Classifications

• • 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
  • A61K39/12—Viral antigens
  • A61K39/155—Paramyxoviridae, e.g. parainfluenza virus
• • 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
  • A61K39/12—Viral antigens
• • 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
  • A61P31/14—Antivirals for RNA viruses
• • 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
  • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
  • A61K2039/6031—Proteins
  • A61K2039/6068—Other bacterial proteins, e.g. OMP
• • 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
  • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
  • C12N2760/00011—Details
  • C12N2760/18011—Paramyxoviridae
  • C12N2760/18511—Pneumovirus, e.g. human respiratory syncytial virus
  • C12N2760/18534—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

• the present invention relates to the respiratory syncytial virus, and more particularly to the identification of new antigens, useful in particular for the therapeutic and prophylactic treatment of conditions caused by this virus.
• the respiratory syncytial virus is classified in the family of Paramyxoviridae, genus pneumovirus comprising a non-segmented AR ⁇ genome, of negative polarity, coding for 11 specific proteins.
• RSVs there may be mentioned in particular human RSV type A and type B and bovine RSV, the genomic sequences of which are known.
• RSV is one of the most common causative agents in infants and the elderly. Bronchiolitis is often severe in children and requires hospitalization. Currently there are no means of prevention against the disease due to RSV. The first RSV infection does not prevent the next. Treatment of severe cases with antibiotic therapy (Ribavirin) and / or combined with immunotherapy (human immunoglobulins) cannot reduce the worsening of the disease. In addition, this type of treatment is still very expensive. Clinical trials with ORAVAX H ⁇ K20 monoclonal antibodies (directed against RSV F protein) have not shown efficacy of treatment compared to placebo against RSV infection in children.
• FI-RSV formalin-inactivated RSV vaccine
• RSV structural proteins for a vaccine, such as the envelope proteins called F protein (fusion protein) or protein G (attachment protein), a 22 Kd glycoprotein, a 9.5 Kd protein, or the major capsid protein (protein N);
• the subject of the present invention is an immunogenic peptide derived from the non-glycosylated RSV protein G and comprising at least the peptide sequence 148-193 of the human RSV protein G of subgroup A or B, or bovine RSV, or a sequence having at least 80% homology with said peptide sequences 148-193 of these G proteins, preferably with the exception of peptides derived from GRS protein of RSV having for sequence a sequence chosen from the sequences: a) SEQ ID Nos. 1 to 3; b) SEQ ID Nos.
• immunogenic peptides those derived from the non-glycosylated RSV protein G containing at least the peptide sequence 148-193 of the human RSV protein G from subgroup A or B, or from bovine RSV, are preferred. or a sequence having at least 80% homology with said peptide sequences 148-193 of these G proteins, and of which the fragment 185-193 of said G proteins is 100% identical to the fragment 185-193 of said G proteins.
• immunogenic peptide is intended to denote any peptide which, when it is preferably associated with a carrier or an adjuvant, is capable of generating or increasing an immune response directed against RSV.
• peptide will also be understood to denote the polypeptides.
• the notation "148-193" for the peptide sequence 148-193 should be understood as meaning that said amino acid sequence is the sequence between the amino acids in positions 148 and 193, ends included, of the protein G, protein G being an envelope protein of the
• amino acid located in first position thus corresponds respectively to the amino acid located in position 130 of the RSV protein A sequence of type A, type B and bovine type.
• the peptides according to the invention in particular the peptide of sequence 148-193, can in particular be obtained by conventional peptide chemical synthesis, without glycosylation stages, known to those skilled in the art or by recombinant route without glycosylation.
• amino acid sequence having a homology of at least 80% after optimal alignment with a determined nucleic acid or amino acid sequence is meant a sequence which after optimal alignment with said determined sequence comprises a percentage of identity of at least 80% with said determined sequence.
