WO1998031807A1 - Novel means for the diagnosis, prevention and treatment of contamination or infections by viruses with mucous tropism - Google Patents

Abstract

The invention concerns means comprising peptides essentially made up of amino acids capable of recognising according to an antigen-antibody type reaction at least an epitope of a virus with mucous tropism, involved in infections caused by such virus. The means also comprise the antibodies directed against these peptides and the ligands of these peptides. The invention is applicable to the diagnosis, therapeutic treatment and vaccination for human beings and animals.

Description

 "New means for diagnosis, prevention and treatment vis-à-vis contaminations or infections by viruses with mucous tropism"

The subject of the invention is new means for the diagnosis, prevention and treatment of humans or animals with respect to contaminations or infections by viruses with mucous tropism.

Viruses with a mucous tropism can infect various human or animal mucous membranes such as the respiratory, intestinal or vaginal mucous membranes, according to different mechanisms. The immunological defenses against these infections frequently involve the secretion of IgA.

Mention will be made of viruses of the family Reoviridae, more particularly of the genus Rotavir s (hereinafter referred to as RV), viruses of the family of Paramyxoviridae, more particularly of the genus Pneumovirus such as respiratory syncytial virus (hereinafter referred to as RSV) . But also papillomavi rus, adenovirus, enteroviruses, poliovi rus, influenza viruses or even human immunodeficiency viruses.

These viruses pose complex problems in human medicine, in communities and in hospitals where people particularly sensitive to such infections are confined: newborns, babies, premature babies in particular, children, immunocompromised adults, the elderly, but also veterinary medicine in the case of animal husbandry such as foals or calves.

Such situations lead to epidemic infections that are all the more burdensome and difficult to manage since they can give rise not only to primary infections, but also to re-infections. Some of these epidemics also appear periodically: this is the case, for example, with RSV infections during the winter months, November, December and January. However, for many of these viruses, the prophylactic or therapeutic means proposed to date do not have the desired effectiveness or, for some, do not are not even available. This is particularly the case with RSV, an infectious agent in the respiratory system and responsible for severe bronchiolitis and pneumonia, and Potavi rus, an infectious agent in the intestinal tract and responsible for severe gastroenteritis, for which it does not There is currently no effective therapy, prophylaxis or vaccination.

The research carried out by the inventors in this field has led them to study more specifically the regions determining the complementarity, or CDR, of anti-virus monoclonal antibodies with mucous tropism and to develop peptide sequences of great interest with regard to their immuno properties. logical. Various useful tools for the diagnosis, prevention and treatment of contaminations and infections by these viruses have thus been developed.

The invention therefore aims to provide such peptide sequences capable of recognizing key epi topes in a contamination or viral infection, and in particular capable of constituting paratopes vis-à-vis RV and RSV. It also aims to provide the corresponding nucleotide sequences.

According to yet another aspect, the invention relates to the applications of these different sequences for diagnostic, preventive or therapeutic purposes in the case of infection by viruses with mucous tropism, and in particular by

FV or VRS.

The peptides of the invention are characterized in that they essentially consist of an amino acid sequence capable of recognizing, according to an antigen-antibody type reaction, at least one epitope of a mucosal tropism virus, involved in infections caused by such a virus.

Such recognition of the viral epitope by the peptide can be demonstrated, for example, by an antigen-antibody reaction such as, for example, ELISA.

The invention relates in particular to peptides as indicated above capable of neutralizing the viral infection and, if necessary, of inhibiting fusion between cells infected and uninfected or between cells and viruses when the viral epitope is involved in fusion, and / or to exert a protective effect by passive or active route and / or to inhibit the transcription of the mucous tropism virus.

Such peptides can exhibit specificity of a viral subgroup in neutralization.

They are characterized in that they are capable of inhibiting an essential stage of viral multiplication. Such peptides are further characterized in that they comprise an amino acid sequence having the properties of a CDR of anti-mucosal anti-virus antibodies, such as RSV or RV.

