroblast migration, proliferation, biosynthetic activity and ability to interact with other cell types, in particular epithelial cells.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a MSF or a polypeptide as hereinbefore defined together with a diluent or carrier therefor and optionally further comprising stabilisers, anti-oxidants, anti ⁇ biotics such as anti-bacterials and/or anti-fungals, buffers, salts and the like.
  • the invention further provides a method for the treatment of the human or animal body comprising administering an effective non-toxic amount of a MSF or a polypeptide as hereinbefore to a patient in need thereof.
  • Administration may be by any suitable route and in any pharmacologically acceptable form adapted to administration by that route and in sufficient amount to achieve a desired effect, for instance on migration of fibroblasts or alteration in fibroblast biosynthetic activity.
  • SUBSTITUTESHEET The invention further provides the use of a MSF or a polypeptide as hereinbefore defined in the preparation of a medicament for use in a method of treatment of the human or animal body by therapy or in a method of diagnosis practiced on the human or animal body.
  • the present invention further comprises a test method or assay which comprises contacting MSF-sensitive cells, which do not secrete MSF's, preferably adult fibroblasts with a sample suspected to contain a MSF or a polypeptide as hereinbefore defined.
  • MSF-sensitive cells which do not secrete MSF's, preferably adult fibroblasts
  • a sample suspected to contain a MSF or a polypeptide as hereinbefore defined is detected and/or determined for instance by observing the migration behaviour of the cells (preferably by measurement of their CDMI) and optionally comparing this behaviour with standards.
  • the MSF-sensitive cells are preferably normal adult skin fibroblasts and are preferably in the form of a confluent culture on a 3-dimensional collagen matrix.
  • the samples may be fractionated, diluted or concentrated in order to adjust the concentration of MSF or polypeptide therein to optimise the response of the cells.
  • the test or assay is conducted in solution for instance in a buffer and most preferably the solution has a concentration of MSF or polypeptide of about lOng/ml.
  • the sample is a cell culture medium or a fraction thereof such as a solution of a partially purified MSF or a polypeptide as hereinbefore
  • SUBSTITUTE SHEET defined and the test or assay is conducted to determine whether cells are able to produce a MSF or a polypeptide as thereinbefore defined (and therefore whether they are "foetal- like" with respect to this particular characteristic; such aberrant fibroblasts in a tissue sample would suggest increased susceptibility to developing cancer) .
  • This method may also be used as a part of a purification process for obtaining a MSF or a polypeptide as hereinbefore defined from cell culture or in order to identify fractions containing MSF or a polypeptide.
  • the sample is a body fluid such as serum and the assay is conducted as an aid to diagnosis or prognosis of cancer; for instance elevated circulating levels of a MSF or a polypeptide as hereinbefore defined may be associated with increased risk of developing cancer or disease prognosis in individuals already having cancer.
  • the sample may be conditioned medium prepared by culturing fibroblasts from a cancer patient or from an individual suspected to be at risk from cancer such as breast cancer and the test or assay may be conducted as an aid to diagnosis or prognosis thereof.
  • MSF's and polypeptides as hereinbefore defined may be used to raise antibodies by conventional immunisation techniques.
  • the antibodies (polyclonal or monoclonal) are a further aspect of the invention. They may also be used in test or assay techniques, such as radio-immunoassay (RIA) or enzyme linked immunosorbent assay (ELISA) techniques for detecting a MSF or a
  • RIA radio-immunoassay
  • ELISA enzyme linked immunosorbent assay
  • SUBSTITUTESHEET polypeptide in a sample such as a culture medium or body fluid.
  • Labelled antibodies and test or assay methods using antibodies against a MSF or a polypeptide are a further aspect of the invention.
  • the invention further provides a process for producing a MSF or polypeptide as hereinbefore defined, which process comprises culturing fibroblasts capable of secreting MSF, such as foetal fibroblasts, foetal-like fibroblasts of cancer patients or other MSF-secreting fibroblasts found in the normal adult such as oral mucosal fibroblasts capable of expressing MSF in a suitable culture medium and recovering the conditioned medium so produced.
  • fibroblasts capable of secreting MSF, such as foetal fibroblasts, foetal-like fibroblasts of cancer patients or other MSF-secreting fibroblasts found in the normal adult such as oral mucosal fibroblasts capable of expressing MSF in a suitable culture medium and recovering the conditioned medium so produced.