• percentage of identity between two amino acid sequences within the meaning of the present invention is meant a percentage of identical amino acid residues between the two sequences to be compared, obtained after the best alignment, this percentage being purely statistics and the differences between the two sequences being distributed randomly and over their entire length.
• Sequence comparisons between two amino acid sequences are traditionally carried out by comparing these sequences after having optimally aligned them, said comparison being carried out by segment or by “comparison window” to identify and compare the local regions of sequence similarity. .
• the optimal alignment of the sequences for comparison can be achieved, besides manually, by means of the local homology algorithm of Smith and Waterman (1981) [Ad. App. Math.
• the percentage of identity between two amino acid sequences is determined by comparing these two optimally aligned sequences per comparison window in which the region of the nucleic acid or amino acid sequence to be compared can comprise additions or deletions from the reference sequence for optimal alignment between these two sequences.
• the percentage of identity is calculated by determining the number of identical positions for which the amino acid residue is identical between the two sequences, by dividing this number of identical positions by the total number of positions in the comparison window and by multiplying the result obtained by 100 to obtain the percentage of identity between these two sequences.
• BLAST 2 sequences available on the site http://www.ncbi.nlm.nih.gov/gorf7bl2.html, the parameters used being those given by default (in particular for the parameters “open gap penaltie”: 5, and “extension gap penaltie”: 2; the chosen matrix being for example the “BLOSUM 62” matrix proposed by the program), the percentage of identity between the two sequences to be compared being calculated directly through the program.
• sequences having a homology of at least 80% preference is given to sequences of peptides capable of inducing an immune response directed against RSV, such as the induction of an immune response measured by means of the standard techniques described in examples below, and presenting the least possible risk of associated immunopathologies, this risk being able to be evaluated in particular by the methods described in example V below.
• said immunogenic peptide derived from the non-glycosylated RSV G protein according to the invention is a fragment of the peptide sequence 130-230 of the human RSV protein G of the subgroup A or B, or bovine RSV, or a fragment of a sequence having at least 80% homology with said peptide sequences 130-230 of these G proteins.
• said peptide sequence 148-193 of protein G of human RSV of the subgroup A or B, or of bovine RSV comprises in position 173, 176, 182 and 186 a cysteine.
• the peptide according to the invention has at least a first disulfide bridge connecting residues 173 and 186 and a second disulfide bridge connecting residues 176 and 182.
• the peptides having a sequence chosen from the sequence 148-193, 148-200, 148-230, 140-193, 140-230, 130 are preferred. -193 and 130-200 of protein G of human RSV of subgroup A or B, or bovine RSV.
• Said immunogenic peptides derived from the RSV G protein according to the invention may also be chosen from the peptides of sequence: a) SEQ ID Nos. 1 to 3; b) SEQ ID Nos. 1 to 3 comprising each of them the mutations C173S and C186S; c) sequences 140-200, 140-198, 140-198, 140-196 and 140-194 of the sequences as described in a) or b); and d) SEQ ID No.
• compositions according to the invention can also contain at least one carrier protein and / or an adjuvant.
• the carrier protein can advantageously be chosen from the TT protein (toxoid tetanus), the DT protein (diphtheria toxoid), the protein for binding to human serum albumin from Streptococcus and its fragments, the B subunit of cholera toxin (CTB) and extracts of bacterial membrane proteins such as OMPCs from Neisseria meningitidis (Vella et al., Infect. Immun., 60: 4977-4983, 1992), TraT of Escherichia coli (Croft et al, J. Immunol., 146 : 793-798, 1991) or PorB of Neisseria meningitidis (Fusco et al., J. Infect. Dis., 175: 364-372, 1997).
• TT protein toxoid tetanus
• DT protein diphtheria toxoid
• CTB cholera toxin
• One of the preferred carrier proteins consists of an OmpA of a bacterium of the genus Klebsiella, a major protein of the outer membrane called P40, which exhibits carrier protein activity, by the systemic route, for subunit antigens.
