FR2758331A1 - NEW MEANS FOR THE DIAGNOSIS, PREVENTION AND TREATMENT OF CONTAMINATIONS OR INFECTIONS WITH MUCOSAL TROPISM VIRUSES - Google Patents
NEW MEANS FOR THE DIAGNOSIS, PREVENTION AND TREATMENT OF CONTAMINATIONS OR INFECTIONS WITH MUCOSAL TROPISM VIRUSES Download PDFInfo
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- FR2758331A1 FR2758331A1 FR9700300A FR9700300A FR2758331A1 FR 2758331 A1 FR2758331 A1 FR 2758331A1 FR 9700300 A FR9700300 A FR 9700300A FR 9700300 A FR9700300 A FR 9700300A FR 2758331 A1 FR2758331 A1 FR 2758331A1
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- C—CHEMISTRY; METALLURGY
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- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1027—Paramyxoviridae, e.g. respiratory syncytial virus
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pulmonology (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
L'invention a pour objet de nouveaux moyens pour le diagnostic, la prévention et le traitement de l'homme ou de l'animal vis-à-vis de contaminations ou d'infections par des virus à tropisme muqueux. The invention relates to new means for the diagnosis, prevention and treatment of humans or animals vis-à-vis contamination or infections with viruses mucosal tropism.
Les virus à tropisme muqueux peuvent infecter diverses muqueuses humaines ou animales telles que les muqueuses respiratoire, intestinale ou vaginale, selon différents mécanismes. Les défenses immunologiques contre ces infections impliquent fréquemment la sécrétion d'IgA. Viruses with a mucosal tropism can infect various human or animal mucosa such as the respiratory, intestinal or vaginal mucosa, according to different mechanisms. Immunological defenses against these infections frequently involve the secretion of IgA.
On citera les virus de la famille des Reoviridae, plus particulièrement du genre Rotavirus (dénommé ci-après RV), les virus de la famille des Paramyxoviridae, plus particulièrement du genre Pneumovirus tel que le virus respiratoire syncytial (dénommé ci-après VRS). Mais aussi les papillomavirus, les adénovirus, les entérovirus, les poliovirus, les virus de la grippe ou encore les virus de l'immunodéficience humaine. There may be mentioned viruses of the family Reoviridae, more particularly of the genus Rotavirus (hereinafter referred to as RV), viruses of the family Paramyxoviridae, more particularly of the genus Pneumovirus such as Respiratory Syncytial Virus (hereinafter referred to as RSV). But also papillomaviruses, adenoviruses, enteroviruses, polioviruses, influenza viruses or even the human immunodeficiency virus.
Ces virus posent des problèmes complexes en médecine humaine, dans les collectivités et en milieu hospitalier où sont confinés des sujets particulièrement sensibles à de telles infections : nouveau-nés, bébés, prématurés en particulier, enfants, adultes immunodéprimés, personnes âgées, mais aussi en médecine vétérinaire dans le cas des élevages d'animaux comme les poulains ou les veaux. These viruses pose complex problems in human medicine, in communities and in hospitals where subjects particularly susceptible to such infections are confined: infants, babies, premature babies in particular, children, immunocompromised adults, the elderly, but also in veterinary medicine in the case of animal farms such as foals or calves.
De telles situations conduisent à des infections épidémiques d'autant plus lourdes et difficiles à gérer qu'elles peuvent donner lieu non seulement à des primoinfections, mais également à des ré-infections. Certaines de ces épidémies apparaissent, de plus, de manière périodique: c'est le cas, par exemple, des infections à VRS au cours des mois d'hiver, de novembre, décembre et janvier. Such situations lead to epidemic infections that are all the more cumbersome and difficult to manage that they can give rise not only to primary infections, but also to re-infections. Some of these epidemics appear, moreover, periodically: this is the case, for example, of RSV infections during the winter months, November, December and January.
Or, pour nombre de ces virus, les moyens prophylactiques ou thérapeutiques proposés à ce jour ne présentent pas l'efficacité souhaitée ou, pour certains, ne sont même pas disponibles. Il en est ainsi en particulier en ce qui concerne le VRS, agent infectieux de l'appareil respiratoire et responsable de bronchiolites et pneumonies sévères, et le Rotavirus, agent infectieux de l'appareil intestinal et responsable de gastroentérites sévères, pour lesquels il n'existe actuellement aucune thérapie, prophylaxie ou vaccination efficace. However, for many of these viruses, the prophylactic or therapeutic means proposed to date do not have the desired efficacy or, for some, are not even available. This is particularly the case with RSV, an infectious agent of the respiratory system responsible for severe bronchiolitis and pneumonia, and Rotavirus, an infectious agent of the intestinal tract and responsible for severe gastroenteritis, for which it is not There is currently no therapy, prophylaxis or effective vaccination.
Les recherches effectuées par les inventeurs dans ce domaine les ont conduits à étudier plus spécialement les régions déterminant la complémentarité, ou CDR, d'anticorps monoclonaux anti-virus à tropisme muqueux et à élaborer des séquences peptidiques de grand intérêt au regard de leurs propriétés immunologiques. Divers outils utiles pour le diagnostic, la prévention et le traitement des contaminations et infections par ces virus ont pu être ainsi élaborés. The research carried out by the inventors in this field has led them to study more specifically the complementarity determining regions, or CDRs, of monoclonal antibodies to mucosal tropism viruses and to elaborate peptide sequences of great interest with regard to their immunological properties. . Various useful tools for the diagnosis, prevention and treatment of infections and infections with these viruses have thus been developed.
L'invention a donc pour but de fournir de telles séquences peptidiques capables de reconnaître des épitopes clés dans une contamination ou infection virale, et en particulier capables de constituer des paratopes vis-à-vis de RV et de VRS. The object of the invention is therefore to provide such peptide sequences capable of recognizing key epitopes in a viral infection or infection, and in particular capable of forming paratopes with respect to RV and RSV.
Elle a également pour but de fournir les séquences de nucléotides correspondantes. It is also intended to provide the corresponding nucleotide sequences.
Selon encore un autre aspect, l'invention vise les applications de ces différentes séquences à des fins de diagnostic, préventives ou thérapeutiques dans le cas d'infection par des virus à tropisme muqueux, et notamment par RV ou VRS. According to yet another aspect, the invention is directed to the applications of these different sequences for diagnostic, preventive or therapeutic purposes in the case of infection with viruses with a mucosal tropism, and in particular by RV or RSV.
Les peptides de l'invention sont caractérisés en ce qu'ils sont essentiellement constitués par une séquence d'acides aminés capable de reconnaître, selon une réaction de type antigène-anticorps, au moins un épitope d'un virus à tropisme muqueux, impliqué dans les infections provoquées par un tel virus. The peptides of the invention are characterized in that they consist essentially of an amino acid sequence capable of recognizing, according to an antigen-antibody type reaction, at least one epitope of a virus with a mucous tropism, involved in infections caused by such a virus.
Une telle reconnaissance de l'épitope viral par le peptide peut être mise en évidence par exemple par une réaction antigène-anticorps comme par exemple l'ELISA. Such recognition of the viral epitope by the peptide can be demonstrated for example by an antigen-antibody reaction such as ELISA.
L'invention vise en particulier des peptides tels qu'indiqués ci-dessus capables de neutraliser l'infection virale et, le cas échéant, d'inhiber la fusion entre cellules infectées et non infectées ou entre cellules et virus lorsque l'épitope viral est impliqué dans la fusion, et/ou encore d'exercer un effet protecteur par voie passive ou active et/ou d'inhiber la transcription du virus à tropisme muqueux. The invention is directed in particular to peptides as indicated above capable of neutralizing viral infection and, where appropriate, of inhibiting fusion between infected and uninfected cells or between cells and viruses when the viral epitope is involved in the fusion, and / or to exert a passive or active protective effect and / or to inhibit the transcription of the mucosal tropism virus.
De tels peptides sont encore caractérisés en ce qu'ils comprennent une séquence d'acides aminés possédant les propriétés d'un CDR d'anticorps anti-virus à tropisme muqueux. Such peptides are further characterized in that they comprise an amino acid sequence having the properties of an anti-mucosal virus anti-virus antibody CDR.
L'expression "CDR" désigne une séquence d'acides aminés de régions hypervariables de l'anticorps impliquées dans la reconnaissance de sites antigéniques viraux majeurs. The term "CDR" refers to an amino acid sequence of hypervariable regions of the antibody involved in the recognition of major viral antigenic sites.
Avantageusement, la séquence d'acides aminés des peptides de l'invention comprend une ou plusieurs séquences de ces régions CDR, et/ou un ou plusieurs analogues de telles séquences. Le terme "analogue", tel qu'utilisé selon l'invention, désigne une séquence d'acides aminés, différant de celle d'une région de CDR natif par un ou plusieurs acides aminés, mais présentant des propriétés immunologiques du type de celles observées avec le CDR natif, telles que mises en évidence dans les exemples. Les différences au niveau des séquences peuvent correspondre à des modifications d'un ou plusieurs acides aminés et/ou des substitutions de natifs d'acides aminés par des groupes chimiques appropriés au regard des applications biologiques envisagées, ou des délétions. Advantageously, the amino acid sequence of the peptides of the invention comprises one or more sequences of these CDR regions, and / or one or more analogs of such sequences. The term "analogue" as used according to the invention, refers to an amino acid sequence, differing from that of a native CDR region by one or more amino acids, but exhibiting immunological properties of the type observed with the native CDR, as highlighted in the examples. The sequence differences may correspond to modifications of one or more amino acids and / or amino acid native substitutions by appropriate chemical groups with respect to intended biological applications, or deletions.
Elles peuvent également correspondre à la présence de natifs additionnels, par rapport aux séquences natives. Des peptides préférés de ce type sont caractérisés en ce qu'ils présentent des propriétés de type antigène-anticorps avec VRS.They can also correspond to the presence of additional natives, compared to native sequences. Preferred peptides of this type are characterized in that they exhibit antigen-antibody properties with RSV.
L'invention vise notamment les peptides caractérisés en ce qu'ils sont capables de réagir avec l'épitope 205-225 et/ou 255-278 de la protéine F de VRS. The invention is directed in particular to peptides characterized in that they are capable of reacting with the 205-225 and / or 255-278 epitope of the RSV F protein.
Il s'agit en particulier de peptides correspondant à, ou analogues de régions CDR d'anticorps monoclonaux spécifiques du VRS, du sous-groupe A ou B. In particular, these are peptides corresponding to, or analogous to, CDR regions of monoclonal antibodies specific for RSV, subgroup A or B.
Des peptides de ce groupe spécialement visés par l'invention répondent aux séquences d'acides aminés SEQ ID N01 à SEQ ID N012 et SEQ ID N025 à SEQ ID N042. Peptides of this group specifically targeted by the invention respond to the amino acid sequences SEQ ID NO1 to SEQ ID NO: 12 and SEQ ID NO: 25 to SEQ ID NO: 42.
D'autres peptides préférés du type mentionné cidessus sont caractérisés en ce qu'ils présentent des propriétés de type antigène-anticorps avec RV. Other preferred peptides of the type mentioned above are characterized in that they exhibit antigen-antibody properties with RV.
L'invention vise notamment les peptides caractérisés en ce qu'ils dérivent d'anticorps capables de réagir avec le site III et/ou IV de la protéine VP6 de RV. The invention is directed in particular to peptides characterized in that they derive from antibodies capable of reacting with the site III and / or IV of the RV VP6 protein.
De tels peptides, avantageusement, correspondent à, ou sont des analogues de régions CDR d'anticorps monoclonaux à spécificité RV. Such peptides, advantageously, correspond to, or are analogues of CDR regions of monoclonal antibodies with RV specificity.