The expression "CDR" designates an amino acid sequence of hypervariable regions of the antibody involved in the recognition of major viral antigenic sites.

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 "analog", as used according to the invention, designates an amino acid sequence, which differs from that of a native CDR region by one or more amino acids, but which exhibits immunological properties of the type of those observed with the native CDR, as highlighted in the examples. The differences in the sequences can correspond to modifications of one or more amino acids and / or substitutions of native amino acids by chemical groups appropriate in view of the biological applications envisaged, or of the statements. They can also correspond to the presence of additional natives, compared to the native sequences. Preferred peptides of this type are characterized in that they exhibit antigen-antibody type properties with RSV.

The invention relates in particular to peptides characterized in that they are capable of reacting with the epitope 205-225 and / or 255-278 of the VRS F protein. Such peptides are in particular characterized in that they are capable in vitro of exerting an activity of neutralizing an infection of cells, such as Hep-2 cells, by RSV, and / or of inhibiting fusion between cells infected with RSV and uninfected cells, or the fusion between cells and RSV. Such peptides are particularly remarkable, characterized in that they are capable in vivo, in particular when administered by the intranasal route, of exerting a protective effect by the passive route against an RSV infection.

They are in particular peptides corresponding to, or analogs of CDR regions of monoclonal antibodies specific for RSV, of the subgroup A or E

Peptides of this group specially targeted by the invention in particular have a size of between 5 and

50 amino acids approximately, preferably between 10 and 30 amino acids approximately.

Peptides of this group specially targeted by the invention correspond to the amino acid sequences SEQ ID No.1 to SEQ ID No.12 and SEQ ID No.25 to SEQ ID No.42.

Preferred peptides from this group essentially respond to the amino acid sequences SEQ ID No. 3 or SEQ ID No. 9 (= SEQ ID No. 27).

Other preferred peptides of the type mentioned above are characterized in that they exhibit properties of the anti gene- anti body type with RV.

The invention relates in particular to peptides characterized in that they are derived from antibodies capable of reacting with site III and / or IV of the protein VPβ of RV. Such peptides advantageously correspond to or are analogs of CDR regions of monoclonal antibodies with RV specificity.

Peptides of this group specially targeted by the invention essentially comprise one or more amino acid sequence (s) chosen from the group consisting of the sequences SEQ ID No. 13 to SEQ ID No. 24, and SEQ

ID N ° 43 to SEQ ID N ° 48. Advantageously, such “anti-RV” peptides can be grafted in place of the CDRs of an immunoglobulin IgG or IgA.

It will be observed that the peptides described above in relation to the regions of CDR can correspond to, or constitute analogs of regions of CDR of heavy chains of anti-mucosal anti-virus antibodies, and / or light chains.

The different peptides can be presented in linear form, or alternatively in cyclized form.

The peptides of the invention are obtained by peptide synthesis, advantageously using conventional techniques, or also by genetic engineering using the nucleic acids defined below. 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. Such modified cells, where appropriate, the organisms or plants made up of such cells are also included in the scope of the invention.

The invention indeed also relates to the nucleic acids corresponding according to the universal genetic code to the peptides defined above.

These nucleic acids include DNA comprising the genetic information corresponding to said peptides, advantageously DNA capable of coding for these peptides. They also include the A ENs, especially the AENm, and the corresponding cDNAs.

Transfer and / or expression vectors such as cosmid, plas ide, phage, animal or plant virus containing such nucleic acids, and host cells containing such vectors also fall within the scope of the invention. The study of the compounds defined above has led to highlight anti-viral properties of great interest, as illustrated by the examples.

Thus, the properties of neutralization and, where appropriate, of inhibition of the fusion of the virus and / or of its transcription, are advantageously used, for the diagnosis, the prevention and the treatment of contaminations and infections by such mucosal tropism viruses and the manufacture of immunogens for vaccines. The invention thus relates to means, namely compositions, methods and kits, for detecting the presence of the virus in humans or animals, or for demonstrating an immune response to contamination or to viral infection. . The diagnostic compositions of the invention are characterized in that they comprise:

. to detect 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 which binds to the peptide, the peptide, the antibody or the ligand, being associated with a marker for the detection reaction, such as a radiolabel or an enzymatic marker and, where appropriate, with a vehicle suitable for carrying out the diagnosis.