• peptides WO 95/27787 and WO 96/14415; Haeuw et al, Eur. J. Biochem., 255: 446-
• compositions according to the invention containing at least one carrier protein said carrier protein will preferably be non-glycosylated.
• the adjuvant can in particular be chosen from MPL-A, Quil-A, ISCOM,
• DDAC deoxyribonucleic acid
• alum aluminum hydroxide
• adjuphos CpG, Leif, CT, (cholera toxoid), LT (Heat labile enterotoxin) and detoxified versions of CT or
• the peptide according to the invention can be associated, by mixing or by coupling, with the carrier protein and / or with the adjuvant.
• the coupling is preferably a covalent coupling, which can be carried out chemically or by recombinant DNA techniques.
• one or more linking elements are introduced into the peptide according to the invention and / or into said carrier or adjuvant to facilitate chemical coupling, preferably, said introduced linking element is an amino acid.
• linking elements in particular amino acids to facilitate the coupling reactions between the peptide according to the invention and the carrier or adjuvant.
• the covalent coupling between the peptide according to the invention and said carrier or adjuvant can be carried out at the N- or C-terminal end of said peptide.
• the bifunctional reagents allowing this coupling will be determined according to the end of said peptide chosen to perform the coupling and the nature of said carrier or adjuvant to be coupled.
• the coupling between the peptide according to the invention and said carrier or adjuvant is carried out by genetic recombination, when said carrier or adjuvant is of peptide nature.
• the conjugates resulting from a coupling between the peptide according to the invention and said carrier or adjuvant can be prepared by genetic recombination.
• the chimeric or hybrid protein (the conjugate) can be produced by recombinant DNA techniques by insertion or addition to the DNA sequence coding for said peptide according to the invention, of a sequence coding for said carrier or adjuvant of protein nature.
• the methods for synthesizing hybrid molecules include the methods used in genetic engineering to construct hybrid polynucleotides encoding the desired polypeptide sequences.
• the peptide according to the invention is conjugated to the carrier protein or to the adjuvant by a binding protein; this binding protein can in particular be chosen from a receptor for serum mammalian albumin and the receptors present on the surface of mucosal cells.
• a subject of the invention is also the composition according to the invention, characterized in that said pharmaceutical composition also comprises at least one second antigen, immunogen or hapten of NRS and / or an antigen, immunogen or haptene derived from responsible microorganism pathologies of the airways chosen from parainfluenza viruses (PIN 1, 2, 3 and 4), influenza virus (A and B), hantaviruses, streptococci, pneumococci, haemophilus influenza type b, rhinoviruses, coronoviruses and meningococci.
• parainfluenza viruses PIN 1, 2, 3 and 4
• influenza virus A and B
• hantaviruses hantaviruses
• streptococci pneumococci
• haemophilus influenza type b haemophilus influenza type b
• rhinoviruses coronoviruses and meningococci.
• immunogen, antigen or hapten is intended to denote in particular any compound expressed by an infectious agent, or one of their structural analogues, which alone or in combination with an adjuvant or carrier is capable of inducing a specific immune response of said agent infectious.
• immunogen, antigen or hapten is also intended to denote in the present description a compound having a structural analogy with said antigen or hapten capable of inducing an immunological response directed against said antigen or hapten in an organism previously immunized with said analogous compound.
• said second NRS antigen comprises at least one fragment of the protein G of the respiratory syncytial virus, said fragment comprising a T epitope or being solely composed of said T epitope.
• said second NRS antigen comprises at least one fragment of the protein F of the respiratory syncytial virus, said fragment comprising a T epitope or being solely composed of said T epitope.
• compositions according to the invention containing at least a second antigen or immunogen derived from NRS and / or an antigen derived from a microorganism responsible for pathologies of the airways, said antigen will preferably be non-glycosylated.
• the pharmaceutically acceptable medium is the medium in which the compounds of the invention are administered, preferably a medium injectable into humans. It can consist of water, an aqueous saline solution or an aqueous solution based on dextrose and / or glycerol.