Des peptides de ce groupe spécialement visés par l'invention répondent aux séquences d'acides aminés SEQ ID N"13 à SEQ ID N024. Peptides of this group specifically targeted by the invention respond to the amino acid sequences SEQ ID NO: 13 to SEQ ID NO: 24.
On observera que les peptides décrits ci-dessus en rapport avec les régions de CDR peuvent correspondre à, ou constituer des analogues de régions de CDR de chaînes lourdes d'anticorps anti-virus à tropisme muqueux, et/ou de chaînes légères. It will be observed that the peptides described above with respect to the CDR regions may correspond to, or be analogous to, heavy chain CDR regions of mucosal tropism antibodies, and / or light chains.
Les différents peptides peuvent se présenter sous forme linéaire, ou en variante sous forme cyclisée. The different peptides may be in linear form, or alternatively in cyclized form.
Les peptides de l'invention sont obtenus par synthèse peptidique, en utilisant avantageusement les techniques classiques, ou encore par génie génétique en utilisant les acides nucléiques définis ci-dessous. The peptides of the invention are obtained by peptide synthesis, advantageously using conventional techniques, or else by genetic engineering using the nucleic acids defined below.
En particulier, ils peuvent être produits par des cellules bactériennes, animales et végétales dans lesquelles sont insérées les séquences d'ADN portant l'information génétique correspondant à ces peptides et placées sous le contrôle de promoteurs appropriés. In particular, they can be produced by bacterial, animal and plant cells into which are inserted the DNA sequences carrying the genetic information corresponding to these peptides and placed under the control of appropriate promoters.
De telles cellules modifiées, le cas échéant, les organismes ou les plantes constitués de telles cellules sont également comprises dans le champ de l'invention. Such modified cells, if any, organisms or plants consisting of such cells are also within the scope of the invention.
L'invention vise en effet également les acides nucléiques correspondant selon le code génétique universel aux peptides définis plus haut. The invention also aims nucleic acids corresponding according to the universal genetic code to the peptides defined above.
Ces acides nucléiques comprennent les ADN comportant l'information génétique correspondant auxdits peptides, avantageusement les ADN capables de coder pour ces peptides. These nucleic acids comprise the DNAs comprising the genetic information corresponding to said peptides, advantageously the DNAs capable of coding for these peptides.
Ils comprennent également les ARN, notamment les ARNm, et les
ADNc correspondants.They also include RNAs, including mRNAs, and
Corresponding cDNAs.
Les vecteurs de transfert et/ou d'expression tels que cosmide, plasmide, phage, virus animal ou végétal renfermant de tels acides nucléiques, et les cellules hôtes contenant de tels vecteurs entrent également dans le champ de l'invention. Transfer and / or expression vectors such as cosmid, plasmid, phage, animal or plant virus containing such nucleic acids, and host cells containing such vectors are also within the scope of the invention.
L'étude des composés définis ci-dessus a conduit à mettre en évidence des propriétés anti-virales de grand intérêt, comme illustré par les exemples. The study of the compounds defined above has led to highlight anti-viral properties of great interest, as illustrated by the examples.
Ainsi, les propriétés de neutralisation et, le cas échéant, d'inhibition de la fusion du virus et/ou de sa transcription, sont avantageusement mises à profit, pour le diagnostic, la prévention et le traitement de contaminations et d'infections par de tels virus à tropisme muqueux et la fabrication d'immunogènes en vue de vaccins. Thus, the properties of neutralization and, where appropriate, of inhibition of the fusion of the virus and / or its transcription, are advantageously used for the diagnosis, prevention and treatment of contaminations and infections with such viruses with mucosal tropism and the manufacture of immunogens for vaccines.
L'invention vise ainsi des moyens, à savoir des compositions, des méthodes et des kits, pour détecter la présence du virus chez l'homme ou l'animal, ou pour mettre en évidence une réponse immunitaire à une contamination ou à une infection virale. The invention thus provides means, namely compositions, methods and kits, for detecting the presence of the virus in humans or animals, or for demonstrating an immune response to a viral contamination or infection. .
Les compositions de diagnostic de l'invention sont caractérisées en ce qu'elles comprennent
pour détecter la présence du virus chez l'homme ou l'animal, d'au moins un peptide tel que défini ci-dessus, ou
pour mettre en évidence une réponse immunitaire, d'au moins un anticorps dirigé contre un peptide de l'invention ou un ligand équivalent, c'est-à-dire se fixant sur le peptide,
le peptide, l'anticorps ou le ligand, étant associé à un marqueur de la réaction de détection, tel qu'un radiomarqueur ou un marqueur enzymatique et, le cas échéant, à un véhicule approprié pour réaliser le diagnostic.The diagnostic compositions of the invention are characterized in that they comprise
for detecting the presence of the virus in humans or animals, at least one peptide as defined above, or
to demonstrate an immune response, at least one antibody directed against a peptide of the invention or an equivalent ligand, that is to say, fixing on the peptide,
the peptide, the antibody or the ligand being associated with a marker of the detection reaction, such as a radiolabel or an enzyme label and, where appropriate, a suitable vehicle for carrying out the diagnosis.
L'invention vise également une méthode de diagnostic in vitro d'une contamination ou d'une infection par un virus à tropisme muqueux, caractérisée en ce qu'elle comprend
- la mise en contact d'un échantillon biologique, tel qu'un fluide corporel, avec
pour détecter la présence du virus chez l'homme ou l'animal, d'au moins un peptide de l'invention, ou une composition de diagnostic telle que définie plus haut, dans des conditions permettant la mise en évidence d'une réaction du type antigène-anticorps, ou
pour mettre en évidence une réponse immunitaire, avec au moins un anticorps anti-peptide, un ligand se fixant au peptide, ou une composition de diagnostic les renfermant, comme défini ci-dessus, et
- la révélation de la réaction produite lorsque l'antigène viral est présent.The invention also relates to a method for in vitro diagnosis of a contamination or infection with a virus with a mucosal tropism, characterized in that it comprises
contacting a biological sample, such as a body fluid, with
for detecting the presence of the virus in humans or animals, at least one peptide of the invention, or a diagnostic composition as defined above, under conditions allowing the demonstration of a reaction of the antigen-antibody type, or
to demonstrate an immune response, with at least one anti-peptide antibody, a ligand binding to the peptide, or a diagnostic composition containing them, as defined above, and
the revelation of the reaction produced when the viral antigen is present.
L'invention vise en outre des kits pour le diagnostic d'une contamination ou d'une infection par un virus à tropisme muqueux. The invention further provides kits for the diagnosis of contamination or infection with a mucosal virus.
Ces kits sont caractérisés en ce qu'ils comprennent au moins un peptide, ou un anticorps anti-peptide, ou un ligand équivalent, et les réactifs appropriés pour la réaction de détection, notamment des marqueurs et des solvants. These kits are characterized in that they comprise at least one peptide, or an anti-peptide antibody, or an equivalent ligand, and the appropriate reagents for the detection reaction, in particular markers and solvents.
L'administration de peptides selon l'invention ou le cas échéant d'anticorps anti-peptides ou de ligands se fixant à ces peptides s'avère de grand intérêt pour prévenir ou traiter des infect ions par les virus à tropisme muqueux, notamment par VRS et RV. The administration of peptides according to the invention or, where appropriate, anti-peptide antibodies or ligands binding to these peptides proves to be of great interest for preventing or treating infections with viruses with a mucosal tropism, in particular by RSV. and RV.
L'invention vise donc également des compositions pharmaceutiques possédant des propriétés anti-virales, caractérisées en ce qu'elles renferment au moins un peptide à propriétés anti-virales tel que défini ci-dessus, un anticorps anti-peptide ou un ligand se fixant à ce peptide, en association avec un véhicule pharmaceutiquement inerte. The invention therefore also relates to pharmaceutical compositions having anti-viral properties, characterized in that they contain at least one peptide with anti-viral properties as defined above, an anti-peptide antibody or a ligand binding to this peptide, in association with a pharmaceutically inert vehicle.
L'invention vise plus spécialement les compositions élaborées à l'aide des peptides anti-VRS ou anti-RV. En particulier, l'invention vise les compositions pharmaceutiques anti-VRS, renfermant au moins un peptide répondant à l'une des séquences SEQ ID N07 à SEQ ID N012 et tout particulièrement à la séquence SEQ ID N09 dont les propriétés neutralisantes présentent un grand intérêt. The invention is more particularly directed to compositions prepared using anti-RSV or anti-RV peptides. In particular, the invention relates to the anti-RSV pharmaceutical compositions containing at least one peptide corresponding to one of the sequences SEQ ID No. 07 to SEQ ID No. 12 and more particularly to the sequence SEQ ID NO9 whose neutralizing properties are of great interest. .
Ces compositions sont administrables de préférence par voie nasale, par voie orale ou par voie parentérale, à raison de 1 à 80 mg/kg, sous différentes formes. On citera à titre d'exemple l'administration sous forme d'esters lourds, tels que décanoate, oenanthate ou palmitate, ou sous forme galénique retard. These compositions are preferably administrable nasally, orally or parenterally, at a rate of 1 to 80 mg / kg, in various forms. By way of example, mention may be made of administration in the form of heavy esters, such as decanoate, oenanthate or palmitate, or in a delayed dosage form.
Un autre aspect de l'invention revêtant un intérêt majeur concerne les applications vaccinales des anticorps dirigés contre lesdits peptides, ou de ligands équivalents. Another aspect of the invention of major interest relates to vaccine applications of antibodies directed against said peptides, or equivalent ligands.
De telles compositions vaccinales, qui sont caractérisées en ce qu'elles renferment une quantité efficace d'anticorps ou de ligands dirigés contre lesdits peptides en association avec un véhicule approprié, entrent également dans le cadre de l'invention. Such vaccine compositions, which are characterized by containing an effective amount of antibodies or ligands directed against said peptides in association with a suitable vehicle, are also within the scope of the invention.
Des compositions particulièrement avantageuses sont associées à au moins un autre vaccin, par exemple des vaccins pour l'enfance, ce qui permet de disposer de compositions vaccinales à large spectre. Particularly advantageous compositions are associated with at least one other vaccine, for example vaccines for childhood, which makes it possible to have broad-spectrum vaccine compositions.
Dans les applications prophylactiques, les anticorps anti-peptides de l'invention ou lesdits ligands sont avantageusement conjugués à une molécule porteuse pour renforcer leur immunogénécité. A titre d'exemple, on citera des molécules de type haptène (anatoxine tétanique, anatoxine diphtérique ou autres). In prophylactic applications, the anti-peptide antibodies of the invention or said ligands are advantageously conjugated to a carrier molecule to enhance their immunogenicity. By way of example, mention may be made of hapten-type molecules (tetanus toxoid, diphtheria toxoid or others).
En variante, les peptides ou anticorps anti-peptides, ou lesdits ligands, sont insérés dans une structure d'immunoglobuline A humaine, le cas échéant modifiée dans la région charpente de ses régions variables adjacentes au peptide, ou à l'anticorps anti-peptide inséré, ou au ligand, de manière notamment à rétablir dans l'IgA résultante, les propriétés dudit peptide ou anticorps anti-peptide. Alternatively, peptides or anti-peptide antibodies, or said ligands, are inserted into a human immunoglobulin A structure, optionally modified in the framework region of its variable regions adjacent to the peptide, or to the anti-peptide antibody. inserted, or to the ligand, so as in particular to restore in the resulting IgA, the properties of said peptide or anti-peptide antibody.
La présentation des peptides est réalisée sous forme de fragment de type ScFv, ou d'insertion dans une structure de protéine hexon d'adénovirus. The presentation of the peptides is carried out as ScFv-like fragment, or insertion into an adenovirus hexon protein structure.