The invention also relates to a method of in vitro diagnosis of contamination or infection by a mucous tropism virus, characterized in that it comprises: - bringing into contact a biological sample, such as a body fluid, with

. to detect 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 disclosure of the reaction produced when the vi al antigen is present. The invention further relates to kits for the diagnosis of contamination or infection by a mucous tropism virus.

These kits are characterized in that they comprise at least one peptide, or an anti-peptide antibody, or an equivalent ligand, and the reagents suitable for the detection reaction, in particular markers and solvents.

The administration of peptides according to the invention or, where appropriate, anti-peptide antibodies or of ligands which bind to these peptides proves to be of great interest for preventing or treating infections by viruses with mucous tropism, in particular by

VRS and RV. Regarding RSV, the preferred administration is intranasally.

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 binding ligand to this peptide, in association with a pharmaceutically inert vehicle.

The invention relates more specifically to the compositions produced using anti-RSV or anti-RV peptides. In particular, the invention relates to anti-RSV pharmaceutical compositions, containing at least one peptide corresponding to one of the sequences SEQ ID No. 7 to SEQ ID No. 12 and very particularly to the sequence SEQ ID No. 9 whose neutralizing properties are of great interest.

These compositions are preferably administered nasally, orally or parenterally, at a rate of 1 to 80 mg / kg, in different forms. By way of example, mention will be made of administration in the form of heavy esters, such as decanoate, oenanthate or palmitate, or in delayed dosage form.

Another aspect of the invention of major interest concerns the vaccine applications of antibodies directed against said peptides, or of equivalent ligands.

Such vaccine compositions, which are characterized in that they contain an effective amount of antibodies or ligands directed against said peptides in association with an appropriate vehicle, also fall within the scope of the invention.

Particularly advantageous compositions are combined with at least one other vaccine, for example childhood vaccines, which makes it possible to have broad spectrum vaccine compositions. In prophylactic applications, the anti-peptide antibodies of the invention or said ligands are advantageously conjugated to a carrier molecule to reinforce their immunogenicity. By way of example, mention will be made of molecules of the hapten type (tetanus toxoid, diphtheria toxoid or others).

As a variant, the anti-peptide peptides or antibodies, or the said ligands, are inserted into a human immunoglobulin A structure, if necessary modified in the framework region of its variable regions adjacent to the peptide, or to the anti-peptide antibody. peptide inserted, or ligand, so as in particular to restore in the resulting IgA, the properties of said peptide or anti-peptide antibody.

The presentation of the peptides is carried out in the form of a fragment of the ScFv type, or of insertion into a hexon protein structure of adenovi rus.

Other characteristics and advantages of the invention are given in the examples which follow.

In the examples which follow, given by way of nonlimiting illustration, reference is made to FIGS. 1 to 7 which represent:

- Figure 1, the inhibition of transcription of double-layered viral particles (Rotavirus) by different anti-VPβ monoclonal antibodies, namely the monoclonal antibodies RV-238, RV-133 and EV-138.

- Figure 2.1a neutralization of the infectious power of RSV by the synthetic peptide homologous to CDR3 of the heavy chain of the antibody RS-348 (PEP3H).

- Figure 3, the sequences of the V _H and VT chains. anti-RSV monoclonal antibodies (CDR underlined),

FIG. 4, the CDRs of these chains,

FIG. 5, the heavy V _H and light V _L chain sequences of the FV-138 and EV-133 monoclonal antibodies (CDR underlined),

- Figure 6, the heavy (V _H ) and light (V _L ) chain sequences of the RV-238 monoclonal antibody (CDR underlined), and - Figure 7, the sequences of anti-RSV synthetic peptides,

EXAMPLE 1 Production of Anti-RSV Monoclonal Antibodies and Anti-VR Monoclonal Antibodies - Obtaining Hybridomas

Wy Ε / c mice were infected

- intranasally with

. 10 pfu (range forming units) of RSV strain A2 or Long or - intraperitoneally

. 10 pfu of EV bovine strain RF.