• the invention also comprises a composition according to the invention, characterized in that said pharmaceutical composition is conveyed in a form making it possible to improve its stability and / or its immunogenicity; thus, it can be conveyed in the form of liposomes, virosomes, nanospheres, microspheres or microcapsules.
• the invention also relates to antibodies, monoclonal or polyclonal, directed against the peptides according to the invention.
• the monoclonal antibodies are preferably humanized and produced by the recombinant route. According to another aspect of the invention, they are obtained by the phage library method.
• the monoclonal, polyclonal antibody or one of their fragments is characterized in that it is capable of binding specifically to an epitope or determining non-glycosylated peptides according to the invention.
• the monoclonal antibodies can advantageously be prepared from hybridomas according to the technique described by Kohler and Milstein in 1975 (Nature, 256: 495-497, 1975).
• the polyclonal antibodies can be prepared, for example by immunization of an animal, in particular a mouse or a rabbit, with the peptide according to the invention associated with an adjuvant of the immune response, then purification of the specific antibodies contained in the serum of the animals immumsed on an affinity column to which has been previously fixed, said peptide having served as an antigen.
• the antibodies of the invention also include any fragment of said monoclonal antibody capable of binding to an epitope of the peptide according to the invention on which the monoclonal or polyclonal antibody from which said fragment is derived binds.
• fragments include in particular single chain monoclonal antibodies or monovalent fragments Fab or Fab 'and divalent fragments such as F (ab') 2, which have the same binding specificity as the monoclonal or polyclonal antibody of which they are from.
• a fragment according to the invention may also be a single chain Fv fragment produced by methods known to those skilled in the art and as described for example by Skerra et al. (Science, 240: 1038-1041, 1988) and King et al. (Biochemical J., 290: 723-729, 1991).
• fragments of monoclonal or polyclonal antibodies of the invention can be obtained from the monoclonal or polyclonal antibodies as described above by methods such as digestion with enzymes, such as pepsin or papain and / or by cleavage of the disulfide bridges by chemical reduction.
• the monoclonal or polyclonal antibody fragments included in the present invention can be synthesized by automatic peptide synthesizers such as those provided by the company Applied Biosystems, etc., or can be prepared manually using techniques known to those skilled in the art and as described for example by Geysen et al. (J. Immunol. Methods, 102: 259-274, 1978).
• humanized monoclonal antibodies according to the invention or their fragments can be prepared by techniques known to those skilled in the art (Carter et al., PNAS, 89: 4285-4289, 1992; Mountain, et al., Biotechnol. Genet Eng. Rev. 10: 1-142, 1992). Such humanized monoclonal antibodies according to the invention are preferred for their use in therapeutic methods.
• the antibodies of the invention, or their fragments can also be labeled with an enzymatic, fluorescent or radioactive type of labeling.
• the monoclonal antibodies labeled according to the invention or their fragments include, for example, antibodies called immunoconjugates which can be conjugated for example with enzymes such as peroxidase, alkaline phosphatase, ⁇ -D-galactosidase, glucose oxidase, glucose amylase , carbonic anhydrase, acetylcholinesterase, lysozyme, malate dehydrogenase or glucose-6 phosphate dehydrogenase or by a molecule such as biotin, digoxigenin or 5-bromo-deoxyuridine.
• Fluorescent markers can also be conjugated to the monoclonal antibodies or their fragments of the invention and include in particular fluorescein and its derivatives, rhodamine and its derivatives, GFP (GFP for "Green
• the monoclonal antibodies of the invention or their fragments can be prepared by methods known to those skilled in the art. They can be coupled to enzymes or fluorescent markers directly or through a spacer group or a linking group such as a polyaldehyde, such as glutaraldehyde, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid
• conjugates comprising markers of the fluorescein type can be prepared by reaction with an isothiocyanate.
• conjugates can also include chemiluminescent markers such as luminol and dioxetanes or bioluminescent markers such as luciferase and luciferin.
