EP0300031A1 - Peptides immunodepresseurs et leurs procedes d'utilisation - Google Patents
Peptides immunodepresseurs et leurs procedes d'utilisationInfo
- Publication number
- EP0300031A1 EP0300031A1 EP88902271A EP88902271A EP0300031A1 EP 0300031 A1 EP0300031 A1 EP 0300031A1 EP 88902271 A EP88902271 A EP 88902271A EP 88902271 A EP88902271 A EP 88902271A EP 0300031 A1 EP0300031 A1 EP 0300031A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- amino acid
- acid sequence
- peptide
- subject
- polypeptide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
- G01N33/57426—Specifically defined cancers leukemia
-
- 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
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/13011—Gammaretrovirus, e.g. murine leukeamia virus
- C12N2740/13022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
- C12N2740/15022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Definitions
- Feline leukemia virus is a leukemia-inducing retrovirus which can also induce aplastic anemia and immunosupression in persistently viremic cats.
- Human acquired immunodeficiency syndrome AIDS
- HIV Human Immunodeficiency Viruses/ e.g., HIV-I and HIV-II, referred to herein collectively as HIV. HIV also causes immune suppression in viremic individuals.
- the retrovirus-mediated immunosuppression in feline leukemia and human AIDS may, in fact, result in susceptibility to opportunistic infections.
- a 17 amino acid synthetic peptide from the murine leukemia virus (MLV) pl5E sequence has been shown by others to exert in vitro immunosuppressive effects similar to those induced by the complete viral protein or the intact virus (Cianciolo, et al., Science 230:453, 1985).
- MLV murine leukemia virus
- Cianciolo, et al. Science 230:453, 1985.
- One measure of this immunosuppressive effect is the in vitro inhibition of mitogen-induced lymphocyte proliferation.
- the peptide disclosed by Cianciolo et al. was derived from MLV and has the amino acid sequence LQNRRGLDLLFLKEGGL.
- Monoclonal antibodies to an uncharacterized antigenic determinant of p15E which detect, by fluorescence-activated cell sorting, antigen in various cell lines derived from human cancers have also been described (J. Exp. Med. 159:964, 1984). However, the biochemical nature of the pl5E-related antigen was not disclosed and no relationship has been shown between it and either the 35,000 dalton protein or the 110 , 000 dalton protein expressed by various human leukemia and cancer cell lines and described herein. Although the monoclonal antibody can be used to absorb and remove in vitro suppressive activity, there have been no reported results indicating that these antibodies bind to the highly conserved immunosuppressive region of viral p15E or that such binding blocks immunosuppression.
- Still another object of the present invention is to provide an antibody for detecting ⁇ 15E-related immunosupressive factors whether virally, non-virally, or endogenous virus induced.
- Novel immunosuppressive peptide sequences which, when conjugated to a carrier molecule, are capable of being used as therapeutic agents in the treatment of immune-related dysfunctions such as autoimmune diseases, graft rejection, and allergies are provided. Also provided are the use of these peptides as vaccines to prevent immunosuppression and disease upon exposure to retroviruses such as FLV, BLV, HTLV, and HIV. Further provided are antibodies to the suppressive peptide(s) which are capable of diagnosing human cancer by identifying in an immunoassay the expression of p15E-related proteins.
- the present invention also provides a soluble, immunosuppressive peptide which is biologically active without being cross-linked to a carrier molecule.
- a peptide included within p15E designated I6B
- I6B One peptide included within p15E
- AKLRERLKQRQQ displays an unusual adhesive property.
- Antiserum to the I6B peptide was found to neutralize virus infectivity.
- I6B peptide which should abrogate antibody-mediated neutralization
- enhanced viral infectivity was detected.
- immunocytochemical studies with I6B antiserum have detected antigen in FLV-infected cells. Blocking of this antiserum with the I6B peptide (which should prevent antibody recognition of antigen) enhanced the cellular staining in an apparent non-specific manner.
- Another novel peptide included within p15E (designated ISP) and having the amino acid sequence LQNRRGLDILFLQEGGLC also displays immunosuppressive activity.
- the present invention provides an immunosuppressive polypeptide, designated ⁇ I6B:ISP, which comprises a portion of the I6B domain synthetically linked to the ISP domain and having the following amino acid sequence:
- ⁇ I6B:ISP is a soluble polypeptide which inhibits in vitro mitogen-induced proliferation of murine splenic T lymphocytes. The observed inhibition proliferation appears not to be a function of cell toxicity.
- Other peptide configurations which are also active include related sequences from retroviral and cellular proteins, inverted structures (ISP:I6B), truncated I6B:ISP and ISP:I6B peptides in monomeric, dimeric and multimeric forms. The advantages of these peptides over carrier molecule-linked peptides include higher solubility, lower immunogenicity and biological activity at lower (w/v) concentrations.
- the present invention also concerns a purified polypeptide having a molecular weight of about 110,000 daltons which is detected on mammalian leukemia and cancer cells.
- This polypeptide is detected with antiserum raised to an immunosuppressive polypeptide from the predicted amino acid sequence of feline leukemia virus p15E.
- Antibodies which detect this 110,000 dalton polypeptide are useful for diagnosing numerous malignancies and for monitoring peripheral blood of remission leukemia patients for residual disease.
- antibodies directed to it or its receptor, as well as synthetic peptides derived from its predicted amino acid sequence have therapeutic applications for modulating suppressed tumor immunity.
- polyclonal rabbit antisera raised to biologically-active KLH conjugates of feline, human T cell and murine leukemia viral suppressive peptides have been generated and affinity purified to obtain FLV-ISP antibodies.
- Immnocytochemical staining with such FLV-ISP antibodies strongly detects antigen in FLV-infected cat cells.
- the ISP antibodies also detect an antigen in diverse cell lines established from human leukemia patients but not in normal murine fibroblasts.
- Antibody staining of peripheral blood leukocytes (PBL) from normal individuals is very weak compared to leukemia cells or phytohemagglutinin (T lymphocyte mitogen) stimulated PBLs.
- PBL peripheral blood leukocytes
- the 110K protein from human leukemia cells was detected in the supernatant fraction of conditioned growth medium.
- This soluble 110K protein which is released into growth media by cell lines established from diverse leukemias and solid tumors, displays an epitope similar in structure and function to the immunosuppressive peptide domain of FLV p15E.