Mouse spleen cells are harvested and fused with SP2 / 0 myeloma cells according to conventional techniques.

The hybridomas (hybridoma cells) secreting either anti-RSV antibodies or anti-RV antibodies were selected by IF or ELISA, cloned and stored by freezing. - growing conditions

After thawing, the cells are cultured in RPMI 1640-10% FCS medium (Fetal Calf Serum) in an oven at 37 ° C, 5% C02. -detection of antibodies by indirect immunofluorescence (IF).

The supernatants of hybridomas are incubated for 30 minutes at 37 ° C. in wells covered with Hep 2 cells (human cells) infected or not (controls) with the A2 or Long strain of the respiratory syncytial virus, or in wells covered with cells. MA104 (monkey kidney cells) infected or not by the bovine RF strain or by the human strain 46, (isolated from a clinical sample then cloned) of the rotavirus.

After 3 washes with P BS, the antibodies present are revealed by a 30-minute incubation with an anti-mouse IgG antibody labeled with fluorescein. The slides are then observed under a fluorescence microscope.

The results reported in the examples below relate to the following seven monoclonal antibodies, namely: four monoclonal anti-RSV antibodies, called respectively

RS-348, RS-18E2, RS-2 B3 and RS-255, and three anti-RV monoclonal antibodies, called RV-133, EV-138 and EV-238. . anti-RSV monoclonal antibodies

The four monoclonal anti-RSV antibodies, RS-348, RS-18E2, RS-2 E8 and RS-255, recognize close epi topes on the fusion protein F of RSV and are all except RS-255 which has been obtained from site 255-275 of the F protein of

VRS, highly neutralizing IgGl.

The RS-348 antibody has a very strong neutralizing activity. It recognizes the strains of RSV of the subgroups

A and B in immunofluorescence while it has a specificity of subgroup in neutralization. The RS antibody epitope below, as identified by different techniques, is very conformational and is located mainly between amino acids 190 and 289 of the RSV fusion protein (sites 205-225 and 255-278).

. monoclonal anti-RV antibodies Anti-rot a monoclonal antibodies to virus, RV-133,

RV-138 and RV-238, all recognize close antigenic sites on the rotavirus internal capsid protein, VP6. However, RV-133 and RV-238, unlike FV-138, recognize a group epitope common to all strains of group A related to the region of VP6 involved in viral transcription. Indeed, the restoration of the transcriptase activity does not take place when VPβ is previously incubated with the antibody RV-133 before the reassociation 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-Mari a SANDINO and Eugenio SPENCER, Archives of Vi rology 1994, 135, 193-200). Briefly, 0.2 μg of double-layered viral particles of the RF bovine strain or of the human strain 46 of Rotavirus are incubated either lh at 37 ° C. or overnight at 0 ° C., in the presence of increasing concentrations. of the anti-VP6 monoclonal antibody tested (total volume of the incubation solution 20 μl). The monoclonal antibodies tested are here FV-238, RV-133 and RV-138. 20 μl of a mixture containing ATP, CTP, GTP, UTP, ³ H-labeled or unlabeled, Tris, MgCl ₂ , DTT and RNasin are added.

The whole is placed at 42 ° C. Samples are taken after 30 minutes, then deposited on a GF / C filter and precipitated with TGA. The strokes per min (cpm) are then counted. The same type of test can be performed with

^• Fab fragments of antibodies which can in particular be obtained by digestion of the papain anticoprs (anti body / papain ratio between 1000 and 2000/1) in the presence of EDTA and β-mercaptoethanol at 37 ° C.