D'autres caractéristiques et avantages de l'invention sont donnés dans les exemples qui suivent. Other features and advantages of the invention are given in the examples which follow.
Dans les exemples qui vont suivre, donnés à titre illustratifs et non limitatifs, il est fait référence aux figures 1 à 5 qui représentent
- la figure 1,la neutralisation du pouvoir infectieux du VRS par le peptide synthétique homologue du CDR3 de la chaîne lourde de l'anticorps RS-348 (PEP3H).In the examples which follow, given by way of illustration and without being limiting, reference is made to FIGS. 1 to 5 which represent
FIG. 1, the neutralization of the RSV infectious capacity by the synthetic peptide homologous to the CDR3 of the RS-348 heavy chain (PEP3H).
- la figure 2, les chaînes VH et V d'anticorps monoclonaux anti-VRS,
- la figure 3, les CDR de ces chaînes,
- la figure 4, les chaînes VH et VL 138 et 133, et
- la figure 5, les séquences de peptides synthétiques anti-VRS.FIG. 2, the VH and V chains of monoclonal anti-RSV antibodies,
FIG. 3, the CDRs of these chains,
FIG. 4, the VH and VL chains 138 and 133, and
- Figure 5, the synthetic anti-RSV peptide sequences.
Exemple 1: Production d'anticorps monoclonaux anti
VRS et d'anticorps monoclonaux anti-VR
- obtention des hybridomes
Des souris BALB/c ont été infectées
- en intranasal avec
104 pfu (unités formant plage) de VRS souche A2 ou Long ou
- en intrapéritonéal
10 pfu de RV souche bovine RF.Example 1 Production of Anti-Monoclonal Antibodies
VRS and anti-VR monoclonal antibodies
- obtaining hybridomas
BALB / c mice were infected
- in intranasal with
104 pfu (range forming units) of VRS strain A2 or Long or
- intraperitoneally
10 pfu of RV bovine strain RF.
Les cellules spléniques de souris sont récoltées et fusionnées avec des cellules de myélome SP2/O selon les techniques classiques. Spleen cells of mice are harvested and fused with SP2 / O myeloma cells according to standard techniques.
Les hybridomes (cellules hybridomales) secrétant soit des anticorps anti-VRS, soit des anticorps anti-RV, ont été sélectionnés par IF ou ELISA, clonées et conservées par congélation. Hybridomas (hybridoma cells) secreting either anti-RSV or anti-RV antibodies were selected by IF or ELISA, cloned and stored by freezing.
- conditions de culture
Après décongélation, les cellules sont cultivées en milieu RPMI 1640-10% SVF (Sérum de Veau Foetal) dans une étuve à 37"C, 5% C02. - growing conditions
After thawing, the cells are cultured in RPMI 1640-10% FCS medium (fetal calf serum) in an oven at 37 ° C., 5% CO 2.
-détection des anticorps par immunofluorescence indirecte (IF). detection of antibodies by indirect immunofluorescence (IF).
Les surnageants d'hybridomes sont incubés 30 minutes à 37"C dans des puits recouverts de cellules Hep 2 (cellules humaines) infectées ou non (témoins) par la souche A2 ou Long du virus syncytial respiratoire, ou cellules MA104 (cellules de rein de singe) infectées ou non par la souche bovine RF du rotavirus. The hybridoma supernatants are incubated for 30 minutes at 37 ° C. in wells covered with infected or uninfected Hep 2 cells (human cells) (controls) with the A2 or Long strain of the respiratory syncytial virus, or MA104 cells (kidney cells). monkey) infected or not with the rotavirus bovine strain RF.
Après 3 lavages au PBS, les anticorps présents sont révélés par une incubation de 30 minutes avec un anticorps anti-IgG de souris marqué à la fluorescéine. Les lames sont ensuite observées au microscope à fluorescence. After 3 washes with PBS, the antibodies present are revealed by a 30 minute incubation with a fluorescein-labeled anti-mouse IgG antibody. The slides are then observed under a fluorescence microscope.
Les résultats rapportés dans les exemples ci-après concernent les six anticorps monoclonaux suivants, à savoir quatre anticorps monoclonaux anti-VRS, appelés respectivement
RS-348, RS-18B2, RS-2B8 et RS-255, et deux anticorps monoclonaux anti-RV, appelés RV-133 et RV-138. The results reported in the following examples relate to the following six monoclonal antibodies, namely four anti-RSV monoclonal antibodies, respectively called
RS-348, RS-18B2, RS-2B8 and RS-255, and two anti-RV monoclonal antibodies, called RV-133 and RV-138.
anticorps monoclonaux anti-VRS
Les quatre anticorps monoclonaux anti-VRS, RS-348, RS -1 8B2 , RS-2B8 et RS-255, reconnaissent des épitopes proches sur la protéine de fusion F du VRS et sont tous, excepté RS-255 qui a été obtenu à partir du site 255-275 de la protéine F du
VRS, des IgGl fortement neutralisants.monoclonal anti-RSV antibodies
The four anti-RSV, RS-348, RS-18B2, RS-2B8 and RS-255 monoclonal antibodies recognize close epitopes on the RSV F fusion protein and are all except for RS-255 which was obtained at from site 255-275 of the F protein
RSV, highly neutralizing IgG1.
L'anticorps RS-348 possède une très forte activité neutralisante. Il reconnaît les souches de VRS des sous-groupes
A et B en immunofluorescence alors qu'il présente une spécificité de sous-groupe en neutralisation. L'épitope des anticorps RS ci-dessous, tel qu'identifié par différentes techniques, est très conformationnel et est situé principalement entre les acides aminés 190 et 289 de la protéine de fusion du VRS (sites 205-225 et 255-278).RS-348 has a very strong neutralizing activity. It recognizes RSV strains from subgroups
A and B in immunofluorescence whereas it has a subunit specificity in neutralization. The RS antibody epitope below, as identified by various techniques, is highly conformational and is located primarily between amino acids 190 and 289 of the RSV fusion protein (sites 205-225 and 255-278).
anticorps monoclonaux anti-RV
Les deux anticorps monoclonaux anti-rotavirus, RV-133 et RV-138, reconnaissent tous deux des sites antigéniques proches sur la protéine de capside interne du rotavirus, VP6.monoclonal anti-RV antibodies
Both anti-rotavirus monoclonal antibodies, RV-133 and RV-138, both recognize close antigenic sites on the internal rotavirus capsid protein, VP6.
Cependant, RV-133 à la différence de RV-138, reconnaît un épitope de groupe commun à toutes les souches du groupe A ayant un rapport avec la région de VP6 impliquée dans la transcription virale. En effet, la restauration de l'activité transcriptase n'a pas lieu lorsque VP6 est préalablement incubée avec l'anticorps RV-133 avant la réassociation avec les cores (voir "Inhibition of in vitro reconstitution of rotavirus transcriptionally active particles by anti-VP6 monoclonal antibodies". Evelyne KOHLI, Pierre POTHIER, Guenola TOSSER,
Jean COHEN, Anna-Maria SANDINO et Eugenio SPENCER, Archives of Virology 1994, 135, 193-200).However, RV-133 unlike RV-138, recognizes a group epitope common to all Group A strains related to the VP6 region involved in viral transcription. Indeed, the restoration of the transcriptase activity does not occur when VP6 is previously incubated with the RV-133 antibody before re-association with the cores (see "Inhibition of in vitro reconstitution of rotavirus transcriptionally active particles by anti-VP6 monoclonal antibodies "Evelyne KOHLI, Pierre Pothier, Guenola TOSSER,
Jean COHEN, Anna-Maria SANDINO and Eugenio SPENCER, Archives of Virology 1994, 135, 193-200).
Exemple 2: Obtention des séquences en acides aminés des chaînes lourdes et légères des anticorps monoclonaux à tropisme muqueux anti-VRS et anti-RV. EXAMPLE 2 Obtaining Amino Acid Sequences of the Heavy and Light Chains of Monoclonal Antibodies to Anti-RSV and Anti-RV Mucous Tropism
Les séquences en acides aminés sont déduites des séquences en ADN des gènes VH et VL. The amino acid sequences are deduced from the DNA sequences of the VH and VL genes.
- Extraction et purification des ARNm
Cette étape est réalisée à l'aide d'un kit QuickPrepR Micro mRNA purification commercialisé par Pharmacia-niotech, à partir de 10 cellules hybridomales.- Extraction and purification of mRNAs
This step is carried out using a QuickPrepR Micro mRNA purification kit marketed by Pharmacia-niotech, from 10 hybridoma cells.
- Extraction des ARN totaux
Les cellules d'hybridome sont centrifugées et le culot est repris dans 0,4 ml de tampon d'extraction
(thiocyanate de guanidium et N-lauroyl sarcosine) puis 0.8 ml de tampon d'élution (Tris-HCl pH 7,5 10 mM ; EDTA lmM). - Total RNA extraction
The hybridoma cells are centrifuged and the pellet is taken up in 0.4 ml of extraction buffer
(guanidium thiocyanate and N-lauroyl sarcosine) then 0.8 ml of elution buffer (10 mM Tris-HCl pH 7.5, 1 mM EDTA).
- purification des ARNm sur colonne oligo(dT)
L'échantillon d'ARN totaux est ajouté au gel de cellulose-oligo (dT) homogénéisé et débarrassé de son tampon de stockage. Le tout est centrifugé et lavé 5 fois avec un tampon à forte concentration en sels puis 3 fois avec un tampon à faible concentration de sels.purification of oligo (dT) column mRNAs
The total RNA sample is added to the cellulose-oligo (dT) gel homogenized and freed of its storage buffer. The whole is centrifuged and washed 5 times with a buffer with a high concentration of salts and then 3 times with a buffer with a low concentration of salts.
Le gel remis en suspension dans ce dernier tampon est transféré dans une colonne (MicroSpin X, Pharmacia) placée dans un microtube. Après 3 lavages avec le tampon low-salt, les
ARNm sont élués avec le tampon d'élution, puis conservés dans la glace.The gel resuspended in this last buffer is transferred to a column (MicroSpin X, Pharmacia) placed in a microtube. After 3 washes with the low-salt buffer, the
MRNAs are eluted with the elution buffer and then stored in ice.
- précipitation des ARNm
L'éluat est additionné d'une solution de glycogène, d'acétate de potassium et d'éthanol 95% avant d'être placé 30 minutes à -20 C. Après centrifugation, on récupère les ARNm dans le culot, puis on les remet en suspension dans du tampon d'élution.- precipitation of the mRNAs
The eluate is supplemented with a solution of glycogen, potassium acetate and 95% ethanol before being placed for 30 minutes at -20 ° C. After centrifugation, the mRNAs are recovered in the pellet and then returned suspended in elution buffer.
- Synthèse de 1'ADNc
La synthèse est réalisée en duplicata, un tube servant pour l'amplification de VH (région variable de chaîne lourde) et l'autre pour VL (région variable de chaîne légère).- Synthesis of cDNA
The synthesis is carried out in duplicate, one tube serving for the amplification of VH (heavy chain variable region) and the other for VL (light chain variable region).
Après chauffage à 65"C pour éliminer les structures secondaires, les ARNm (5u1) sont incubés pendant 1 heure en présence de lui de dithiothréitol (DTT) 200 mM, ilul d'un mélange réactionnel contenant une transcriptase inverse
(origine : virus de la leucémie murine), des amorces et les 4 didéoxynucléotides (ddNTP) à 1,25 mM chacun, et 16 ul d'eau distillée.After heating to 65 ° C to remove the secondary structures, the mRNAs (5u1) are incubated for 1 hour in the presence of it with 200 mM dithiothreitol (DTT), ilul of a reaction mixture containing a reverse transcriptase
(origin: murine leukemia virus), primers and 4 dideoxynucleotides (ddNTP) at 1.25 mM each, and 16 μl of distilled water.