  • fibroblasts capable of secreting MSF
  • foetal fibroblasts such as foetal fibroblasts, foetal-like fibroblasts of cancer patients or other MSF-secreting fibroblasts found in the normal adult such
  • a suitable bioassay technique is that described in Example 1 below using FSF 37 cells or any other fibroblasts highly sensitive to the presence of MSF or polypeptide as hereinbefore defined.
  • Highly sensitive cells can be identified by screening fibroblasts and fibroblast cell lines using a foetal or transformed fibroblast conditioned medium containing a MSF or a
  • the present invention further provides a process for increasing the migration of fibroblasts comprising contacting fibroblasts with a MSF or a polypeptide as hereinbefore defined.
  • antibodies against a MSF or a polypeptide as hereinbefore defined RNA and DNA fragments encoding a MSF or a polypeptide as hereinbefore defined; genes comprising regulatory DNA sequences and DNA sequences encoding MSF or a polypeptide as hereinbefore defined; cloning and/or expression vectors comprising DNA or genes as hereinbefore defined; cells transformed with such cloning or expression vectors and nucleic acid probes for detecting RNA or DNA fragments or genes as hereinbefore defined.
  • SUBSTITUTE SHEET Figure 1 Scatter diagram of migration values of normal adult, fetal and breast cancer patient (BSF) skin fibroblasts plated at high and low cell densities.
  • Figure 2 Dose-response data concerning the effects of fetal (0- 0) and BSF (•-•) conditioned medium on the migration of a foreskin fibroblast target line (FSF37) plated at high density.
  • FIG. 3 Fetal fibroblast (FS6) CM was fractionated by gel filtration chromatography and the collected samples then tested for their ability to stimulate the migration of FSF37 target cells. As in the standard migration assay, the FS6 CM fractions were tested at a final concentration of 25% in medium containing 5% serum. The first bar (labelled "C") is the level of FSF37 migration achieved in control cultures in which SF-MEM was used instead of the FS6 CM fractions.
  • Figure 4 The effects of fetal and BSF CM on the proliferation of fetal (FS6) and foreskin (FSF37) fibroblasts.
  • FS6 fetal
  • FSF37 foreskin
  • Cells were plated in 35 mm plastic tissue culture dishes at 2 x 10 4 cells per dish in medium containing 5% serum (X-X) , or this medium supplemented with 25% fetal (0-0) or BSF (o-o) CM.
  • the fetal fibroblasts achieved a higher plateau cell density (4.9 x 10 5 ) than the adult cells (1.4 x 10 5 ) .
  • Neither fetal nor BSF CM affected cell proliferation.
  • This stimulation of migration is specific to confluent cells, as the migration of subconfluent adult fibroblasts is unaffected by these conditioned media.
  • Gel filtration chromatography of fetal fibroblast conditioned medium indicates that migration stimulating activity is recovered in a single peak with an apparent molecular mass in the range of 50-60 kD.
  • the active migration stimulating factor (MSF) in both fetal and cancer patient fibroblast conditioned media appears to be a protein stable at acid pH, but inactivated by heat, alkaline pH and reductive alkylation. MSF produced by fetal and cancer patient fibroblasts is presumably responsible for the characteristically elevated levels of migration displayed by these cells in
  • MSF - - confluent culture, thereby suggesting an autocrine mode of action for this factor. Stimulation of adult cell migration by MSF requires the presence of either serum or platelet-poor plasma and is not observed in serum-free medium. MSF does not appear to affect either the proliferation of morphology of normal adult cells under any of the culture conditions examined.
  • fetal and normal adult skin fibroblasts may be distinguished on the basis of the distinctive CDMI values they express (Schor et al. 1985a) and (b) ostensibly normal skin fibroblasts from
  • the CDMI is specifically a measure of the effects of cell density on migration.
  • This differential effect of cell density may be mediated by a number of mechanisms, including (a) cell- induced alterations in the orientation and/or packing density of collagen fibres in the gel (Grinnell and Lamke, 1984) , (b) density-dependent changes in the deposition of specific matrix macromolecules (eg. fibronectin) known to affect cell migration (Mautner and Hynes, 1977; Schor et al. 1981), (c) social interactions between cells (Abercrombie, 1970) , and (d) the secretion of a migration stimulating or inhibiting soluble factor.