- Balb/c spleen cells were cultured for 4 days in the presence of the murine T cell mitogen Con A (4 ⁇ g/ml) and titrated amounts of ⁇ I6B:ISP peptide. Proliferation of mitogen-stimulated cultures exposed to the 5I6B:ISP peptide is presented as a percentage of control cultures (cells and mitogen only). The dashed line indicates proliferation of positive control cultures (cells + mitogen only).
- Balb/c spleen cells were cultured for 4 days in the presence of Con A and titrated amounts of these three peptides.
- the dashed line indicates stimulation of control cultures (cells + mitogen only).
- Balb/c spleen cells were stimulated with either Con A (A) or LPS (B) in the presence of titrated amounts of the ⁇ I6B:ISP peptide. Cell cultures were incubated for either 4 or 5 days before harvesting.
- A Effect on T Cell Proliferation.
- B Effect on B Cell Proliferation.
- Balb/c spleen cells were cultured in the presence of Con A and titrated amounts of ⁇ I6B:ISP peptide for either 3, 4, or 5 days before harvesting.
- the proliferation values are a percentage of control cultures (cells with Con A only).
- the 5I6B:ISP peptide was bound to microtiter wells and incubated with different anti-peptide antibody preparations in a standard enzyme-linked immunosorbent assay (ELISA).
- ELISA enzyme-linked immunosorbent assay
- AP558-28 affinity purified rabbit antiserum against the ISP peptide
- R112-5 rabbit antiserum against the I6B peptide
- AP67 affinity purified rabbit antiserum against the c-abl oncogene product (negative control).
- the present invention provides an immunosuppressive peptide which comprises a peptide having less than about 40 amino acid residues, said amino acid residues comprising an amino acid sequence of at least 5 amino acid residues, said amino acid sequence being selected from amino acid sequences included within the amino acid sequence LQNRRGLDILFLQEGGLCAALKEECCF.
- peptide means a chain of amino acid residues having between 2 and about 100 amino acid residues, and includes peptides which are purified from naturally occuring products, or produced by synthetic or recombinant DNA methods. Amino acid chains having greater than about 100 amino acid residues are referred to herein as polypeptides.
- the peptide is conjugated to a carrier molecule so as to form an immunosuppressive compound.
- carrier mo lecule means a molecule which , when conj ugated, e.g., cross-linked, to a ligand of interest, either increases the immunogenicity of the ligand or activates the biological activity, e.g., immunosupressive activity, of the ligand.
- Carrier molecules which increase the immunogencity of ligands are known in the art and include large proteins such as keyhole limpet hemocyanin (KLH), ovalbumin, porcine thyroglobulin, and bovine serum albumin (BSA), lipids, and peptides.
- Carrier molecules which activate the biological activity of ligands are also known in the art, e.g., polyethylene glycol.
- Coupling agents useful for preparing peptide carrier molecule conjugates are known in the art and include conventional cross-linking agents such as aldehydes, e.g., glutaraldehyde, carbodiimides, succinimides, bis-diazotized benzadines, and imidates.
- Applicants also contemplate the addition of certain amino acids, i.e., cysteine or lysine, to either the carboxy terminus or the amino terminus of the peptides of the present invention for the purpose of cross-linking to a carrier molecule.
- the carrier molecule is keyhole limpet hemocyanin.
- the carrier molecule is conjugated to the peptide with glutaraldhyde.
- the present invention also provides an immunosuppressive compound which comprises a peptide having less than about 40 amino acid residues, said amino acid residues comprising an amino acid sequence of at least 5 amino acid residues, said amino acid sequence being selected from amino acid sequences included within an amino acid sequence selected from the group of amino acid sequences consisting of
- LGNRRALILLGQMGRIS LNNRRTLMLMAQMRRIS,
- the present invention provides still further immunosuppressive peptides which comprise a peptide having less than about 40 amino acid residues, said amino acid residues comprising an amino acid sequence of at least 5 amino acid residues, said amino acid sequence being selected from amino acid sequences included within the amino acid sequence QREKRAVGIGALFLGFLG or the amino acid sequence QLTVWGIKQLQARIL.
- Yet another immunosuppressive peptide is provided which comprises an antigenic determinant homologous to an antigenic determinant of the peptide having the amino acid sequence LQNRRGLDILFLQEGGLC.
- an antigenic determinant is homologous to another antigenic determinant if each antigenic determinant binds to the same antibody.
- an immunosuppressive peptide which comprises a first amino acid sequence of at least 5 amino acid residues, said first amino acid sequence being selected from amino acid sequences included within the amino acid sequence AKLRERLKQRQQ, and at least one other amino acid sequence of at least 5 amino acid residues, said other amino acid sequence being selected from amino acid sequences included within an amino acid sequence selected from the group of amino acid sequences consisting of
- LQNRRGLDILFLQEGGLC AALKEECCFLKEEC, QEGGLCAALKEEC, KSLTSLSEWLQNRRG, LQARILAVERYLKDQQL,
- the peptides provided by the present invention may be cyclic or may comprise repeating units of a polymer or a dimer.
- amino terminus of the amino acid sequence included within the amino acid sequence AKLRERLKQRQQ is linked to the carboxy terminus of the amino acid sequence included within an amino acid sequence selected from the group of amino acid sequences consisting of
- LGNRRALILLAQMRRIS LGNRRALILLGQMGRIS, LNNRRTLMLMAQMRRIS, PVNPRSLEKLEIIPASQ, LGSRRTLMLLAQMRKIS, QREKRAVGIGALFLGFLG, and QLTVWGIKQLQARIL.
- the carboxy terminus of the amino acid sequence included within the amino acid sequence AKLRERLKQRQQ is linked to the amino terminus of the amino acid sequence included within an amino acid sequence selected from the group of amino acid sequences consisting of
- LGNRRALILLAQMRRIS LGNRRALILLGQMGRIS, LNNRRTLMLMAQMRRIS, PVNPRSLEKLEIIPASQ, LGSRRTLMLLAQMRKIS,
- the carboxy terminus and the amino terminus of the amino acid sequence included within the amino acid sequence AKLRERLKQRQQ are each linked to an amino acid sequence included within an amino acid sequence selected from the group of amino acid sequences consisting of
- LQNRRGLDILFLQEGGLC AALKEECCFLKEEC, QEGGLCAALKEEC, KSLTSLSEWLQNRRG, LQARILAVERYLKDQQL,
- PVNPRSLEKLEIIPASQ LGSRRTLMLLAQMRKIS, QREKRAVGIGALFLGFLG, and QLTVWGIKQLQARIL.