FIG. 1 illustrates the inhibition of the transcription of double-layered viral particles ("doule- * layer particles") (Rotavirus) exerted by the anti-VP6 RV- monoclonal antibodies 238, RV-133 and RV-138 (overnight incubation at 0 ° C in the presence of double-layer viral particles of the RF strain, or if appropriate 46, of Rotavirus.

The results obtained with the Fab fragments of these antibodies RV-238, RV-133 and RV-138 are comparable to those obtained with the respective complete anticorsp. It is therefore demonstrated that, surprisingly, the Fab fragments of the RV-238 and RV-138 antibodies exert an inhibitory effect on the transcription of double-layered viral particles (Rotavirus).

Example 2: Obtaining amino acid sequences of the heavy and light chains of monoclonal antibodies with mucous tropism anti-RSV and anti-RV.

The amino acid sequences are deduced from the DNA sequences of the V and V _L genes.

- Extraction and purification of mRNA

This step is carried out using a QuickPrepR Micro mRNA purification kit sold by Pharmacia-E otech, using 10 hybridoma cells. - Extraction of total RNA:

The hybridoma cells are centrifuged and the pellet is taken up in 0.4 ml of extraction buffer (guanidiu thiocyanate and N-lauroyl sarcosine) then 0.8 ml of elution buffer (Tris-HCl pH 7.5 10 mM ; EDTA ImM). - purification of mRNA on oligo column (dT)

The total RNA sample is added to the homogenized cellulose-oligo (dT) gel and freed from its storage buffer. The whole is centrifuged and washed 5 times with a buffer with a high concentration of salts then 3 times with a buffer with a low concentration of salts.

The gel resuspended in the latter buffer is transferred to a column (MicroSpin®, Pharmacia) placed in a microtube. After 3 washes with the lo-sal buffer, the mRNAs are eluted with the elution buffer, then stored in ice.

- precipitation of mRNAs The eluate is added with a solution of glycogen, potassium acetate and 95% ethanol before being placed for 30 minutes at -20 ° C. After centrifugation, the

RNA & α in the pellet, then they are resuspended in elution buffer.

- Synthesis of cDNA

The synthesis is carried out in duplicate, one tube used for the amplification of VH (variable region of heavy chain) and the other for VL (variable region of light chain). After heating to 65 ° C. to remove the secondary structures, the mRNAs (5 μl) are incubated for 1 hour in the presence of lμl of 200 mM dithiothreitol (DTT), ll μl of a reaction mixture containing a reverse transcriptase.

(origin: murine leukemia virus), primers and the 4 dideoxynucleotides (ddNTP) at 1.25 mM each, and 16 μl of distilled water.

- PCR amplification of DNA coding for the VH and VL genes

- amplification conditions: The amplification of the genes coding for VH and VL is carried out separately by PCR using specific commercial primers: Hl (Heavy primer 1) and H2 (Heavy primer 2) to amplify VH, L (Light primer mix) to amplify VL (Pharmacia-E otech).

The reaction mixtures are as follows:

* for VH: 33 μl of cDNA, 2 μl of Hl primer, 2 μl of H2 primer and 62 μl of distilled water.

* for VL: 33 μl of cDNA, 2 μl of primer L and 64 μl of distilled water.

Each sample is covered with mineral oil and, after denaturation at 95 ° C for 1 minute, 1 μl of Taq polymerase (ELoprobe) is added. The tubes are then placed in the thermal cycler (PHC-3, Techne) programmed for 30 cycles of 3 stages:

. denaturation of double stranded DNA at 94 ° C, 1 minute,. priming hybridization at 55 ° C, 2 minutes,. elongation of the complementary strand at 72 ° C., 2 minutes.

- purification of PCR products

The PCR products are purified using a QIAquick PCR purification® kit from QIAGEN. An aliquot is then deposited on agarose-EET gel (BET = ethidium bromide) to verify the good amplification of the genes.

- Sequencing of PCR products

Sequencing of PCR products is carried out on a thermocycler (GeneAmp PCR syste 2400) according to the non-radioactive method of 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 DNA chain in formation to terminate and to be simultaneously labeled with the fluorophore corresponding to the last base added.