  • matrix macromolecules eg. fibronectin
  • the objective of the present study is to learn more about the biochemical basis of the different CDMI values displayed by fetal, normal adult and cancer patient skin fibroblasts.
  • Our data suggest that fetal fibroblasts and the fetal-like fibroblasts of cancer patients secrete an autocrine migration stimulating factor not produced by normal adult cells.
  • Fibroblast lines were established from explant cultures, as described by Ham (1980) .
  • FSF37 cells were derived from a foreskin biopsy of a 6 year old child. Further details regarding the normal adult and fetal skin fibroblasts used in this study may be found in Schor et al (1985a) ; similar data regarding the breast cancer patient skin fibroblasts (BSF) are presented in Haggie et al (1987) .
  • CM conditioned medium
  • samples of CM were treated as follows: (a) dialysis: against lOOx volume of SF-MEM for 24 hr at 4°C;
  • fetal fibroblast (FS6) CM were concentrated tenfold using an Amicon filtration cell fitted with a YM5 membrane (molecular weight cut off 5000 kD) .
  • Neat or concentrated CM was fractionated by gel filtration chromatography using a Pharmacia fast protein liquid chromatography system (FPLC ⁇ m ) .
  • 200 ul of CM was applied to a Superose 12 column and fractionated at a flow rate of 0.3 ml/min in 20 mM Tris buffer (pH 7.4) containing 0.15 M NaCl. 1 ml fractions were collected and then dialysed against SF-MEM for 48 hr at 4°C.
  • Type I collagen was extracted from rat tail tendons in 3% acetic acid, dialysed for two days against distilled water and used to make 2 ml collagen gels in 35 mm plastic tissue culture dishes as described previously (Schor and Court, 1979) .
  • collagen gels we ' re overlaid with 1 ml of either SF-MEM or CM.
  • Fibroblasts growing in stock culture were trypsinized and resuspended in growth medium containing 20% serum. This cell suspension was then used to prepare two plating inocula (high and low density, respectively) .
  • CDMI cell density migration index
  • S UB STI TUTESHEET range is renamed A (for normal adult) , whilst the the T/F and F/N ranges are collectively referred to as the F range (for fetal) .
  • F range for fetal
  • SUBSTITUTESHEET cells were in the F range. effects of conditioned media on cell migration
  • CM Conditioned media
  • FS6 fetal fibroblasts displayed characteristically fetal-like migratory behaviour under all culture conditions. None of the CMs examined had a significant effect on cell migration at either high or low cell density. It should be noted that FSF37 fibroblast CM did not inhibit the migration of fetal fibroblasts in high density culture. The migration of BSF cells at both high and low cell densities was similarly unaffected by all of the CMs examined.
  • CMs produced by a number of other normal adult, fetal and BSF skin fibroblast lines are presented in Table 2. None of the adult CMs had any demonstrable effect on cell migration. In contrast, CMs produced by all of the fetal and BSF lines induced a significant stimulation of migration. None of these CMs affected the already high levels of migration of FSF37 cells in low density cultures (data not presented)
  • NSF130 1.1 mean 1.0 +/- 0.2
  • FSF37 CELLS Data are presented concerning the effects of conditioned media produced by different fetal, normal adult and breast cancer patient skin fibroblasts on the migration of a target foreskin fibroblast line (FSF37) in high density culture.
  • the mean +/- SD for each class of fibroblast (fetal, adult and cancer patient) are also given.
  • Neat CM produced by FS6 fetal fibroblasts was fractionated by gel filtration chromatography as described in Materials and Methods. Individual fractions were then tested for their ability to stimulate the migration of FSF37 fibroblasts plated at high
  • fetal and BSF fibroblasts migrate to a significantly greater extent in high density culture than do normal adult cells
  • fetal and BSF fibroblasts produce a soluble factor (MSF) which stimulates the migration of normal adult cells in high density culture (with a consequent expression of CDMI values falling in the fetal range)
  • MSF soluble factor
  • fetal and BSF CM do not affect the migration of adult cells in low density culture
  • FSF37 foreskin fibroblasts were plated onto collagen gels at high density in the presence and absence of fetal (FS6) and breast cancer patient (BSFll) fibroblast conditioned media in
  • the migration stimulating activity in fetal and BSF CM displayed the same sensitivity to various treatments (trypsinization, dialysis, heat, pH change, reductive alkylation) .