- the amino acid sequences linked to the carboxy terminus of the amino acid sequence included within the amino acid sequence AKLRERLKQRQQ may be the same or may be different from the amino acid sequence linked to the amino terminus of the amino acid sequence included within the amino acid sequence AKLRERLKQRQQ.
- the immunosuppressive peptide comprises the amino acid sequence AKLRERLKQRQQLQNRRGLDILFLQEGGLC.
- the immunosuppressive peptide comprises the amino acid sequence AKLRELKQRQQLQNRRGLDILFLQEGGLC.
- the present invention also provides a purified polypeptide which comprises an antigenic determinant for which an antibody generated against the peptide having the amino acid sequence LQNRRGLDILFLQEGGLC has affinity, the polypeptide being expressed in mammalian cancer cells.
- an antibody having affinity for an antigenic determinant means the antibody is capable of binding to the antigenic determinant.
- the purified polypeptide has an apparent molecular weight of about 110,000 daltons. In another embodiment of the invention, the purified polypeptide has an apparent molecular weight of about 35,000 daltons.
- nucleic acid sequences which encode each of the purified polypeptides provided herein.
- nucleic acid sequences including DNA, RNA, and cDNA sequences, are useful for preparing expression vectors capable of expressing the purified polypeptides of the present invention.
- antibodies which have affinity for each of the purified the polypeptides of the present invention are provided.
- the antibody is a polyclonal antibody.
- the antibody is a monoclonal antibody.
- the present invention provides a purified protein which affinity for the purified polypeptides of the present invention.
- This purified protein is present on the surface of hematopoietic cells.
- a therapeutic composition which comprises an antibody of the present invention and a pharmaceutically acceptable carrier is also provided.
- This therapeutic composition is useful in a method for treating an immunologically or hematopoietically suppressed subject by administering to the subject an effective, immunosuppressmg blocking amount of the therapeutic composition.
- This therapeutic composition comprises a purified polypeptide of the present invention, or a peptide having an amino acid sequence of at least 5 amino acids, said amino acid sequence being included within the purified polypeptide, and a pharmaceutically acceptable carrier.
- This therapeutic composition is useful in a method for suppressing the immune system of a subject by administering to the subject an effective immunosuppressing amount of the therapeutic composition.
- a therapeutic composition which comprises a portion of the purified protein of the present invention having immunosuppressive peptide-binding activity and a pharmaceutically acceptable carrier.
- This therapeutic composition is useful in a method for treating an immunologically or hematopoietically suppressed subject by administering to the subject an effective, immunosuppressmg blocking amount of the therapeutic composition.
- a method for detecting a cancer cell in sample e.g., a whole blood sample or bone marrow sample, which comprises detecting a cell from the sample which expresses a polypeptide having an antigenic determinant which binds to an antibody raised to the peptide having the amino acid sequence LQNRRGLDILFLQEGGLC, said polypeptide being expressed in mammalian cancer cells.
- a method for diagnosing cancer in a subject comprises detecting a polypeptide having an antigenic determinant which binds to an antibody raised to the peptide having the amino acid sequence LQNRRGLDILFLQEGGLC, said polypeptide being expressed in mammalian cancer cells, or a portion of said polypeptide which includes said antigenic determinant, in a body fluid sample taken from the subject.
- a vaccine which comprises an immunosuppressive peptide of the present invention and a pharmaceutically acceptable carrier.
- This vaccine is useful for immunizing a subject against a retroviral infection by administering to the subject an ef fective immunizing amount of the vaccine.
- Still yet another vaccine is provided which comprises an immunosuppressive compound of the present invention and a pharmaceutically acceptable carrier.
- This vaccine is useful for immunizing a subject against a retroviral infection by administering to the subject an effective immunizing amount of the vaccine.
- the present invention further provides a therapeutic composition which comprises an immunosuppressive peptide of the present invention and a pharmaceutically acceptable carrier.
- This therapeutic composition is useful for suppressing the immune system of a subject by administering to the subject an effective immunosuppressmg amount of the therapeutic composition.
- a therapeutic composition which comprises an immunosuppressive compound of the present invention and a pharmaceutically acceptable carrier.
- This therapeutic composition is useful for suppressing the immune system of a subject by administering to the subject an effective immunosuppressing amount of the therapeutic composition.
- ISP synthetically produced and cross-linked with glutaraldehyde to keyhole limpet hemocyanin (KLH)
- KLH keyhole limpet hemocyanin
- Synthetic ISP crosslinked to KLH with gluteraldehyde was also formulated with Freund's adjuvant and used to generate a rabbit polyclonal antiserum using standard immunization techniques. It was observed that this antiserum recognized ISP specifically in a standard ELISA immunoassay using ISP as immobilized antigen and peroxidase-labeled anti-rabbit antibody.
- Peptide affinity purified rabbit antibody to ISP was used to screen by Western blot analysis protein antigens derived from cell lysates of several human leukemia cell lines not overtly or exogenously infected by retroviruses. Includded in the study were K562, EM2, CEM and Raji human leukemia cells. Surprisingly, the antibody also reacted with and specifically identified a protein or proteins with an apparent molecular weight of about 35,000 daltons in each of these cells. This protein was designated p35. Normal human peripheral blood leukocytes and normal fibroblasts do not contain this ⁇ rotein(s) and thus did not provide binding sites for the anti-peptide antibodies.
- the antibodies to ISP of the present invention are useful for detecting ⁇ 15E-related proteins in human leukemia cells and for diagnosing a variety of naturally occurring human cancers in which ⁇ 15E-like proteins are expressed. Furthermore, since cells infected with retroviruses also express p15E-related proteins, e.g.,
- FLV-infected cells antibody to ISP or related sequences is useful for detecting viral antigen in tissues or body fluids containing such viruses and for diagnosing retrovirus-induced diseases such as HIV-induced AIDS, HTLV-induced leukemia, FLV-induced feline leukemia,
- BLV-induced bovine leukemia and other as yet unknown diseases induced by endogenous retroviral sequences.
- p35 is an immunosuppressive protein or set of related proteins. This link between immunosuppression and p35 may be deduced from studies on a human tumor cell line designated K562.
- K562 cells were derived from a chronic myelogenous leukemia (CML) patient in erythroleukemic blast crisis. The established cell line is characterized by the expression of a cancer gene called bcr-abl.
- this gene is a result of an exchange of genetic information between chromosomes in the patient resulting in the formation of an aberrant chromosome called the Philadelphia chromosome. Formation of this altered chromosome results in the expression of a hybrid gene composed of so-called bcr sequences and abl sequences. Expression of this gene is thought to result in chronic myelogenous leukemia as the abl gene is a known oncogene.