• radioactive markers such as
• the peptides and / or the antibodies according to the invention can, according to a mode of implementation of the invention, enter into the composition of a diagnostic kit.
• the peptides and antibodies according to the invention can be used as a medicament, and more particularly for the preparation of a composition intended for the preventive or curative treatment of conditions caused by human NRS, subgroup A or B, or by bovine NRS, preferably by human NRS, in particular by subgroup A.
• the invention also relates to the use of an immunogenic peptide derived from the non-glycosylated NRS protein G and comprising at least the peptide sequence 185-193 of human NRS protein G, subgroup A or B, or bovine, preferably human NRS from subgroup A or B, in particular from subgroup A of sequence SEQ ID ⁇ o. 4, or comprising a sequence having at least 80% homology with said peptide sequences 185-193 of these G proteins, or of an antibody according to the invention:
• a pharmaceutical composition preferably a vaccine, intended for the prophylactic or therapeutic treatment of conditions caused by human NRS, subgroup A or B, or bovine and not inducing immunopathologies; or - for the preparation of a pharmaceutical composition intended to generate or increase an immune response against NRS and not inducing immunopathologies.
• the immunogenic peptides according to the present invention are preferred, in particular: a) those derived from the non-glycosylated NRS protein G comprising at least the peptide sequence 148- 193 of protein G of human NRS of subgroup A or B, or of bovine NRS, or a sequence having at least 80% homology with said peptide sequences 148-193 of these G proteins, and of which the fragment 185- 193 is 100% identical to fragment 185-193 of said G proteins; or b) those as above defined in a) and the sequence of which is included in the sequence 130-230 of these G proteins, in particular the non-glycosylated immunogenic peptides of sequence SEQ ID ⁇ o. 1, ⁇ o. 2 and ⁇ o. 3 noted respectively G2A (or G2 ⁇ a), G2B and G2V, the peptide G2A being particularly preferred.
• Figure 1 Migration on SDS page gel of the BBG2Na protein expressed in E. coli and in H ⁇ p-2 cells before and after treatment with deglycosylation enzymes.
• Figure 2 Antigenicity of non-glycosylated and glycosylated BBG2Na against a panel of monoclonal antibodies specific for the NRS protein G fragment and for the BB part of BBG2 ⁇ a.
• the monoclonal antibodies 5B7, 5C2, 8A3, 11F7 and 18D1 are specific for the fragment of the NRS G protein in BBG2 ⁇ a.
• the 13F 10 monoclonal antibody is specific for the BB part of BBG2Na.
• FIG. 3 Immunogenicity of glycosylated and non-glycosylated BBG2Na in mice.
• BBG2Na non-glycosylated BBG2Na
• gBBG2Na glycosylated BBG2Na
• Cell Ag cell control antigen
• FI-RSV VRS inactivated by formalin
• PBS buffered saline phosphate.
• Figure 4 Protective efficacy of glycosylated and non-glycosylated BBG2Na in BALB / c mice.
• BBG2Na non-glycosylated BBG2Na
• gBBG2Na glycosylated BBG2Na
• Cell Ag cell control antigen
• FI-RSV VRS inactivated by formalin
• PBS buffered saline phosphate.
• Figure 5 Number of nucleated cells infiltrating the lungs after challenge and cell populations present in these lungs represented by the CD4 / CD8 ratio.
• Figure 6 Number of granulocytes (LGL) and cells labeled with the antibody RB6- 8B5 (polynuclear).
• Figure 7 Secretion of Th2 cytokines (IL-5 and IL-10); significant increase in cytokine secretion in mice immunized with gBBG2Na and FI-VRS compared to those treated with BBG2Na.
• Th2 cytokines IL-5 and IL-10
• the fusion peptide BBG2Na is composed of a very conserved fragment of the G protein of VRS-A, commonly called G2Na (fragment 130-230 of protein G of human RSV type A), fused by genetic engineering at the site of binding to albumin of the streptococcus protein G, site called BB.