- Amplification par PCR de l'ADN codant pour les gènes VH et VL
- conditions d'amplification
L'amplification des gènes codant pour VH et VL est réalisée séparément par PCR grâce à des amorces spécifiques du commerce : H1 (Heavy primer 1) et H2 (Heavy primer 2) pour amplifier VH, L (Light primer mix) pour amplifier VL
(Pharmacia-Biotech).- PCR amplification of DNA coding for VH and VL genes
- amplification conditions
The amplification of the genes coding for VH and VL is carried out separately by PCR using commercially specific primers: H1 (Heavy primer 1) and H2 (Heavy primer 2) to amplify VH, L (Light primer mix) to amplify VL.
(Pharmacia-Biotech).
Les mélanges réactionnels sont les suivants
* pour VH : 33 ul d'ADNc, 2 ul d'amorce Hi, 2 pi d'amorce H2 et 62 pi d'eau distillée.The reaction mixtures are as follows
for VH: 33 μl of cDNA, 2 μl of Hi primer, 2 μl of H2 primer and 62 μl of distilled water.
* pour VL : 33 pi d'ADNc, 2 pi d'amorce L et 64 pi d'eau distillée. for VL: 33 μl of cDNA, 2 μl of L primer and 64 μl of distilled water.
Chaque échantillon est recouvert d'huile minérale et, après dénaturation à 95"C pendant 1 minute, 1 pi de Taq polymérase (Bioprobe) est ajouté. Les tubes sont ensuite placés dans le thermocycleur (PHC-3, Techne) programmé pour 30 cycles de 3 étapes
dénaturation de l'ADN bicaténaire à 94"C, 1 minute,
. hybridation des amorces à 55"C, 2 minutes,
. élongation du brin complémentaire à 72"C, 2 minutes.Each sample is coated with mineral oil and, after denaturation at 95 ° C for 1 minute, 1 μl of Taq polymerase (Bioprobe) is added and the tubes are placed in the thermocycler (PHC-3, Techne) programmed for 30 cycles. of 3 steps
denaturation of double stranded DNA at 94 ° C, 1 minute,
. hybridization of the primers at 55 ° C, 2 minutes,
. elongation of the complementary strand at 72 ° C, 2 minutes.
- purification des produits de PCR
Les produits de PCR sont purifiés à l'aide d'un kit
QIAquick PCR purification8 de QIAGEN. Une aliquote est ensuite déposée sur gel d'agarose-BET (BET = bromure d'éthidium) pour vérifier la bonne amplification des gènes.- purification of PCR products
PCR products are purified using a kit
QIAquick PCR purification8 from QIAGEN. An aliquot is then deposited on a BET-agarose gel (BET = ethidium bromide) to verify the good amplification of the genes.
- Séquençage des produits de PCR
Le séquençage des produits de PCR est réalisé sur un thermocycleur (GeneAmp PCR system 2400) selon la méthode nonradioactive des terminateurs colorants. Cette technique s'apparente à la méthode de séquençage de Sanger basée sur les didéoxynucléotides (ddNTP). Chaque ddNTP est marqué par un fluorophore différent, ce qui permet à la chaîne d'ADN en formation de se terminer et d'être simultanément marquée par le fluorophore correspondant à la dernière hase ajoutée.- Sequencing of PCR products
The sequencing of the PCR products is carried out on a thermocycler (GeneAmp PCR system 2400) according to the nonradioactive method of the dye terminators. This technique is similar to the Sanger sequencing method based on dideoxynucleotides (ddNTP). Each ddNTP is labeled with a different fluorophore, which allows the forming DNA chain to terminate and be simultaneously labeled with the fluorophore corresponding to the last added hast.
Les produits séquencés sont ensuite séparés par migration électrophorétique dans un séquenceur automatique, tel que le séquenceur à ADN 373 stretch qui possède un système optique basé sur un laser couplé à un programme d'analyse informatique. Tous les appareils et réactifs utilisés sont commercialisés par Perkin-Elmer. The sequenced products are then separated by electrophoretic migration into an automatic sequencer, such as the 373 stretch DNA sequencer which has a laser-based optical system coupled to a computer analysis program. All devices and reagents used are marketed by Perkin-Elmer.
Les amorces de séquençage ont été déduites de diverses séquences consensus de gènes VH et VL synthétisées par Eurogentec (KABAT E.A., WU T.T, REID-MILLER M., PERRY H.M.,
GOTTESMAN K.S. 1987. Sequences of proteins of immunological interest, U.S. Dept of Health and Human Services, U.S.The sequencing primers were deduced from various consensus sequences of VH and VL genes synthesized by Eurogentec (KABAT EA, WU TT, REID-MILLER M., PERRY HM,
GOTTESMAN KS 1987. Sequences of proteins of immunological interest, US Dept. of Health and Human Services, US
Government Printing Office ; KABAT E.A., WU T.T., PERRY H.M.,
GOTTESMAN K.S., FOELLER C. 1991. Sequences of proteins of immunological interest, U.S. Department of Health and Human
Services, NIH, Bethesda, MD).Government Printing Office; EA KABAT, WU TT, PERRY HM,
GOTTESMAN KS, FOELLER C. 1991. Sequences of proteins of immunological interest, US Department of Health and Human
Services, NIH, Bethesda, MD).
- réaction de séquençage
La réaction de séquençage est réalisée à l'aide d'un mélange réactionnel prêt à l'emploi : le kit de séquençage par cycle pour terminateurs colorants ABI PRISME . Ce milieu contient les 4 ddNTP marqués différemment (ddATP, ddCTP, ddGTP et ddTTP), les 4 dNTP non marqués (dITP, dATP, dCTP et dTTP), du Tris-HCl (pH9,0), MgCl2, une pyrophosphatase et l'ADN polymérase AmpliTaq FS.- sequencing reaction
The sequencing reaction is carried out using a ready-to-use reaction mixture: the cycle sequencing kit for ABI PRISME dye terminators. This medium contains the 4 ddNTPs labeled differently (ddATP, ddCTP, ddGTP and ddTTP), the 4 unlabeled dNTPs (dITP, dATP, dCTP and dTTP), Tris-HCl (pH9.0), MgCl2, pyrophosphatase and AmpliTaq FS DNA polymerase.
Dans un tube à PCR adapté au thermocycleur, environ 30 ng de produit de PCR purifié sont ajoutés à 1 ul d'amorce de séquençage (à 3,2 pmol/ul), à 8 pi du milieu réactionnel et d'eau ultrapure (qsp 20 pi)
Les tubes de réaction sont ensuite placés dans le thermocycleur programmé pour 25 cycles de 3 étapes
dénaturation : 96 C, 10s,
* hybridation de l'amorce : 50 C, 5s,
élongation : 60 C, 4 min.In a PCR tube adapted to the thermal cycler, about 30 ng of purified PCR product is added to 1 μl of sequencing primer (at 3.2 pmol / μl), 8 μl of the reaction medium and ultrapure water (qs 20 feet)
The reaction tubes are then placed in the thermocycler programmed for 25 cycles of 3 steps
Denaturation: 96 C, 10s,
* hybridization of the primer: 50 C, 5s,
elongation: 60 C, 4 min.
- purification des produits séquences
L'excès de nucléotides est éliminé par une précipitation à I'éthanol des produits de séquençage. Les 20 ul de réaction sont transférés dans un microtube à centrifuger de 1,5 ml où 2 l d'acétate de sodium 3M (pH4,6) et 50 ul d'éthanol 95 % ont été déposés. Les tubes sont placés 10 minutes dans la glace, puis centrifugés 20 à 30 minutes à vitesse maximale. Après décantation, les culots d'ADN sont lavés à l'méthanol 70% puis séchés.- purification of the sequenced products
Excess nucleotides are removed by ethanol precipitation of the sequencing products. The 20 μl of reaction are transferred to a 1.5 ml microcentrifuge tube where 2 μl of 3M sodium acetate (pH4.6) and 50 μl of 95% ethanol are deposited. The tubes are placed in the ice for 10 minutes and then centrifuged for 20 to 30 minutes at maximum speed. After decantation, the DNA pellets are washed with 70% methanol and then dried.
Un tampon de dépôt est préparé en mélangeant 5 ul de formamide déionisé et 1 ul d'EDTA 50 mM (pH 8,0). Chaque culot de produit de séquençage est repris dans 4 ul de ce mélange avant d'être déposé sur le gel de migration. A deposition buffer is prepared by mixing 5 μl of deionized formamide and 1 μl of 50 mM EDTA (pH 8.0). Each pellet of sequencing product is taken up in 4 μl of this mixture before being deposited on the migration gel.
- séparation des produits de séquençage par migration électrophorétique. separation of the sequencing products by electrophoretic migration.
Un gel de polyacrylamide à 4,75 % est préparé au moins 2 heures avant la migration afin d'obtenir une bonne polymérisation. A 4.75% polyacrylamide gel is prepared at least 2 hours before migration to obtain good polymerization.
Pour 80 ml de gel, 40 g d'urée sont dissous dans environ 27 ml d'eau ultrapure auxquels sont ajoutés 1 g de résine et 9,5 ml d'une solution stock d'acrylamide à 40 % (38 g d'acrylamide et 2 g de bis-acrylamide dans qsp 100 ml d'eau). For 80 ml of gel, 40 g of urea are dissolved in about 27 ml of ultrapure water to which 1 g of resin and 9.5 ml of a 40% acrylamide stock solution (38 g of acrylamide) are added. and 2 g of bis-acrylamide in qs 100 ml of water).
Le mélange est agité pendant 5 minutes, puis filtré et dégazé.The mixture is stirred for 5 minutes, then filtered and degassed.
8 ml d'une solution stock de Tris Borate EDTA 10X (108g de Tris base, 55 g de borate et 8,3 g d'EDTA pour 1 litre) sont ajoutés et le volume final est porté à 80 ml avec de l'eau. Le gel, d'une épaisseur de 0,4 mm, est coulé entre 2 plaques de verre après l'addition des catalyseurs : Temed (45 ul), Temed = N, N,
N', N'- tétraméthyléthylènediamine et ammonium peroxydisulfate à 0,lg/ml (400 l). La face interne des plaques est préalablement nettoyée grâce à un détergent, puis rincée plusieurs fois à niveau distillée et séchée. 8 ml of a stock solution of Tris Borate EDTA 10X (108 g of Tris base, 55 g of borate and 8.3 g of EDTA per liter) are added and the final volume is brought to 80 ml with water . The gel, having a thickness of 0.4 mm, is cast between 2 glass plates after the addition of the catalysts: Temed (45 μl), Temed = N, N,
N, N'-tetramethylethylenediamine and ammonium peroxydisulfate at 0.1 g / ml (400 l). The inner side of the plates is cleaned with detergent, then rinsed several times at distilled level and dried.
Après polymérisation du gel, les plaques de verre sont nettoyées extérieurement de la même manière que précédemment et leur propreté est rif;ée directement dans la cuve à électrophorèse du séquenceur par le laser. Une fois les plaques bien propres, le gel peut être placé dans la cuve et le tampon de migration ajouté (TBE lX). Une pré-migration est ensuite effectuée pendant 15 minutes afin de préchauffer le gel avant le dépôt des échantillons. After polymerization of the gel, the glass plates are cleaned externally in the same manner as before and their cleanliness is rifled directly into the electrophoresis tank of the sequencer by the laser. Once the plates are clean, the gel can be placed in the vessel and the added migration buffer (TBE 1X). Pre-migration is then performed for 15 minutes to preheat the gel prior to sample deposition.