- P210 bcr-abl Antisera directed to components of bcr and abl proteins have been developed and have been used to identify the bcr-abl hybrid gene product (called P210 bcr-abl or P210) in these K562 cells (Nature 315:550, 1985).
- P210 is known to possess kinase enzymatic activity. P210 can be detected by its ability to autophosphorylate while in a complex with antibody (an immune complex).
- Treatment of K562 cells with certain drugs such as phorbol 12-myristate 13 acetate (PMA) and mezerein induces a change in expression of the activated oncoprotein P210 such that intracellular expression of P210 is drastically reduced. Treatment with these agents also causes differentiation of K562 cells and a loss of transformed phenotype.
- PMA phorbol 12-myristate 13 acetate
- K562 is one of the human cell lines that contains p35 as shown by detection with the anti-ISP antibody of the present invention.
- treatment of K562 cells with PMA also causes a drastic reduction in p35 levels.
- ⁇ 35 expression is directly correlated with the expression of the CML oncogene P210.
- K562 cells and other established cell lines derived from human myeloid leukemia patients have been shown to secrete several factors which inhibit in vitro growth of normal bone marrow cells (Olofsson and Olsson, Leukemia REs 4:437, 1980; and 8:387, 1984; Steinberg et al., Blood 65:100, 1985) and mitogen induction proliferation of peripheral blood lymphocytes (Chiao, et al., PNAS 83:3432, 1986). It has also been shown that expression of these suppressive factors diminishes in K562 cells upon induction of differentiation with hemin.
- p35 represents a target for development of new therapeutics or vaccines.
- Antibodies to p35 or antibodies to immunosuppressive peptides derived from p15E or p35 sequences will therefore have value in blocking the suppressive effects of these p15E-related proteins in human tumors and in retroviral induced diseases.
- synthetic peptide analogues will block the suppressive effects of the suppressive proteins.
- Such analogues compete for immunosuppressive peptide receptors, thereby blocking binding of the immunosuppressive protein, but are biologically inactive because they cannot by themselves initiate the sequence of events to immunosuppression.
- Applicants have further identified three peptides derived from HIV sequences that are capable of suppressing mitogen induced proliferation of T-cells in vitro.
- One peptide designated SUP2 with the amino acid sequence
- QREKRAVGIGALFLGFLG spans the junction of the HIV major envelope glycoprotein gp120 and the transmembrane glycoprotein gp41 (amino acids 514-531). This peptide shows a slight degree of homology with ISP.
- Another immunosuppressive peptide designated SUP1 having the amino acid sequence LQARILAVERYLKDQQL was derived from the gp41 region of HIV (amino acids 583-599) and has no significant homology to ISP. Both SUP1 and SUP2, when conjugated to KLH, suppress T-cell proliferation in response to mitogen stimulation. Unexpectedly, however, SUP2 is also immunosuppressive unconjugated.
- Another immunosuppressive peptide (designated 34.1 and having the amino acid sequence AVERYLKDQQLLGIWGCSGKLIC) is derived from gp41 and has no homology to ISP or SUP2 but overlaps the SUP1 sequence. 34.1 has also been shown to be immunosuppressive in vitro when conjugated to KLH or when used unconjugated. Applicants maintain that these peptides are useful as therapeutic immunosuppressants and vaccines to prevent infection with HIV. Antibodies .(monoclonal or polyclonal) to these HIV immunosuppressive peptides are also expected to have diagnostic and therapeutic potential in AIDS.
- Peptides were synthesized by conventional solid-phase methods and crosslinked (conjugated) to KLH in the following manner. Peptide (5mg/ml in water) and KLH (5 mg/ml in water) were mixed together. Glutaraldehyde was added to this mixture to a final concentration of 0.04% (v/v). The reaction mixture was stirred for 30 minutes at room temperature and then dialyzed overnight against phosphate buffered saline (PBS) at 4°C.
- PBS phosphate buffered saline
- New Zealand White rabbits were injected with 200 ⁇ g of conjugate in 0.50 ml PBS and 0.50 ml Complete Freund's Adjuvant. Two booster injections of 200 ⁇ g conjugate/PBS in Freund's Incomplete Adjuvant were administered at four week intervals. Weekly serum samples were monitored for antibody titers to immobilized synthetic peptide by ELISA. Serum antibody samples found to recognize synthetic peptide were then tested for recognition of intact antigen by immunoblot analysis pursuant to the method of Example 3 below. In this test, extracts of FLV-infected cells (the cell line FL74) were resolved by SDS slab gel electrophoresis and electrophoretically transferred to a nitrocellulose membrane.
- the membrane was sliced vertically into identical strips. These strips of resolved cellular proteins were probed with antisera to the p15E synthetic peptide and peroxidase-labelled anti-rabbit Ig diluted in Tris buffered saline containing 1% gelatin. Final visualization of antibody reactivity was obtained by incubating strips in an enzyme substrate solution of 4-chloro-1-naphthol. All serum samples that strongly recognized viral ⁇ 15E were pooled and again titered by ELISA against peptide and by immunoblot analysis against intact (pl5E) antigen. In all immunoblot studies, non-specific antibody staining was readily distinguished from specific antigen detection by probing identical blots with antiserum blocked with unlinked peptide.
- Ir ⁇ munocytochemical detection of antigen required affinity purification of antibody.
- Rabbit anti-peptide antibody was purified by passing antiserum through a CM-Affigel Blue (Bio-Rad) column to obtain an enriched Ig fraction. This Ig fraction was applied to a peptide affinity column prepared with epoxy-activated Sepharose 4B. The column was washed with phosphate buffer/0.5M KC1 and antibody eluted with 1M acetic acid into tubes containing 3M phosphate buffer, pH 8. Active fractions were pooled, dialyzed and concentrated by ultrafiltration. All steps of antibody enrichment were monitored by peptide ELISA. The immunocytochemistry procedure used gold labelled second antibody and silver enhancement as described in European patent publication 158,746.
- Cells were prepared for immunoblot analysis by first rinsing in PBS and then lyophilizing. The resulting cell powder was suspended (6.0 mg/ml) in SDS sample buffer and further denatured in rapidly boiling water. The cell lysate was clarified (30,000 rpm; Beckman 50Ti rotor) at room temperature. Extracts from 200 ⁇ g were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) using a 3% stacking/12% resolving gel. Proteins were electrophoretically transferred to nitrocellulose membranes in 192 mM glycine/20% methanol/10 mM Tris, pH 8.3 at 100 volts for 3 hours and 40 volts overnight.