  • the similarity of fetal and BSF migration stimulating activity is again indicated by the identical dose- response curves of the respective CMs. Further characterization and purification of the respective factors will reveal whether fetal and breast cancer patient fibroblast MSF are in fact identical.
  • Gel filtration chromatography of fetal fibroblast CM indicates that MSF has an apparent molecular mass in the range of 50-60 kD.
  • SUBSTITUTESHEET level corresponding to one unit of migration stimulating activity is achieved at a concentration of 10% CM. Since both fetal and BSF CM contain approximately 50ug protein per ml, we calculate that these CMs contain in the region of 10 units per ml of 0.2 units per ug protein.
  • SUBSTITUTE SHEET Migration stimulating factors produced by a variety of cell types and displaying a diversity of target cell specificities have recently been described. It is of interest to note that many of these factors have apparent molecular masses in the range of 50-60 kD (Stoker and Pennyman, 1986;
  • fetal fibroblast CM fetal fibroblast migration stimulating factor
  • scatter factor acts in a paracrine fashion, since it is produced by fetal fibroblasts, but exerts its biological activity on normal epithelial cells; in contrast, the migration stimulating factor described in this communication is assayed by virtue of its effect upon target adult fibroblasts.
  • the elevated levels of migration displayed by fetal and BSF fibroblasts in high density culture most probably result from the constitutive production of MSF by these cells, thereby suggesting an autocrine mode of action for this factor.
  • MSF is identified by its stimulation of fibroblast migration into three-dimensional collagen gels during an extended incubation period of 4 days, scatter factor by its dispersion of epithelial cells growing on plastic dishes and AMF by its effect upon cell migration into a Nucleopore filter during an incubation period of only 4 hours.
  • SUBSTITUTESHEET displayed by these various factors raises the intriguing possibility that they may nonetheless be members of a related family of molecules.
  • Fibroblast lines were established from explant cultures, as described by Ham (1980) .
  • the cell lines used in this study were: FSF37 foreskin fibroblasts obtained from a 6 year old male donor; FS6 fetal limb dermal fibroblasts obtained from a 12 week female fetus; BSFll forearm dermal fibroblasts obtained from a 50 year old female patient with familial breast cancer.
  • the FSF37 foreskin fibroblasts display a characteristically adult pattern of migratory behavior and do not produce MSF; these cells will therefore be referred to as adult fibroblasts in this communication.
  • CM conditioned medium
  • CM is adsorbed to a heparin affinity column and elutes at 0.3-
  • YM10 Diaflo membrane (Amicon Ltd, Gloucestershire, UK) .
  • the resultant concentrated material was then fractionated by gel filtration chromatography using a Pharmacia fast protein liquid chromatography system (FPLC tm ) as described in Example 1. This involved applying 200 ul aliquots to a Superose-12 column and running it at a flow rate of 0.3 ml/min in 20 mM Tris-HCl buffer
  • Type I collagen was extracted from rat tail tendons in 3% acetic acid, dialyzed for two days against distilled water and used to make 2 ml collagen gels in 35 mm plastic tissue culture dishes (Schor and Court 1979) .
  • collagen gels were overlaid with 1 ml of either SF-MEM (controls) , neat CM or SF-MEM containing 40 ng/ml MSF.
  • FSF37 fibroblasts were used as target cells in the assay since they do not produce MSF, but are responsive to it.
  • Confluent stock cultures of FSF37 foreskin fibroblasts were trypsinized and resuspended in growth medium containing 20% serum.
  • Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature 327. 239-242 VOGEL, A.E., RAINES, B. , KARIYA, B. , RIVEST, M. and ROSS, R. (1978) Coordinate control of 3T3 cell proliferation by platelet derived growth factor and plasma components. Proc. Nat. Acad Sci. (USA) 25, 2810-2814

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Abstract

L'invention concerne le facteur-1 stimulant la migration, lequel est un polypeptide capable de stimuler la migration de fibroblastes adultes normaux, qui ne produisent pas eux-mêmes le polypeptide, et ayant un poids moléculaire apparent de 70kD par électrophorèse sur gel de polyacrylamide. Ce composé cationique à un pH physiologique, est précipité à partir d'une solution aqueuse par du sulfate d'ammonium à une saturation de 10 %, est stable en solution à un pH de 2 mais pas à un pH de 10, est dénaturé à 56°C, est sensible à la trypsine et à l'alkylation/réduction et lie l'héparine. D'autres facteurs de stimulation de migration sont similaires mais anioniques. Ils sont produits par des fibroblastes foetaux ou analogues au foetus provenant de patients atteint du cancer (mais pas par des fibroblastes de la peau adultes normaux), et on peut utiliser leur production comme indicateur de diagnostic ou de pronostic de divers cancers.
PCT/GB1989/000768 1988-07-06 1989-07-06 Facteur stimulant la migration Ceased WO1990000567A1 (fr)

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GB8816095.7 1988-07-06
GB888816095A GB8816095D0 (en) 1988-07-06 1988-07-06 Protein

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WO1990000567A1 true WO1990000567A1 (fr) 1990-01-25

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999031233A1 (fr) * 1997-12-16 1999-06-24 University Of Dundee Polypeptides, polynucleotides et leurs utilisations
US7647197B2 (en) 2002-08-09 2010-01-12 Surveylab Group Limited Mobile instrument, viewing device, and methods of processing and storing information
WO2019057780A1 (fr) 2017-09-19 2019-03-28 Humanitas Mirasole S.P.A. Anticorps dirigé contre le facteur de stimulation de la migration (msf) humain et utilisations associées

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CANCER RESEARCH, Vol. 45, 1985, MICHAEL L. BASARA et al., "Stimulation of Haptotaxis and Migration of Tumor Cells by Serum Spreading Factor", pages 2487-2494. *
J. CELL. SCI., Vol. 77, 1985, (Great Britain), MICHAEL STOKER and MARION PERRYMAN, "An Epithelial Scatter Factor Released by Embryo Fibroblasts", pages 209-223. *
JOURNAL OF CELL SCIENCE, Vol. 90, 1988, (Great Britain), SETH L. SCHOR et al., "Foetal and Cancer Patient Fibroblasts Produce an Autocrine Migrationstimulating Factor Not Made by Normal Adult Cells", pages 391-399. *
NATURE, Vol. 327, 1987, MICHAEL STOKER et al., "Scatter Factor is a Fibroblast-Derived Modulator of Epithelial Cell Mobility", pages 239-242. *
PROC. NATL. ACAD. SCI. U.S.A., Vol. 83, 1986, (USA), LANCE A. LIOTTA et al., "Tumor Cell Autocrine Motility Factor", pages 3302-3306. *
PROC. NATL. ACAD. SCI. U.S.A., Vol. 86, 1989, (USA), ANNE-MARIE GREY et al., "Purification of the Migration Stimulating Factor Produced by Fetal and Breast Cancer Patient Fibroblasts", pages 2438-2442. *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999031233A1 (fr) * 1997-12-16 1999-06-24 University Of Dundee Polypeptides, polynucleotides et leurs utilisations
US7351810B1 (en) 1997-12-16 2008-04-01 University Of Dundee Polypeptides, polynucleotides and uses thereof
US7811789B2 (en) 1997-12-16 2010-10-12 University Of Dundee Polypeptides, polynucleotides and uses thereof
US7647197B2 (en) 2002-08-09 2010-01-12 Surveylab Group Limited Mobile instrument, viewing device, and methods of processing and storing information
US8024151B2 (en) 2002-08-09 2011-09-20 Surveylab Group Ltd. Mobile instrument, viewing device, and methods of processing and storing information
WO2019057780A1 (fr) 2017-09-19 2019-03-28 Humanitas Mirasole S.P.A. Anticorps dirigé contre le facteur de stimulation de la migration (msf) humain et utilisations associées
US11254739B2 (en) 2017-09-19 2022-02-22 Humanitas Mirasole S.P.A. Anti-human migration stimulating factor (MSF) and uses thereof

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JPH03505732A (ja) 1991-12-12
EP0423207A1 (fr) 1991-04-24
GB8816095D0 (en) 1988-08-10

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