Les échantillons sont déposés en haut du gel après une dénaturation de 2 minutes à 90"C et la migration est lancée en même temps que la collection des données par le programme informatique. The samples are deposited at the top of the gel after a denaturation of 2 minutes at 90 ° C and the migration is started at the same time as the data collection by the computer program.
Les produits purifiés et séparés sont ensuite clonés selon les techniques classiques, puis séquencés. The purified and separated products are then cloned according to standard techniques, then sequenced.
Le séquençage des acides nucléiques a été réalisé sur des ADN double brin à l'aide d'un séquenceur à ADN automatisé (ABI). Nucleic acid sequencing was performed on double-stranded DNA using an automated DNA sequencer (ABI).
- séquences : Après séquençage, la déduction de la séquence en acides aminés suivant le code génétique a permis d'identifier les 3 régions de CDR sur la chaîne lourde et les 3 régions de CDR sur la chaîne légère, chez chaque anticorps monoclonal. Sequences: After sequencing, the deduction of the amino acid sequence according to the genetic code made it possible to identify the 3 CDR regions on the heavy chain and the 3 CDR regions on the light chain, in each monoclonal antibody.
Chacune des régions CDR est identifiée par homologie avec les séquences d'immunoglobulines déjà publiées. Each of the CDR regions is identified by homology with previously published immunoglobulin sequences.
L'ensemble de ces séquences est rapporté dans la liste de séquences en fin de description. All of these sequences are reported in the sequence list at the end of the description.
De plus, on a représenté sur la figure 2, la séquence en acides aminés, selonle code à 1 lettre, des VH et V pour RS-348, RS-18B2, RS-2B8 et RS-255. Les CDR sont indiqués et soulignés et sont donnés sur la figure 3. In addition, FIG. 2 shows the amino acid sequence, according to the 1-letter code, of the VH and V for RS-348, RS-18B2, RS-2B8 and RS-255. The CDRs are indicated and underlined and are given in Figure 3.
De plus, les chaînes V et V 138 et 133 sont données, selon le code à 1 lettre, sur la figure 4. In addition, the V and V chains 138 and 133 are given, according to the 1-letter code, in FIG. 4.
Pour l'anticorps monoclonal RS-348, les séquences en acides aminés des CDR 1,2,3 de chaîne lourde sont référencées, respectivement, sous SEQ ID n01,2,3, et celles des CDR 1,2,3 de chaîne légère sous SEQ ID n04,5,6. For the RS-348 monoclonal antibody, the amino acid sequences of the heavy chain CDRs 1,2,3 are referenced, respectively, under SEQ ID No. 1,2,3,3, and those of the light chain 1,2,3 CDRs. under SEQ ID NO: 4,5,6.
Pour l'anticorps monoclonal RV-138, les séquences en acides aminés des CDR 1,2,3 de chaîne lourde sont référencées, respectivement, sous SEQ ID ne13,14,15 et celles des CDR 1,2,3 de chaîne légère sous SEQ ID n"16,17,18. For the monoclonal antibody RV-138, the amino acid sequences of the heavy chain 1,2,3 CDRs are referenced, respectively, under SEQ ID ne13,14,15 and those of the light chain 1,2,3 CDRs. SEQ ID NO: 16,17,18.
Pour l'anticorps monoclonal RV-133, les séquences en acides aminés des CDR 1,2,3 de chaîne lourde sont référencées, respectivement, sous SEQ ID n019,20,21 et celles des CDR 1,2,3 de chaîne légère sous SEQ ID n"22,23,24. For the monoclonal antibody RV-133, the amino acid sequences of the heavy chain CDRs 1,2,3 are referenced, respectively, under SEQ ID No. 19,20,21 and those of the light chain 1,2,3 CDRs. SEQ ID NO: 22,23,24.
Pour l'anticorps monoclonal RS-18B2, les séquence protégés, sur une résine polystyrène (PEG-PS). For the RS-18B2 monoclonal antibody, the protected sequences, on a polystyrene resin (PEG-PS).
L'acylation a été réalisée dans du DMF anhydre en utilisant des esters activés de chaque acide aminé (Dhbt pour Thr et Ser, Pfp pour les autres avec de l'l-hydroxybenzotriazole (HOBt) ou de l'l-hydroxy 7-azabenzotriazole (HOAt) comme réactifs de couplage. De la pipéridine à 20, dans du DMF a été utilisée pour les étapes de déprotection en Nα. The acylation was carried out in anhydrous DMF using activated esters of each amino acid (Dhbt for Thr and Ser, Pfp for the others with 1-hydroxybenzotriazole (HOBt) or 1-hydroxy 7-azabenzotriazole (HOAt) as coupling reagents Piperidine at 20 in DMF was used for the N & alpha deprotection steps.
En fin de synthèse, les chaînes latérales peptidiques ont été déprotégées et extraites de la phase solide par clivage à l'acide trifluoroacétique avec le réactif dérivé de King pendant 2 heures, en l'absence de lumière et d'oxygène. Les groupements thiol des cystéines C- et N-terminales étaient ainsi libres de leurs groupements trityl protecteurs et ont donc pu former des ponts disulfure pour la cyclisation peptidique. At the end of the synthesis, the peptide side chains were deprotected and extracted from the solid phase by cleavage with trifluoroacetic acid with the reagent derived from King for 2 hours, in the absence of light and oxygen. The thiol groups of the C- and N-terminal cysteines were thus free of their protective trityl groups and thus could form disulfide bridges for peptide cyclization.
Les peptides ont alors été récupérés par précipitation dans de l'éther d'éthyle froid, centrifugations et lavages répétés dans de l'éther. Les précipités ont été remis en suspension dans de l'eau distillée. The peptides were then recovered by precipitation in cold ethyl ether, centrifugation and repeated washing in ether. The precipitates were resuspended in distilled water.
La forme cyclique des peptides a été obtenue par oxydation spontanée des groupements Cys thiol : un aliquot de 25 umole (lmg/ml) déprotoné par NaOH (pH final = 8 à 8,5) a été maintenu une nuit durant sous forte agitation. The cyclic form of the peptides was obtained by spontaneous oxidation of Cys thiol groups: a 25 μmol aliquot (lmg / ml) deprotonated with NaOH (final pH = 8 to 8.5) was maintained overnight with vigorous stirring.
La forme linéaire des peptides a été obtenue en maintenant la protonation (pH = 5,5 à 6,5) et, en cas d'insolubilisation, par mélange avec du PBS dégazé (pH = 7,4) sous bullage d'azote de manière à empêcher la cyclisation. The linear form of the peptides was obtained by maintaining the protonation (pH = 5.5 to 6.5) and, in case of insolubilization, by mixing with degassed PBS (pH = 7.4) under nitrogen bubbling. to prevent cyclization.
Les solutions de peptides sont ensuite rapidement congelées. Peptide solutions are then rapidly frozen.
Les séquences des peptides synthétisés homologues des 6 CDRs de l'anticorps monoclonal RS-348 sont rapportées dans le listing de séquences joint. The sequences of the synthesized peptides homologous to the 6 CDRs of the RS-348 monoclonal antibody are reported in the attached sequence listing.
Les séquences référencées sous SEQ ID ne7,8,9 représentent, respectivement, les séquences des peptides PEP1H348, PEP2H348, PEP3H348, c'est-à-dire les séquences des peptides synthétiques construits par homologie avec les CDR 1,2,3, respectivement, de la chaîne lourde de RS-348. The sequences referenced under SEQ ID No. 7,8,9 represent, respectively, the sequences of the peptides PEP1H348, PEP2H348, PEP3H348, that is to say the sequences of the synthetic peptides constructed by homology with the CDRs 1,2,3, respectively , of the RS-348 heavy chain.
Les séquences référencées sous SEQ ID ne10,11,12 représentent, respectivement, les séquences des peptides PEP1L348, PEP2L348, PEP3L348, c'est-à-dire les séquences des peptides synthétiques construits par homologie avec les CDR 1,2,3, respectivement, de la chaîne légère de RS-348. The sequences referenced under SEQ ID No. 10,11,12 represent, respectively, the sequences of the peptides PEP1L348, PEP2L348, PEP3L348, that is to say the sequences of the synthetic peptides constructed by homology with the 1,2,3 CDRs, respectively , of the RS-348 light chain.
De plus, on a représenté sur la figure 5, les séquences de ces peptides synthétiques selon le code à 1 lettre. In addition, FIGS. 5 show the sequences of these synthetic peptides according to the 1-letter code.
Exemple 4: Etude des propriétés fonctionnelles immunologiques des peptides de l'exemple 3
- activité de neutralisation
Des tests de neutralisation de VRS de souche Long
(sous-groupe A) ont été réalisés par mesure de réduction de plaques.Example 4 Study of the Immunological Functional Properties of the Peptides of Example 3
- neutralization activity
Long-term strain RSV neutralization tests
(subgroup A) were made by plate reduction measure.
5 x 10 pfu/ml de virus ont été mélangées pendant 1h à 37"C avec une dilution en série des peptides (de 15 ug à 0,875 ug) sous la forme cyclique ou linéaire. 5 x 10 pfu / ml of virus were mixed for 1h at 37 ° C with serial dilution of the peptides (15 μg to 0.875 μg) in cyclic or linear form.
Des monocouches de cellules Hep-2 sur plaques à 6 puits ont alors été infectées. Hep-2 cell monolayers on 6-well plates were then infected.
La neutralisation a été mesurée, pour chaque concentration en peptides testée, lorsqu'une réduction de plaques de 50% est observée et est exprimée en logi0 moyen par quantité de peptides. Neutralization was measured for each peptide concentration tested when a 50% plaque reduction was observed and was expressed as mean log per peptide count.
Aucune toxicité des peptides synthétiques n' a été détectée. L'activité neutralisante apparaît particulièrement élevée avec le peptide SEQ ID n0 9. Celle-ci s'observe que le peptide soit présenté sous forme cyclique ou linéaire. Le peptide linéaire a, cependant, une activité neutralisante dans une plus large gamme de concentrations. No toxicity of the synthetic peptides was detected. The neutralizing activity appears particularly high with the peptide SEQ ID No. 9. This is observed that the peptide is presented in cyclic or linear form. The linear peptide, however, has a neutralizing activity in a wider range of concentrations.
Les résultats obtenus avec le peptide sont rapportés sur la figure 1 où le d'inhibition du pouvoir infectieux du virus est donné en ordonnée et la quantité de peptides est indiqué en abscisse,(--c- pour la forme cyclique du peptide, -IC}- pour la forme linéaire). The results obtained with the peptide are reported in FIG. 1 where the inhibition of the infectivity of the virus is given on the ordinate and the amount of peptides is indicated on the abscissa, (- c- for the cyclic form of the peptide, -IC } - for the linear form).
En revanche, l'étude de la capacité à neutraliser une souche de sous-groupe B montre qu'aucun des peptides SEQ ID n07 à 12 ne présente une forte activité neutralisante sur ce sousgroupe. Ces résultats indiquent que le peptide homologue au
CDR3 de la chaîne lourde de RS-348 (SEQ ID n09) est fortement neutralisant, qu'il porte de plus une spécificité de sousgroupe (A) et que la conformation imposée par la cyclisation n'influe pas sur la spécificité de cette activité.On the other hand, the study of the ability to neutralize a subgroup B strain shows that none of the peptides SEQ ID Nos. 07 to 12 show a strong neutralizing activity on this subgroup. These results indicate that the peptide homologous to
CDR3 of the RS-348 heavy chain (SEQ ID NO: 9) is strongly neutralizing, it further carries a subgroup specificity (A) and that the conformation imposed by the cyclization does not affect the specificity of this activity.
- Immunisation passive de souris (effet protecteur). - Passive immunization of mice (protective effect).