- SDS-PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis
- EXAMPLE 4 Comparison of antiserum detection of antigen in extracts of various tumor cell lines by Western blot analysis.
- Rabbit anti-sera to a non-suppressive feline p15E peptide and ISP were immunoblot tested for detection of antigen in virus-infected cell extracts.
- Goat polyclonal antisera to intact murine ⁇ 30gag and g ⁇ 70env were included to confirm the presence of viral proteins in FL74 (FLV-infected lymphoma derived cell line) and NRK206-2/IC (murine leukemia/sarcoma virus [MLV/SV] infected) cells.
- Both antisera to pl5E synthetic peptides detected Pr85env, pl5E and pl2E (proteolytic processed pl5E) in FL74 cells, but not the MLV/SV or adult T cell leukemia viral (HTLV 1) homologs.
- the anti-ISP serum detected a 35,000 dalton protein (p35) in extracts of HTLV 1 infected cells (HUT102) but not the other two cell lines.
- Anti-ISP serum was used to immunoblot extracts of normal PBLs and various cell lines derived primarily from human acute leukemias (Table 1). Every leukemia cell line examined, but not normal PBLs, expressed the p35 protein. Antiserum reactivity with antigen was blocked in all cell lines by soluble unconjugated peptide. The highest level of 35K protein expression was detected in the Raji cell line.
- P210bcr-abl levels were determined by in vitro kinase assay. Detection of P210bcr-abl and 35K protein were estimated as none (-), weak (+), moderate (++) or strong (+++).
- Anti-ISP serum specifically recognized Pr85env, p15E and pl2E in FLV-infected cells, and a 35,000 dalton cellular antigen in all human leukemia cell lines examined.
- the specificity of the anti-ISP serum for inact protein was tested by blocking the antiserum with homologous, i.e., similar but not identical to, peptides synthesized from murine, human, and bovine leukemia viral env sequences (Table 3). Overlapping feline p15E peptides were also evaluated for their ability to inhibit antibody detection of intact antigen. Results of these experiments show that antibody bound to the SDS-denatured protein is directed primarily against the variable portion of the feline ISP.. TABLE 3
- EXAMPLE 6 Antibody blocking of immunosuppression attributed to viral p15E and p15E-like proteins.
- Persistent infection by feline leukemia virus is frequently associated with non-regenerative aplastic anemia and opportunistic infections resulting from suppressed cell-mediated immunity. These clinical features are attributed to the direct effects of the viral p15E.
- a biologically active synthetic peptide selected from the murine p15E amino acid sequence has been shown by others to exhibit in vitro effects similar to the intact viral protein. Applicants have confirmed that a synthetic peptide from the homologous region of feline viral pl5E has similar in vitro effects.
- the unique advantage of this approach is the generation of monoclonal antibodies against the biologically active site on native protein. After preliminary selection of clones for recognition of antigen, all antibodies may be screened for the ability to block virus-mediated inhibition of mitogen-treated spleen cells. A monoclonal antibody that blocks the suppressive activity of viral p15E by binding to the active site may be tested for the ability to ameliorote symptoms of virus induced disease. Similar testing of effects on pl5E-like proteins detected in various human cancers may also be tested as a passive immunotherapy reagent or as means of targeting other drugs to cancer cells.
- Synthetic or recombinant (DNA)-derived peptides with amino acid sequences derived from the conserved domain of viral ⁇ l5E (entire FLV domain shown in Table 5) or p15E-like proteins can serve as immunosuppressive agents. Such peptides are useful for suppressing the immune system after tissue or organ grafts. In addition, biologically active peptides may provide therapeutic benefits to patients with autoimmune diseases.
- the feline ISP:KLH conjugate was used to immunize four cats. Two injections of 200 ⁇ g conjugate in 0.5ml DPBS plus 1.0 mg 7-methyl-8-oxoguanosine (immune stimulator) in 0.5 ml Montinide/Draekol were administered 14 weeks apart. Similar injections of a neutralizing antibody inducing peptide, called I85B, from the gp70 region of the FLV envelope protein were given to two cats. At week 28 following the last injection, the six peptide vaccinated cats and six untreated cats were immunosuppressed with glucocorticoids and challenged with live Rickard strain of feline leukemia virus.
- I85B neutralizing antibody inducing peptide
- Peptide sequences derived from the HIV sequences have been synthesized using standard solid phase peptide technology and have been tested for the ability to suppress mitogen-induced proliferation of mouse T-cells (Table 8). Applicants contemplate that those peptides observed to have suppressive activity are useful as a vaccine against Acquired Immunodeficiency Syndrome.
- HIV peptides
- EXAMPLE 10 Assay for immunosuppression - Concanavalin A-induced T-cell proliferation of murine (C57BL/6 strain) spleen cells
- a spleen cell supspension was prepared from C57BL/6-strain mice using asceptic technique.
- the spleen cell suspension was applied onto a pre-washed and pre-warmed (37°C) nylon-wool column (ca. 10 cells/0.6 gr. nylon-wool). The cells were incubated for 45 minutes and eluted dropwise with warmed medium. An enriched T cell population was collected.
- Concanavalin A (Con A) mitogen was then added (1 microgram/well) to respective wells in the plate. Control wells included cells with and without Con A. Final volumes in each well were 200 microliters. the following exemplifies a typical protocol culture set up
- Spleen cells 50 ⁇ l/well (2 X 10 6 /ml)
- the H-thymidine-pulsed plates were then harvested using a PHD cell harvester.
- the harvester filter discs were placed in individual scintillation vials, scintillation fluid added, and the vials counted for presence of radioisotope.
- Proliferation was determined as counts per minute (CPM) or as a percent of control proliferation (i.e., CPM of experimental/CPM of Con A control X 100).
- the basic proliferation assay was performed in 96-well microtiter plates and involved stimulating murine spleen cells (1 ⁇ 10 5 cells/well) with a mitogen, e.g., Concanavalin A (Con A) for T cells and lipopolysaccaride (LPS) for B cell, which induces lymphoid cells to become activated and proliferate in culture.
- a mitogen e.g., Concanavalin A (Con A) for T cells and lipopolysaccaride (LPS) for B cell
- Con A Concanavalin A
- LPS lipopolysaccaride
- the lymphoid cell cultures were incubated for 3-7 days, depending on the experiment, and the cultures were pulsed for the last 12-24 hours with the radio-labeled nucleotide 3 H-thymidine, which is incorporated into the deoxyribonucleic acid (DNA) of the proliferating cells.