• G2Na fragment 130-230 of protein G of human RSV type A
• BBG2Na a recombinant protein, designated BBG2Na, in E.coli and in eukaryotic HEp-2 cells.
• the proteins were purified on HSA-Sepharose columns. Confirmation of glycosylation and non-glycosylation of proteins expressed in eukaryotic and prokaryotic systems has been demonstrated by treatment of the proteins with deglycosylation enzymes and analysis of the products on SDS-PAGE gel of 9%.
• the protein resulting from prokaryotic expression migrates at the same height, regardless of the treatment or not with the deglycosylation enzymes.
• the protein derived from eukaryotic expression migrates less than the prokaryotic protein before enzymatic treatment, after deglycosylation it migrates at the same height as the prokaryotic protein.
• BBG2Na from E. coli (non-glycosylated) or H ⁇ p-2 cells (glycosylated) are similar or not from an antigenic point of view
• the 2 forms of protein were tested in ⁇ LISA against a panel of monoclonal antibodies specific for BBG2Na. Briefly, the proteins were brought into contact with these antibodies at the same concentration on ⁇ LISA plates and the titer in monoclonal antibody was determined according to the last dilution of the antibody giving an OD greater than 2 times the background noise. of the test. As can be seen in Figure 2, the 2 forms of BBG2Na could not be distinguished from each other, which indicates that the proteins are very similar from an antigenicity point of view.
• Example III
• mice were immunized 3 times (on D0, D14 and D24) intraperitoneally (ip) with 2 ⁇ g of non-glycosylated or glycosylated BBG2Na, or by the HEp-2 control cell antigen, FI-VRS or PBS.
• ip intraperitoneally
• the sera of the mice were collected and were tested in ELISA against antigens of RSV, as described by Power, U.F. et al. (Virology, 230: 155-166, 1997).
• the mice immunized with the peptide BBG2Na glycosylated or non-glycosylated had practically the same titre in anti-RSV antibodies. Therefore, the two forms of the protein are also very similar in terms of their immunogenicity.
• mice are immunized on D0, D14, D24. They are challenged with 10 TCID 50 of RSN-A on D34 and are sacrificed, after intracardiac blood puncture, 7 days later.
• the lungs are removed, reduced to small fragments and treated with an enzymatic mixture of coUagenase, Dnase and Dispase as described (H. Plotnicky-Gilquin et al., Nirol., 258: 128-40, 1999).
• the pulmonary infiltrating cells are scanned and then labeled using fluorescent antibodies specific for the different types of cell populations.
• the intracellular cytokines are detected after stimulation of the cells and intracellular labeling with specific antibodies.
• the analysis of the labeled cells is carried out using FACSvantage (Becton Dickinson).
• Th2 cytokines IL Secretion of Th2 cytokines
• IL-5 and IL-10 Th2 cytokines
• the response profile with BBG2Na is comparable to that of mice treated with the cellular antigen alone.
• the secretion of Th2 cytokines (IL-5 and IL-10) is shown in Figure 7.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Virology (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Microbiology (AREA)
• Epidemiology (AREA)
• Mycology (AREA)
• Immunology (AREA)
• Oncology (AREA)
• Molecular Biology (AREA)
• Communicable Diseases (AREA)
• Pulmonology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Peptides Or Proteins (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=8859130

Family Applications (1)

Country Status (4)

Families Citing this family (13)

Family Cites Families (3)

• 2001
  • 2001-01-23 FR FR0100875A patent/FR2819810B1/fr not_active Expired - Fee Related
• 2002
  • 2002-01-23 EP EP02700379A patent/EP1353690A2/de not_active Withdrawn
  • 2002-01-23 WO PCT/FR2002/000270 patent/WO2002058725A2/fr not_active Application Discontinuation
  • 2002-01-23 AU AU2002233457A patent/AU2002233457A1/en not_active Abandoned

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events