Une préparation de peptides, d'anticorps monoclonal, ou de PBS (témoin), a été administrée par voie nasale à des lots de 10 souris Balb/c. Les animaux ont été infectés 4 heures plus tard intranasalement avec la souche Long du virus respiratoire syncytial diluée dans du milieu BME. A preparation of peptides, monoclonal antibody, or PBS (control), was administered nasally to batches of 10 Balb / c mice. The animals were infected 4 hours later intranasally with Long strain of respiratory syncytial virus diluted in BME medium.
Cinq jours après exposition au VRS, les poumons de chaque souris ont été homogénéisés et le taux d'infection par
VRS mesuré en unités formant plaque (pfu). Five days after exposure to RSV, the lungs of each mouse were homogenized and the infection rate
VRS measured in plaque forming units (pfu).
Les résultats indiquent que la protection par l'immunisation passive est totale avec l'anticorps RS-348 et nulle avec le PBS témoin. The results indicate that protection by passive immunization is complete with the RS-348 antibody and zero with the control PBS.
Un pouvoir protecteur important a été observé avec les peptides synthétiques homologues des CDRs de RS-348 (SEQ
ID n"7 à 12), tout particulièrement avec PEP3H, le peptide synthétique homologue du CDR3 de la chaîne lourde de l'anticorps RS-348(SEQ ID n09), comme indiqué sur le tableau ci-dessous:
ID Nos. 7 to 12), most particularly with PEP3H, the synthetic peptide homologous to the RS-348 heavy chain CDR3 (SEQ ID NO: 9), as shown in the table below:
<tb> Molécule <SEP> testée <SEP> Diminution <SEP> du <SEP> titre <SEP> en <SEP> virus
<tb> <SEP> dans <SEP> les <SEP> poumons <SEP> de <SEP> souris
<tb> RS-348 <SEP> > <SEP> 1,5 <SEP>
<tb> (dilué <SEP> au <SEP> 1/25 <SEP> dans <SEP> fluide <SEP> ascitique)
<tb> PEP3H <SEP> (0ug/souris) <SEP> 0,22
<tb> PEP3H <SEP> (140 <SEP> ug/souris) <SEP> 1,02
<tb> <SEP> cyclique
<tb>
Dans ce tableau, la diminution du titre en virus dans les poumons de souris a été calculée de la manière suivante:
(logio moyen des pfu par gramme de tissus de poumons de souris témoins) - (logo moyen des pfu par gramme de tissus de poumons de souris ayant reçu une dose de molécules à tester) . Les titres moyens en virus sont statistiquement différents de ceux des souris témoins.<tb> Molecule <SEP> tested <SEP> Decrease <SEP> of <SEP> titre <SEP> in <SEP> virus
<tb><SEP> in <SEP> the <SEP> lungs <SEP> of <SEP> mice
<tb> RS-348 <SEP>><SEP> 1.5 <SEP>
<tb> (diluted <SEP> at <SEP> 1/25 <SEP> in <SEP> fluid <SEP> ascitic)
<tb> PEP3H <SEP> (0ug / mouse) <SEP> 0.22
<tb> PEP3H <SEP> (140 <SEQ> ug / mouse) <SEP> 1.02
<tb><SEP> cyclic
<Tb>
In this table, the decrease in virus titre in mouse lungs was calculated as follows:
(mean log 10 pfu per gram of control mouse lung tissues) - (mean pfu logo per gram of mouse lung tissues that received a dose of test molecules). Mean virus titers are statistically different from control mice.
Exemple 5: Tests thérapeutiques chez les souris
Six lots de chacun 10 souris femelles BALB/c âgées de 10 semaines ont été utilisés. Chaque animal pesait environ 20g.Example 5: Therapeutic tests in mice
Six batches of each 10 week old female BALB / c mice were used. Each animal weighed about 20g.
Chacune des souris a été inoculée intranasalement avec 108 pfu de VRS souche Long dilué dans du milieu BME. Each of the mice was inoculated intranasally with 108 pfu of long strain RSV diluted in BME medium.
Deux jours plus tard, chacune des souris a ensuite subi l'un des traitements suivants:
- aucun traitement: témoin expérimental,
- inoculation intranasale de PBS :témoin inoculation,
- inoculation intranasale de PEP3H (peptide homologue au CDR3 de la chaîne lourde de RS-348, (SEQ ID n09 ) sous forme linéaire à raison de 70ug par souris, ou
- inoculation intranasale de PEP3H (SEQ ID n09) sous forme linéaire à raison de 140ug par souris,
- inoculation intranasale de PEP3H (SEQ ID n09) sous forme cyclique à raison de 70ug par souris, ou
- inoculation intranasale de PEP3H (SEQ ID n09) sous forme cyclique à raison de l40ug par souris.Two days later, each of the mice then underwent one of the following treatments:
- no treatment: experimental control,
- intranasal inoculation of PBS: inoculation control,
intranasal inoculation of PEP3H (peptide homologous to the CDR3 of the RS-348 heavy chain, (SEQ ID No. 9) in linear form at the rate of 70 μg per mouse, or
intranasal inoculation of PEP3H (SEQ ID No. 9) in linear form at the rate of 140 μg per mouse,
intranasal inoculation of PEP3H (SEQ ID NO: 9) in cyclic form at the rate of 70 μg per mouse, or
intranasal inoculation of PEP3H (SEQ ID NO: 9) in cyclic form at a rate of 140 μg per mouse.
Toutes les inoculations ont été réalisées sous anesthésie à la kétamine/xylamine. All inoculations were performed under ketamine / xylamine anesthesia.
Un jour plus tard, toutes les souris ont été sacrifiées et leurs poumons récoltés. La concentration en RSV des homogénats de poumons a été mesurée par test sur plaque avec des cellules Hep-2 et par coloration au rouge neutre. One day later, all the mice were sacrificed and their lungs harvested. The RSV concentration of the lung homogenates was measured by plaque assay with Hep-2 cells and by neutral red staining.
La diminution moyenne des concentrations en RSV mesurées pour chacun des traitements thérapeutiques testés a été calculée de la manière suivante : (logo moyen des pfu par gramme de tissus de poumons de souris témoins expérimentaux)
(long10 moyen des pfu par gramme de tissus de poumons des souris ayant subi le traitement testé). The mean decrease in RSV concentrations measured for each of the therapeutic treatments tested was calculated as follows: (average pfu logo per gram of lung tissues from experimental control mice)
(average pfu per gram of lung tissue of the mice undergoing the tested treatment).
LISTE DE SEQUENCES (1) INFORMATIONS GENEPALES: (1) DEPOSkIT:
(A) NON: Universite de Bourgogne
(B) RUE: Esplanade Erasme
(C) VILLE: DIJON
(E) PAYS: FRANGE
(F) CODE POSTAL: 21000
(G) TELEPHONE: 03 80 39 50 00
(ii) TITRE DE L'INVENTION: Nouveaux moyens pour le diagnostic, la prévention et le traitement vis-à-vis de contaminations ou d'infections par des virus à tropisme muqueux.SEQUENCE LIST (1) GENEPAL INFORMATION: (1) DEPOSkIT:
(A) NO: University of Burgundy
(B) STREET: Esplanade Erasmus
(C) CITY: DIJON
(E) COUNTRIES: FRINGE
(F) POSTAL CODE: 21000
(G) TELEPHONE: 03 80 39 50 00
(ii) TITLE OF THE INVENTION: New means for the diagnosis, prevention and treatment of infections or infections with viruses with mucous tropism.
(iii) NOMBRE DE SEQUENCES: 42
(iv) FORME DECHIFFRABLE PAR ORDINATEUR:
(A) TYPE DE SUPPORT: Floppy disk
(B) ORDINATEUR: IBM PC compatible
(C) SYSTEME D' EXPLOITATION: PC-DOS/MS-DOS
(D) LOGICIEL: PatentIn Release #1.0, Version #1.30 (OEB) (2) INFORMATIONS POUR LA SEQ ID NO: 1:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 5 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR1H348
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 1:
Asn Tyr Ala Val His
1 5
(3) INFORMATIONS POUR LA SEQ ID NO: 2:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 16 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR2H348
(i) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 2:
Val lie Trp Ala G1ï Gly Gly Thr Leu Tyr Lys Ser Ala Leu Met Pro
i 5 10 15
(4) INFORMATIONS POUR LA SEQ ID NO: 3:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 14 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR3H348
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 3:
Asp Pro Asp Tyr Tyr Asp Asn Tyr Phe Tyr Ala Met Asp Tyr
1 5 10 (5) INFORMATIONS POUR LA SEQ ID NO: 4:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 17 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR1L348
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 4:
Lys Ser Ser Gln Ser Leu Phe Asn Thr Arg Thr Arg Lys Asn Tyr
1 5 10 15
Leu Ala (6) INFORMATIONS POUR LA SEQ ID NO: 5:
(i) CAPACTEPISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 7 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR2L348
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 5:
Trp Ma Ser Thr Arg Asp Ser
1 5 (7) INFORMATIONS POUR LA SEQ ID NO: 6:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 8 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR3L348
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 6:
Lys Gln Ser Tyr Asn Leu Phe Thr
1 5 (8) INFORMATIONS POUR LA SEQ ID NO: 7:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 14 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(vii) SOURCE IMMEDIATE:
(B) CLONE: PEP1H348
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 7:
Cys Gly Phe Ser Leu Thr Asn Tyr Ala Val His Trp Val Cys
1 5 10 (9) INFORMATIONS POUR LA SEQ ID NO: 8:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 19 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(vii) SOURCE IMMEDIATE:
(B) CLONE: PEP2H348
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 8:
Cys Val Ile Trp Ala Gly Gly Gly Thr Leu Tyr Lys Ser Ala Leu Met
1 5 10 15
Pro Arg Cys (10) INFORMATIONS POUR LA SEQ ID NO: 9:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 23 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(vii) SOURCE IMMEDIATE:
(B) CLONE: PEP3H348
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 9:
Cys Ala Arg Asp Pro Asp Tyr Tyr Asp Asn Tyr Phe Tyr Ala Met Asp
l 5 10 15
Tyr Trp G1ï Pro Gly Thr Cys
20 (11) INFORMATIONS POUR LA SEQ ID NO: 10:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 17 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(vii) SOURCE IMMEDIATE:
(B) CLONE: PEP1L348
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 10:
Cys Lys Ser Ser Gln Ser Leu Phe Asn Thr Arg Lys Asn Tyr Leu Ala
1 5 10 15
Cys (12) INFORMATIONS POUR LA SEQ ID NO: 11:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 19 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(vii) SOURCE IMMEDIATE:
(B) CLONE: PEP2L348
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 11:
Cys Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Asp Ser Gly Pro Asp
1 5 10 15
Arg Phe Cys (13) INFORMATIONS POUR LA SEQ ID NO: 12:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 18 acides amines
(B) TYPE: acide amine
(Cj NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ji) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(vii) SOURCE IMMEDIATE:
(B) CLONE: PEP3L348
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 12:
Cys Tyr Tyr Lys Gln Ser Tyr Asn Leu Phe Thr Phe Gly Ser Gly Thr
1 5 10 15
Lys Cys (14) INFORMATIONS POUR LA SEQ ID NO: 13:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 5 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDRlHl38
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 13:
Ser His Trp Ile Glu
1 5 (15) INFORMATIONS POUR LA SEQ ID NO: 14:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 17 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
v) TYPE DE FRAGMENT: interne
(Vil) SOURCE IMMEDIATE:
(B) CLONE: CDR2Hl38
(1) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 14:
Glu Ile Phe Pro Gly Arg Ile Ile Thr Asn Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly (16) INFORMATIONS POUR LA SEQ ID NO: 15:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 8 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR3H138
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 15:
Glu Gly Ala Tyr Gly Asn His Val
1 5 (17) INFORMATIONS POUR LA SEQ ID NO: 16:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 16 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDRlLl38
(i) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: ló:
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Ala Thr Tyr Leu Glu
1 5 10 15
(18) INFORMATIONS POUR LA SEQ ID NO: 17:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 7 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR2L138
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 17:
Lys Val Ser Asn Arg Phe Ser
1 5
(19) INFORMATIONS POUR LA SEQ ID NO: 18:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 8 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR3L138
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 18:
Phe Gln Gly Ser His Val Pro Arg Thr
1 5 (20) INFORMATIONS POUR LA SEQ ID NO: 19:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 5 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDRlHl33
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 19:
Ser Tyr Trp Ile His
1 5 (21) INFORMATIONS POUR LA SEQ ID NO: 20:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 17 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR2H133
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 20:
Ile Ile Tyr Pro Gly Ser Gly Gly Thr His Tyr Asp Glu Lys Phe Phe
1 5 10 15
Thr (22) INFORMATIONS POUR LA SEQ ID NO: 21:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 13 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE LE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(Bj CLONE: CDR3H133
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 21:
Ser Tyr Arg Asn Asp Asp Gly Tyr Tyr Ala Met Asp Tyr
1 5 10
(23) INFORMATIONS POUR LA SEQ ID NO: 22:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 16 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDRlLl33
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 22:
Ser Ser Ser Gln Ser Leu Val His Arg Asp Gly Asn Thr Tyr Leu His
1 5 10 15 (24) INFORMATIONS POUR LA SEQ ID NO: 23:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 7 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR2L133
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 23:
Lys Val Ser Asn Arg Phe Ser
1 5 (25) INFORMATIONS POUR LA SEQ ID NO: 24:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 9 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR3L133
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 24:
Ser Gln Ser Thr His Val Pro Leu Thr
1 5 (26) INFORMATIONS POUR LA SEQ ID NO: 25:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 5 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDRlH18B2
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 25:
Asn Tyr Ala Val His
1 5 (27) INFORMATIONS POUR LA SEQ ID NO: 26:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 16 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR2H18B2
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 26:
Val Ile Trp Ala Gly Gly Gly Thr Leu Tyr Lys Ser Ala Leu Met
1 5 10 15
Pro (28) INFORMATIONS POUR LA SEQ ID NO: 27:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 14 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR3H18B2
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 27:
Asp Pro Asp Tyr Tyr Asp Asn Tyr Phe Tyr Ala Met Asp Tyr
1 5 10 (29) INFORMATIONS POUR LA SEQ ID NO: 28:
(i) CARACTERISTIQUES DE LA SEQUENCE:
A LONGUEUR: 17 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDRlL18B2
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 28:
Ser Ala Arg Ser Ser Val Xaa Xaa Xaa Xaa Xaa Xaa Xaa Pro Tyr Met
1 5 10 15
His (30) INFORMATIONS POUR LA SEQ ID NO: 29:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 7 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR2L18B2
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 29:
Asp Thr Phe Lys Leu Ala Ser
1 5 (31) INFORMATIONS POUR LA SEQ ID NO: 30:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 9 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR3L18B2
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 30:
Phe Gln Gly Ser Glu Phe Pro His Thr
l 5 (32) INFORMATIONS POUR LA SEQ ID NO: 31:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 5 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR1H2B8
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 31:
Ser Tyr Asp Ile Ser
1 5 (33) INFORMATIONS POUR LA SEQ ID NO: 32:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 16 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR2H2B8
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 32:
Val Ile Trp Thr Gly Gly Gly Thr Try Try Asn Ser Ala Phe
1 5 10
Met Ser
15 (34) INFORMATIONS POUR LA SEQ ID NO: 33:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 9 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR3H2B8
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 33:
Arg Thr Gly Thr Gly Pro Phe Ala Tyr
1 5 (35) INFORMATIONS POUR LA SEQ ID NO: 34:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 17 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDRlL2B8
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 34:
Arg Ala Ser Lys Ser Val Ser Thr Ser Gly Tyr Ser Xaa Xaa Tyr
1 5 10 15
Met His (36) INFORMATIONS POUR LA SEQ ID NO: 35:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 7 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR2L2B8
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 35:
Leu Val Cys Asp Leu Glu Ser
1 5 (37) INFORMATIONS POUR LA SEQ ID NO: 36:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 8 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR3L2B8
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 36:
Gln His Ile Arg Gln Pro Tyr Thr
1 5 (38) INFORMATIONS POUR LA SEQ ID NO: 37:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 5 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR1H255
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 37:
Ser Phe Gly Met His
1 5 (39) INFORMATIONS POUR LA SEQ ID NO: 38:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 17 acides amines
(B TYPE: acide amine
(C) NOMBRE DE BRINS:
)D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR2H255
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 38:
Tyr Ile Ser Ser Gly Ser Ser Thr Ile Tyr Tyr Ala Asp Thr Val
1 5 10 15
Lys Gly (40) INFORMATIONS POUR LA SEQ ID NO: 39:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 9 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR3H255
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 39:
Ser Arg Leu Arg Thr Val Met Asp Tyr
1 5 (41) INFORMATIONS POUR LA SEQ ID NO: 40:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 17 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDRlL255
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 40:
Arg Ala Ser Gln Pro Asp Ile Gly Ser Ser Leu Asn Xaa Xaa Xaa
1 5 10 15
Xaa Xaa (42) INFORMATIONS POUR LA SEQ ID NO: 41:
(i) CARACTERISTIQUES DE LA SEQUENCE:
(A) LONGUEUR: 7 acides amines
(B) TYPE: acide amine
(C) NOMBRE DE BRINS:
(D) CONFIGURATION: des deux
(ii) TYPE DE MOLECULE: peptide
(iii) HYPOTHETIQUE: NON
(iv) ANTI-SENS: NON
(v) TYPE DE FRAGMENT: interne
(vii) SOURCE IMMEDIATE:
(B) CLONE: CDR2L255
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 41:
Ala Thr Ser Ser Leu Asp Ser
(xi) DESCRIPTION DE LA SEQUENCE: SEQ ID NO: 42:
Leu Gln Tyr Ala Ser Ser Pro The Thr
1 5 (iii) NUMBER OF SEQUENCES: 42
(iv) COMPUTER-DEPENDABLE FORM:
(A) SUPPORT TYPE: Floppy disk
(B) COMPUTER: IBM PC compatible
(C) OPERATING SYSTEM: PC-DOS / MS-DOS
(D) SOFTWARE: PatentIn Release # 1.0, Version # 1.30 (EPO) (2) INFORMATION FOR SEQ ID NO: 1:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 5 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR1H348
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 1:
Asn Tyr Ala Val His
1 5
(3) INFORMATION FOR SEQ ID NO: 2:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 16 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR2H348
(i) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 2:
Val lie Trp Ala G1i Gly Gly Thr Leu Tyr Ser Lys Ser Ala Leu Met Pro
i 5 10 15
(4) INFORMATION FOR SEQ ID NO: 3:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 14 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR3H348
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 3:
Asp Asp Asp Asp Asp Asp Asp Tyr Tyr Phe Tyr Asp Asp Asp
(5) INFORMATION FOR SEQ ID NO: 4:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 17 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR1L348
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 4:
Ser Ser Ser Gln Ser Leu Phe Asn Thr Arg Arg Arg Lys Asn Tyr
1 5 10 15
Leu Ala (6) INFORMATION FOR SEQ ID NO: 5:
(i) CAPACTEPISTICS OF THE SEQUENCE:
(A) LENGTH: 7 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR2L348
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 5:
Trp My Ser Thr Asp Arg Asp Ser
(7) INFORMATION FOR SEQ ID NO: 6:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 8 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR3L348
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 6:
Lys Gln Tyr Ser Asn Leu Phe Thr
1 (8) INFORMATION FOR SEQ ID NO: 7:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 14 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(vii) IMMEDIATE SOURCE:
(B) CLONE: PEP1H348
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 7:
Cys Gly Phe Ser Leu Thr Asn Tire Ala Val His Trp Val Cys
(9) INFORMATION FOR SEQ ID NO: 8:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 19 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(vii) IMMEDIATE SOURCE:
(B) CLONE: PEP2H348
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 8:
Cys Val Ile Trp Ala Gly Gly Gly Thr Leu Tyr Lys Ser Ala Leu Met
1 5 10 15
Pro Arg Cys (10) INFORMATION FOR SEQ ID NO: 9:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 23 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(vii) IMMEDIATE SOURCE:
(B) CLONE: PEP3H348
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 9:
Cys Ala Asp Asp Asp Asp Asp Tyr Asp Asp Tyr Tyr Asp Ala Asp Asp
l 5 10 15
Tyr Trp G1i Pro Gly Thr Cys
(11) INFORMATION FOR SEQ ID NO: 10:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 17 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(vii) IMMEDIATE SOURCE:
(B) CLONE: PEP1L348
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 10:
Cys Lys Ser Ser Gln Ser Leu Phe Asn Thr Arg Lys Asn Tyr Leu Ala
1 5 10 15
Cys (12) INFORMATION FOR SEQ ID NO: 11:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 19 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(vii) IMMEDIATE SOURCE:
(B) CLONE: PEP2L348
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 11:
Cys Lys Leu Leu Tyr Island Trp Ala Ser Thr Asp Asp Ser Gly Asp Asp
1 5 10 15
Arg Phe Cys (13) INFORMATION FOR SEQ ID NO: 12:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 18 amino acids
(B) TYPE: Amino acid
(Cj NUMBER OF BRINS:
(D) CONFIGURATION: of the two
(ji) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(vii) IMMEDIATE SOURCE:
(B) CLONE: PEP3L348
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 12:
Cys Tyr Tire Tyr Lys Gln Ser Tire Asn Leu Phe Thr Phe Gly Ser Gly Thr
1 5 10 15
Lys Cys (14) INFORMATION FOR SEQ ID NO: 13:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 5 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDRlHl38
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 13:
Ser His Trp Glu Island
(5) INFORMATION FOR SEQ ID NO: 14:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 17 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
v) TYPE OF FRAGMENT: internal
(Vil) IMMEDIATE SOURCE:
(B) CLONE: CDR2Hl38
(1) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 14:
Glu Isle Phe Pro Gly Arg Island Thr Island Tyr Asn Asn Glu Lys Phe Lys
1 5 10 15
Gly (16) INFORMATION FOR SEQ ID NO: 15:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 8 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR3H138
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 15:
Glu Gly Ala Gly Asn His Val
1 5 (17) INFORMATION FOR SEQ ID NO: 16:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 16 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDRlLl38
(i) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: ló:
Ser Ser Ser Gln Ser Val Her Ser Asn Gly Ala Thr Tyr Leu Glu
1 5 10 15
(18) INFORMATION FOR SEQ ID NO: 17:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 7 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR2L138
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 17:
Lys Val Ser Asn Arg Phe Ser
1 5
(19) INFORMATION FOR SEQ ID NO: 18:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 8 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR3L138
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 18:
Phe Gln Gly Ser His Val Pro Arg Thr
(5) INFORMATION FOR SEQ ID NO: 19:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 5 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDRlHl33
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 19:
Ser Tyr Trp Island His