- the cells from individual culture wells were harvested onto glass-fiber discs using a multichannel cell harvester and the individual discs, placed in fluor-containing scinti l lation fluid, and analyzed in a scintillation spectrophotometer for the presence of radioactivity.
- the level of cell activation, i.e., proliferation was measured as the amount of DNA-mcorporated 3 H-thymidme detected in mitogen-stimulated cultures relative to that of non-stimulated control cultures, i.e., cultures with cells alone.
- the data was recorded as the stimulation index
- CPM control culture CPM
- control proliferation i.e., experimental CPM/positive control cultures (cells + mitogen) X 100.
- ⁇ I6B:ISP Mediated Supression Balb/c spleen cells were stimulated with Con A (4 micrograms/ml) in the presence of titrated amounts of ⁇ I6B:ISP and the level of 3 H-thymidine incorporation was determined on day 4. ⁇ I6B:ISP induced significant suppression of T cell proliferation (60%) at a concentration of 12.5 ⁇ g/ml (Fig.
- peptides were synthesized which are extensions of the ISP peptide in the context of the native viral sequence as well as an analog form. These peptides were examined in order to determine whether a longer peptide would be suppressive without requiring conjugation to a carrier or if suppressive activity could be improved.
- extension peptide sequences were LQNRRGLDILFLQEGGLCAALKECCFYADH and LQNRRGLDILFLQEGGLCAALKECCFLKEE.
- BALB/c mouse spleen cells were cultured for 4 days in the presence of mitogen (Con A) and varying concentrations of the two extension peptides. Neither peptide exhibited any suppressive activity in the murine T cell proliferation assays.
- PWM pokeweed mitogen
- ⁇ I6B:ISP Recognition of ⁇ I6B:ISP by Anti-Peptide Sera: Applicants examined the ability of anti-I6B serum (R112-5) and affinity-purified rabbit antiserum (AP558-28) against the ISP peptide, as well a monoclonal antibody (9-14F2-3) which reacts with ISP, to bind ⁇ I6B:ISP in order to determine whether the respective antibody-binding sites remained intact after combining the ⁇ I6B and ISP sequences. A control affinity-purified rabbit antibody (AP67) against the c-abl oncogene was also used. The results obtained indicate that both the anti-I6B and anti-ISP antibodies react with ⁇ I6B:ISP (Fig. 5).
- Protein sequence alignment methods Identification of proteins with sequences related to the selected polypeptides was accomplished using the SCANSIM program (verison 3.02) of PC Gene (release 4.05 from
- Polypeptide sequences Polypeptides were selected from the predicted protein sequence of the FLV envelope gene precursor (Elder et al., J. Virology 46: 871-880, 1983) and were synthesized by conventional solid phase methods.
- Synthetic polypeptides were chemically coupled to keyhole limpet hemocyanin (KLH) at 1:1 (w/w) ratios by mixing 30 min. at room temp. in 0.04% glutaraldehyde. New Zealand White rabbits were injected with 200 ⁇ g of dialyzed conjugate in Complete Freund's Adjuvant followed by two or more booster injections of 200 ⁇ g conjugate in Incomplete Freund's Adjuvant.
- KLH keyhole limpet hemocyanin
- Protein labeling by metabolic incorporation of [ 35 S] amino acids For each immunoprecipitation, 2 x 10 cells were metabolically labeled with 0.5 mCi [ 35 S]methionine (or a [ 35S]met/[ 35 S]cys mixture) in 2.0 ml methionine-deficient RPMI 1640 supplemented with L-lysine,
- Antigen was precipitated by addition of 0.020 ml antiserum for 18 hrs. on ice. Immune complexes were absorbed by incubation with 0.100 ml Sepharose: Protein A (Pharmacia) for 60 min. on ice. The Sepharose-immobilized immune complex was washed with cell lysis buffer, denatured by addition of 0.050 ml SDS sample buffer (2% SDS, 10% glycerol, 0.125 M Tris-HCl, pH 6.8), and immersed for 3 minutes in rapidly boiling water. The beads were pelleted by centrifugation, the supernatant fluid was diluted 20 times in cell lysis buffer, and the immunoprecipitation steps were repeated.
- SDS sample buffer 2% SDS, 10% glycerol, 0.125 M Tris-HCl, pH 6.8
- the resulting immune complex was dissociated with 2% SDS sample buffer containing 10% 2-mercaptoethanol. Samples were resolved by SDS-polyacrylamide gel electrophoresis using 3% stacking gels and either single concentration (12%) or gradient (10-20%) resolving gels (Laemmli, Nature 227: 680-685,
- Immunocytochemical detection of antigen Rabbit antibody to synthetic peptide was purified in two steps. An immunoglobulin fraction was collected from serum by 25% to 50% (w/v) ammonium sulfate precipitation. After di alysis against phosphate buffered saline, the sample was applied to a peptide affinity column prepared with epoxy-activated Sepharose 4B (Pharmacia). The column was washed with phosphate buffer/0.5M KCl and antibody was eluted using 1 M acetic acid into tubes containing 3 M phosphate buffer, pH 8. Active fractions were pooled, dialyzed and concentrated by ultrafiltration. The immunocytochemistry procedure used gold-labeled second antibody and subsequent silver enhancement described in Eureopean patent publication 158,746.
- the ISP domain of FLV p15E is highly conserved among RNA tumor viruses.
- a SCANSIM program search of the entire Swiss Protein database (release 2) identified nine viral envelope sequences with peptide domains very similar to FLV-ISP.
- the common sequence "QNRRGLDXL" at the carboxyl terminus of all nine env peptides was used to search the entire Protein database for related sequences.
- Table 9 below summarizes results of a search for QNRRGLDXL-containing sequences in a subset of the Swiss Protein database selected with the keywords " interferon",
- ISP-related antigens are released into the growth medium of divese human leukemia cell lines
- the conditioned growth medium was clarified by low and high speed centrifugation. Antigen was then immunoprecipitated from the resulting supernatant fractions. The purified antigens were separated on 10-20% gradient SDS-gels and detected by fluorography. A soluble 110K antigen was detected in the conditioned growth medium of all leukemia cell lines tested including the FLV + FL74 cells. Overlapping FLV ISP peptides block FLV ISP antiserum recognition of the 110,000 dalton antigen from Raji cells. The effects of overlapping FLV ISP peptides were compared for their ability to block FLV ISP antiserum detection of [ 35 S]met-labeled FLV gPr85 env / ⁇ 15E and Raji cell antigens. The results summarized in Table 10 show that overlapping FLV peptides display very similar abilities to block detection of feline viral and human leukemia cell derived antigens.
- Histopaque enriched peripheral blood leukocytes from a normal, healthy donor were stimulated with 10 ⁇ g/ml phytohemagglutinin. After four days in culture, unstimulated and stimulated cells were labeled for 4 hours with [ 35 S]met and lysed for immunoprecipitation. The results indicate that very low levels of [ 35 S]met-labeled antigen were detected in unstimulated cells and high levels of antigen were detected in the mitogen stimulated cells.
- the 110K antigen is detected in the human epidermoid carcinoma-derived cell line A431 but not in murine 3T3 fibroblasts Immunocytochemistry results indicate that the 110K antigen can be weakly detected in the human cell line A431 cells but not in Swiss Albino 3T3 cells. An initial immunoprecipitation experiment was conducted with 4 hour [ 35 S]met-labeled cell extracts to determine if the 110K antigen is detected in either cell line. The 110K protein was clearly detected in A431 cells but not in 3T3 cells.
- the peptides of the present invention may be modified by substitution of conservative or non-conservative amino acids in the peptides.
- the subject peptides may be subject to various other changes, such as insertions or deletions of amino acids where such changes may provide for or have no substantial affect upon, the desired immunosuppressive activity in vitro or in vivo.
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Abstract
Des séquences nouvelles de peptides sont utiles pour vacciner les chats contre le virus de la leucémie féline et les êtres humains contre des rétrovirus, pour détecter la présence d'une protéine ayant un poids moléculaire apparent d'environ 35.000 daltons et une protéine ayant un poids moléculaire apparent d'environ 110.000 daltons, les deux étant exprimées par des cellules cancéreuses et leucémiques de mammifères. L'invention concerne également des applications thérapeutiques associées à ces séquences.
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EP19880902271 Withdrawn EP0300031A4 (fr) | 1987-01-28 | 1988-01-25 | Peptides immunodepresseurs et leurs procedes d'utilisation. |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0300031A4 (fr) |
JP (1) | JPH01501939A (fr) |
KR (1) | KR890700602A (fr) |
AU (1) | AU1366088A (fr) |
DK (1) | DK535988A (fr) |
WO (1) | WO1988005783A1 (fr) |
Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5128319A (en) * | 1987-08-28 | 1992-07-07 | Board Of Regents, The University Of Texas System | Prophylaxis and therapy of acquired immunodeficiency syndrome |
SE8705197D0 (sv) * | 1987-12-30 | 1987-12-30 | Jonas Blomberg | New peptides, two diagnostic methods using the peptides and a medicament based on the peptides |
ATE128730T1 (de) * | 1988-12-13 | 1995-10-15 | Univ Harvard | Prototypische felv-isolate für die verwendung als krankheitsmuster oder impfstoffe. |
US5268455A (en) * | 1989-05-25 | 1993-12-07 | Genentech, Inc. | Process for making biologically active polypeptides based on transforming growth factor-βsequences |
US5061786A (en) * | 1989-05-25 | 1991-10-29 | Genentech, Inc. | Biologically active polypeptides based on transforming growth factor-β |
JP2807287B2 (ja) * | 1989-10-13 | 1998-10-08 | 株式会社医学生物学研究所 | ペプチドおよびその用途 |
US5567805A (en) * | 1990-03-09 | 1996-10-22 | Administrators Of The Tulane Educational Fund | The cellular receptor for the CS3 peptide of human immunodeficiency virus |
FR2677654B1 (fr) * | 1991-06-17 | 1995-11-17 | Pasteur Merieux Serums Vacc | Composes a effet immunogene anti-cytokine, a effet immunogene anticytostatique ou a effet vaccinal anti-infection a hiv. |
DE69328726D1 (de) * | 1992-02-10 | 2000-06-29 | Univ Durham | Verwendung synthetischer peptide zur induktion der toleranz gegen t- und b-zell epitope von autoantigenen |
SE9202318L (sv) * | 1992-08-10 | 1994-02-11 | Replico Medical Ab | Nya peptider, diagnostiska antigen, användning därav, vacciner och medikamenter |
DE59505786D1 (de) | 1994-02-07 | 1999-06-02 | Qiagen Gmbh | Verfahren zur abreicherung oder entfernung von endotoxinen |
DE4405810A1 (de) | 1994-02-23 | 1995-08-24 | Behringwerke Ag | Von einem Retrovirus aus der HIV-Gruppe abgeleitete Peptide und deren Verwendung |
SE9403526D0 (sv) | 1994-10-14 | 1994-10-14 | Astra Ab | New Peptides |
DZ1964A1 (fr) * | 1995-01-13 | 2002-10-15 | Nika Health Products Ltd | Nouvelle applications d'un dimère de lysozyme. |
SE9501067D0 (sv) | 1995-03-24 | 1995-03-24 | Astra Ab | New peptides |
US5994292A (en) * | 1995-05-31 | 1999-11-30 | The United States Of America As Represented By The Department Of Health And Human Services | Interferon-inducible protein 10 is a potent inhibitor of angiogenesis |
AU2417597A (en) * | 1996-04-12 | 1997-11-07 | Astra Aktiebolag | Cysteine-containing or methioine-containing peptides with immunomodulatory ef fects |
AU6887096A (en) * | 1996-09-11 | 1998-04-02 | Patrick T. Prendergast | Immune direction therapy |
SE9603462D0 (sv) * | 1996-09-23 | 1996-09-23 | Astra Ab | New compounds |
SE9603468D0 (sv) * | 1996-09-23 | 1996-09-23 | Astra Ab | New compounds |
SE9603461D0 (sv) * | 1996-09-23 | 1996-09-23 | Astra Ab | New compounds |
IT1307826B1 (it) | 1999-12-16 | 2001-11-19 | Dipartimento Di Medicina Speri | Metodo diagnostico per il riconoscimento di cellule mieloidi normali eleucemiche, ligandi utilizzati in detto metodo e formulazioni ad uso |
US9777044B2 (en) | 2003-05-02 | 2017-10-03 | Centre National De La Recherche Scientifique (Cnrs) | GLUT-1 as a receptor for HTLV envelopes and its uses |
DK1648926T3 (da) | 2003-05-02 | 2013-10-14 | Centre Nat Rech Scient | Glut-1 som en receptor til htlv-kapper og anvendelser heraf |