(5) INFORMATION FOR SEQ ID NO: 20:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 17 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR2H133
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 20:
Island Tire Island Pro Gly Ser Gly Gly Thr His Tyr Asp Asp Glu Lys Phe Phe
1 5 10 15
Thr (22) INFORMATION FOR SEQ ID NO: 21:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 13 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) TYPE THE FRAGMENT: internal
(vii) IMMEDIATE SOURCE:
(Bj CLONE: CDR3H133
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 21:
Ser Tyr Arg Asp Asn Asp Asp Gly Tire Tyr Asp Ala Asp Tyr
1 5 10
(23) INFORMATION FOR SEQ ID NO: 22:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 16 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDRlLl33
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 22:
Ser Ser Ser Gln Ser Leu Val His Arg Asp As Gly Asn Thr Tyr Leu His
(24) INFORMATION FOR SEQ ID NO: 23:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 7 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR2L133
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 23:
Lys Val Ser Asn Arg Phe Ser
(25) INFORMATION FOR SEQ ID NO: 24:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 9 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR3L133
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 24:
Ser Gln Ser Thr His Val Pro Leu Thr
1 (26) INFORMATION FOR SEQ ID NO: 25:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 5 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDRlH18B2
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 25:
Asn Tyr Ala Val His
1 5 (27) INFORMATION FOR SEQ ID NO: 26:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 16 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR2H18B2
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 26:
Val Ile Trp Ala Gly Gly Gly Thr Leu Tyr Lys Ser Ala Leu Met
1 5 10 15
Pro (28) INFORMATION FOR SEQ ID NO: 27:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 14 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR3H18B2
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 27:
Asp Asp Asp Asp Asp Asp Asp Tyr Tyr Phe Tyr Asp Asp Asp
1 5 10 (29) INFORMATION FOR SEQ ID NO: 28:
(i) CHARACTERISTICS OF THE SEQUENCE:
LENGTH: 17 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDRlL18B2
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 28:
Ser Ala Arg Ser Ser Xaa Xaa Xaa Xaa Xaa Xaa Pro Tyr
1 5 10 15
His (30) INFORMATION FOR SEQ ID NO: 29:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 7 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR2L18B2
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 29:
Asp Thr Phe Lily Leu Ala Ser
1 (31) INFORMATION FOR SEQ ID NO: 30:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 9 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR3L18B2
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 30:
Phe Gln Gly Ser Phe Glu Pro His Thr
(5) INFORMATION FOR SEQ ID NO: 31:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 5 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR1H2B8
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 31:
Ser Tyr Asp Isle Ser
1 (33) INFORMATION FOR SEQ ID NO: 32:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 16 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR2H2B8
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 32:
Val Island Trp Thr Gly Gly Gly Thr Try Try Asn Ser Ala Phe
1 5 10
Met Ser
(34) INFORMATION FOR SEQ ID NO: 33:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 9 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR3H2B8
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 33:
Arg Thr Gly Thr Pro Gly Phe Ala Tyr
(35) INFORMATION FOR SEQ ID NO: 34:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 17 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDRlL2B8
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 34:
Arg Ala Ser Lys Ser Ser Ser Ser Ser Ser Gly Tyr Ser Xaa Xaa Tyr
1 5 10 15
Met His (36) INFORMATION FOR SEQ ID NO: 35:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 7 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR2L2B8
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 35:
Leu Val Cys Leu Asp Glu Ser
1 (37) INFORMATION FOR SEQ ID NO: 36:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 8 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR3L2B8
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 36:
Gln His Isle Arg Gln Pro Tyr Thr
1 (38) INFORMATION FOR SEQ ID NO: 37:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 5 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR1H255
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 37:
Ser Phe Gly Met His
1 (39) INFORMATION FOR SEQ ID NO: 38:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 17 amino acids
(B TYPE: amino acid
(C) NUMBER OF STRANDS:
) D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR2H255
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 38:
Tire Ser Ser Ser Gly Ser Ser Thr Tyr Tyr Island Ala Asp Thr Val
1 5 10 15
Lys Gly (40) INFORMATION FOR SEQ ID NO: 39:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 9 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR3H255
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 39:
Ser Arg Leu Arg Thr Val Met Asp Asp Tyr
1 (41) INFORMATION FOR SEQ ID NO: 40:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 17 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDRlL255
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 40:
Arg Ala Ser Asp Gln Pro Gly Ser Ser Ser Asn As Xaa Xaa Xaa
1 5 10 15
Xaa Xaa (42) INFORMATION FOR SEQ ID NO: 41:
(i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 7 amino acids
(B) TYPE: Amino acid
(C) NUMBER OF STRANDS:
(D) CONFIGURATION: of the two
(ii) TYPE OF MOLECULE: peptide
(iii) Hypothesis: No
(iv) ANTI-SENS: NO
(v) FRAGMENT TYPE: internal
(vii) IMMEDIATE SOURCE:
(B) CLONE: CDR2L255
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 41:
Ala Ser Ser Ser Ser Ser Ser Ser
(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 42:
Leu Gln Tyr Ser Ser Ser Pro The Thr
1 5
Claims (23)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9700300A FR2758331B1 (en) | 1997-01-14 | 1997-01-14 | NEW MEANS FOR DIAGNOSIS, PREVENTION AND TREATMENT FOR CONTAMINATION OR INFECTIONS WITH MUCOUS TROPISM VIRUSES |
| PCT/FR1997/002433 WO1998031807A1 (en) | 1997-01-14 | 1997-12-26 | Novel means for the diagnosis, prevention and treatment of contamination or infections by viruses with mucous tropism |
| EP97953956A EP0953050A1 (en) | 1997-01-14 | 1997-12-26 | Novel means for the diagnosis, prevention and treatment of contamination or infections by viruses with mucous tropism |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9700300A FR2758331B1 (en) | 1997-01-14 | 1997-01-14 | NEW MEANS FOR DIAGNOSIS, PREVENTION AND TREATMENT FOR CONTAMINATION OR INFECTIONS WITH MUCOUS TROPISM VIRUSES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2758331A1 true FR2758331A1 (en) | 1998-07-17 |
| FR2758331B1 FR2758331B1 (en) | 1999-03-05 |
Family
ID=9502577
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR9700300A Expired - Fee Related FR2758331B1 (en) | 1997-01-14 | 1997-01-14 | NEW MEANS FOR DIAGNOSIS, PREVENTION AND TREATMENT FOR CONTAMINATION OR INFECTIONS WITH MUCOUS TROPISM VIRUSES |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0953050A1 (en) |
| FR (1) | FR2758331B1 (en) |
| WO (1) | WO1998031807A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7132100B2 (en) | 2002-06-14 | 2006-11-07 | Medimmune, Inc. | Stabilized liquid anti-RSV antibody formulations |
| US7425618B2 (en) | 2002-06-14 | 2008-09-16 | Medimmune, Inc. | Stabilized anti-respiratory syncytial virus (RSV) antibody formulations |
| US8568726B2 (en) | 2009-10-06 | 2013-10-29 | Medimmune Limited | RSV specific binding molecule |
| US9321831B2 (en) | 2007-06-01 | 2016-04-26 | Medimmune Limited | RSV-specific binding molecules and means for producing them |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2349348T3 (en) | 2000-01-27 | 2010-12-30 | Medimmune, Llc | ULTRA HIGH AFFINITY RSV NEUTRALIZING ANTIBODIES. |
| CA2401652A1 (en) | 2000-03-01 | 2001-09-07 | Medimmune, Inc. | High potency recombinant antibodies and method for producing them |
| US7179900B2 (en) | 2000-11-28 | 2007-02-20 | Medimmune, Inc. | Methods of administering/dosing anti-RSV antibodies for prophylaxis and treatment |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1993020210A1 (en) * | 1992-04-06 | 1993-10-14 | Scotgen Limited | Antibodies for treatment and prevention of respiratory syncytial virus infection |
| WO1994006448A1 (en) * | 1992-09-16 | 1994-03-31 | The Scripps Research Institute | Human neutralizing monoclonal antibodies to respiratory syncytial virus |
| WO1995004081A1 (en) * | 1993-07-30 | 1995-02-09 | Oravax, Inc. | MONOCLONAL IgA ANTIBODY AGAINST RESPIRATORY SYNCYTIAL VIRUS |
| WO1996040252A1 (en) * | 1995-06-07 | 1996-12-19 | Idec Pharmaceuticals Corporation | High affinity human monoclonal antibodies specific for rsv f-protein |
-
1997
- 1997-01-14 FR FR9700300A patent/FR2758331B1/en not_active Expired - Fee Related
- 1997-12-26 WO PCT/FR1997/002433 patent/WO1998031807A1/en not_active Application Discontinuation
- 1997-12-26 EP EP97953956A patent/EP0953050A1/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993020210A1 (en) * | 1992-04-06 | 1993-10-14 | Scotgen Limited | Antibodies for treatment and prevention of respiratory syncytial virus infection |
| WO1994006448A1 (en) * | 1992-09-16 | 1994-03-31 | The Scripps Research Institute | Human neutralizing monoclonal antibodies to respiratory syncytial virus |
| WO1995004081A1 (en) * | 1993-07-30 | 1995-02-09 | Oravax, Inc. | MONOCLONAL IgA ANTIBODY AGAINST RESPIRATORY SYNCYTIAL VIRUS |
| WO1996040252A1 (en) * | 1995-06-07 | 1996-12-19 | Idec Pharmaceuticals Corporation | High affinity human monoclonal antibodies specific for rsv f-protein |
Non-Patent Citations (2)
| Title |
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| E. KOHLI ET AL.: "Epitope mapping of the major inner capsid protein of group A rotavirus using peptide synthesis.", VIROLOGY, vol. 194, no. 1, May 1993 (1993-05-01), SAN DIEGO, CA, ÉTATS-UNIS, pages 110 - 116, XP002042517 * |
| G. LOUNSBACH ET AL.: "Binding of neutralizing monoclonal antibodies to regions of the fusion protein of respiratory syncytial virus expressed in Escherichia coli.", JOURNAL OF GENERAL VIROLOGY, vol. 74, no. 12, December 1993 (1993-12-01), LONDON, GRANDE BRETAGNE, pages 2559 - 2565, XP002042518 * |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7132100B2 (en) | 2002-06-14 | 2006-11-07 | Medimmune, Inc. | Stabilized liquid anti-RSV antibody formulations |
| US7294336B2 (en) | 2002-06-14 | 2007-11-13 | Medimmune, Inc. | Stabilized liquid anti-RSV antibody formulations |
| US7425618B2 (en) | 2002-06-14 | 2008-09-16 | Medimmune, Inc. | Stabilized anti-respiratory syncytial virus (RSV) antibody formulations |
| US9879067B2 (en) | 2002-06-14 | 2018-01-30 | Medimmune, Llc | Stabilized liquid anti-RSV antibody formulations |
| US10604560B2 (en) | 2002-06-14 | 2020-03-31 | Arexis Ab | Stabilized liquid anti-RSV antibody formulations |
| US11180542B2 (en) | 2002-06-14 | 2021-11-23 | Arexis Ab | Stabilized liquid anti-RSV antibody formulations |
| US9321831B2 (en) | 2007-06-01 | 2016-04-26 | Medimmune Limited | RSV-specific binding molecules and means for producing them |
| US10059757B2 (en) | 2007-06-01 | 2018-08-28 | Medimmune Limited | RSV-specific binding molecules and means for producing them |
| US10730931B2 (en) | 2007-06-01 | 2020-08-04 | Medimmune Limited | RSV-specific binding molecules and means for producing them |
| US8568726B2 (en) | 2009-10-06 | 2013-10-29 | Medimmune Limited | RSV specific binding molecule |
| US10035843B2 (en) | 2009-10-06 | 2018-07-31 | Medimmune Limited | RSV-specific binding molecule |
| US10723786B2 (en) | 2009-10-06 | 2020-07-28 | Medimmune, Limited | RSV-specific binding molecule |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2758331B1 (en) | 1999-03-05 |
| WO1998031807A1 (en) | 1998-07-23 |
| EP0953050A1 (en) | 1999-11-03 |
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