CA2571710A1 (fr) | 2004-06-24 | 2006-11-02 | Nicholas Valiante | Immuno-potentialisateurs a petites molecules et analyses visant a detecter leur presence |
CA2749183C (fr) | 2009-01-09 | 2017-11-28 | Marc Sitbon | Nouveaux ligands de liaison de recepteur, et leur utilisation dans la detection de cellules ayant un interet biologique |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1985004871A1 (fr) * | 1984-04-24 | 1985-11-07 | Scripps Clinic And Research Foundation | Analyse, vaccin et immunogene du virus associe a la leucemie |
JPS6130600A (ja) * | 1984-06-20 | 1986-02-12 | オ−ソ・ダイアグノステイツク・システムズ・インコ−ポレ−テツド | ペプチド |
WO1986006414A1 (fr) * | 1985-04-29 | 1986-11-06 | Genetic Systems Corporation | Antigenes synthetiques permettant la detection d'une infection apparentee au sida |
US4629783A (en) * | 1985-04-29 | 1986-12-16 | Genetic Systems Corporation | Synthetic antigen for the detection of AIDS-related disease |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1262014A (fr) * | 1983-01-07 | 1989-09-26 | Mitsuaki Yoshida | Peptides relies au virus de la leucemie humaine, anticorps de ces peptides et procede de production de ceux-ci |
GB8301928D0 (en) * | 1983-01-24 | 1983-02-23 | Nicholson B H | Process for producing polypeptides |
-
1988
- 1988-01-25 AU AU13660/88A patent/AU1366088A/en not_active Abandoned
- 1988-01-25 EP EP19880902271 patent/EP0300031A4/fr not_active Withdrawn
- 1988-01-25 JP JP63502107A patent/JPH01501939A/ja active Pending
- 1988-01-25 WO PCT/US1988/000176 patent/WO1988005783A1/fr not_active Application Discontinuation
- 1988-09-27 DK DK535988A patent/DK535988A/da not_active Application Discontinuation
- 1988-09-27 KR KR1019880701169A patent/KR890700602A/ko not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1985004871A1 (fr) * | 1984-04-24 | 1985-11-07 | Scripps Clinic And Research Foundation | Analyse, vaccin et immunogene du virus associe a la leucemie |
JPS6130600A (ja) * | 1984-06-20 | 1986-02-12 | オ−ソ・ダイアグノステイツク・システムズ・インコ−ポレ−テツド | ペプチド |
WO1986006414A1 (fr) * | 1985-04-29 | 1986-11-06 | Genetic Systems Corporation | Antigenes synthetiques permettant la detection d'une infection apparentee au sida |
US4629783A (en) * | 1985-04-29 | 1986-12-16 | Genetic Systems Corporation | Synthetic antigen for the detection of AIDS-related disease |
Non-Patent Citations (12)
Title |
---|
CHEMICAL ABSTRACTS, Vol. 105, No. 19, November 10, 1986, page 802, Abstract 173060j, Columbus, Ohio, US; & JP-A-61 030 600 (ORTHO DIAGNOSTIC SYSTEMS, INC.), Abstract. * |
CHEMICAL ABSTRACTS, Vol. 105, No. 7, August 18, 1986, page 503, Abstract 59310r, Columbus, Ohio, US; R.A. HARRELL et al.: "Suppression of the respiratory burst of human monocytes by a synthetic peptide homologous to envelope proteins of human and animal retroviruses", & J. Immunol. 1986, 136(10), 3517-20, Abstract. * |
CHEMICAL ABSTRACTS, Vol. 106, No. 15, April 13, 1987, page 488, Abstract 117946m, Columbus, Ohio, US; M. MITANI et al.: "Suppressive effect on polyclonal B-cell activation of a synthetic peptide homologous to a transmembrane component of oncogenic retroviruses", & Proc. Natl. Acad. Sci. USA, 1987, 84(1), 237-40, Abstract. * |
Journal of Experimental Medicine, Vol. 159, March 1984, pages 964-969, CIANCI OLO et al.: "Human malignant and mitogen-transformed cells contain retroviral P15E-related antigen", whole document. * |
Journal of Immunology, Vol. 137, No. 9, November 1, 1986, pages 2945-2951; Baltimore, MD, US; T.D. COPELAND et al.: "Envelope proteins of human T cell leukemia virus type I: Characterization by antisera to synthetic peptides and identification of a natural epitope", whole article. esp. the peptide SP-74 on table 1. * |
Journal of Virology, Vol. 61, No. 1, January 1987, pages 8-15, Am. Soc. for Microbiology, US; J.H. ELDER et al.: "Localization of neutralizing regions of the envelope gene of feline leukemia virus by using anti-synthetic peptide antibodies", complete document, esp. table 1, page 11. * |
Nature, Vol. 311, 11 October 1984, page 515, G.J. CIANCIOLO et al.: "Similarity between p15E of murine and feline leukaemia viruses and p21 of HTLV", whole document. * |
Nature, Vol. 312, December 1984, page 496, London, GB; PATARCA et al.: "Similarities among retrovirus proteins", whole document, esp. figure 2. * |
Proc. Natl. Acad. Sci. USA, Vol. 83, August 1986, pages 6159-6163, J.J.G. WANG et al.: "Detection of antibodies to human T-lymphotoropic virus type III by using a synthetic peptide of 21 amino acid residues corresponding to a highly antigenic segment of gp41 envelope protein", whole document, esp. table 1, page 6161. * |
Proc. Natl. Acad. Sci., USA, Vol. 82, February 1985, pages 677-681, N. SAGATA et al.: "Complete nucleotide sequence of the genome of bovine leukemia virus, Its evolutionary relationship to other retroviruses", whole document. esp. figure 3. * |
Science, Vol. 230, October 25, 1985, pages 453-455; Am. Ass. for the Adv. of Science, Washington, DC, US; G.J. CIANCIOLO et al.: "Inhibition of lymphocyte proliferation by a synthetic peptide homologous to retroviral envelope proteins", whole document. * |
See also references of WO8805783A1 * |
Also Published As
Publication number | Publication date |
---|---|
JPH01501939A (ja) | 1989-07-06 |
EP0300031A4 (fr) | 1990-05-14 |
DK535988D0 (da) | 1988-09-27 |
AU1366088A (en) | 1988-08-24 |
KR890700602A (ko) | 1989-04-26 |
DK535988A (da) | 1988-11-25 |
WO1988005783A1 (fr) | 1988-08-11 |
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