The sequenced products are then separated by electrophoretic migration in an automatic sequencer, such as the DNA 373 stretch sequencer which has an optical system based on a laser coupled to a computer analysis program. All the devices and reagents used are marketed by Perkin-Elmer.

The sequencing primers were deduced from various consensus sequences of VH and VL genes synthesized by Eurogentec (KABIT EA, WU T. T, REID-MILLER M., PERRY HM, GOTTESAN KS 1987. Sequences of proteins of immunological interest, US Dept of Health and Human Services, US Government Printing Office; KAEAT EA, WU TT, PERRY HM, GOTTE__MAN KS, FOELLER C. 1991. Séquences of proteins of immunological interest, US Department of Health and Human Services, NIH, Bsthesda, MD).

- sequencing reaction The sequencing reaction is carried out using a ready-to-use reaction mixture: the cycle sequencing kit for ABE PRISM® dye terminators. This medium contains the 4 differently labeled ddNTPs (ddATP, ddCTP, ddGTP and ddTTP), the 4 unlabeled dNTPs (dITP, dATP, dCTP and dTTP), Tris-HCl (pH9.0), MgCl ₂ , a pyrophosphatase and l Taq FS DNA polymerase.

In a PCR tube suitable for the thermal cycler, approximately 30 ng of purified PCR product are added to 1 μl of sequencing primer (at 3.2 pmol / μl), to 8 μl of the reaction medium and of ultrapure water (qs 20 μl).

The reaction tubes are then placed in the thermocycler programmed for 25 cycles of 3 stages:

* denaturation: 96 ° C, 10s, * primer hybridization: 50 ° C, 5s,

* elongation: 60 ° C, 4 min.

- purification of sequenced products

The excess nucleotides are removed by ethanol precipitation of the sequencing products. The 20 μl of reaction are transferred to a 1.5 ml micro-centrifuge tube in which 2 μl of 3M sodium acetate (pH4.6) and 50 μl of 95% ethanol have been deposited. The tubes are placed for 10 minutes in ice, then centrifuged for 20 to 30 minutes at maximum speed. After decantation, the DNA pellets are washed with 70% ethanol and then dried.

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. - separation of sequencing products by electrophoretic migration.

A 4.75% polyacrylamide gel is prepared at least 2 hours before migration in order to obtain good polymerization. For 80 ml of gel, 40 g of urea are dissolved in approximately 27 ml of ultrapure water to which are added 1 g of resin and 9.5 ml of a 40% acrylamide stock solution (38 g of acrylamide and 2 g of bis-acrylamide in qs 100 ml of water). The mixture is stirred for 5 minutes, then filtered and degassed.

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 for 1 liter) are added and the final volume is brought to 80 ml with water. The gel, 0.4 mm thick, is poured between 2 glass plates after the addition of the catalysts: Temed (45 μl), Temed = N, N,

N ¹ , N ¹ - tetramethylethylenediamine and ammonium peroxydisulfate at 0, lg / ml (400 μl). The internal face of the plates is cleaned beforehand with a detergent, then rinsed several times with distilled water and dried.

After polymerization of the gel, the glass plates are cleaned externally in the same manner as previously and their cleanliness is checked directly in the electrophoresis tank of the sequencer by the laser. Once the plates are clean, the gel can be placed in the tank and the migration buffer added (Tffi IX). A pre-migration is then carried out for 15 minutes in order to preheat the gel before depositing the samples.

The samples are deposited on top of the gel after a denaturation of 2 minutes at 90 ° C and the migration is launched at the same time as the collection of the data by the computer program.

The purified and separated products are then cloned according to conventional techniques, then sequenced. The nucleic acid sequencing was carried out on double stranded DNA using an automated DNA sequencer (ABC).

- sequences: After sequencing, deduction of the amino acid sequence according to the genetic code made it possible to identify the 3 regions of CDR on the heavy chain and the 3 regions of CDR on the light chain, in each monoclonal antibody. Each of the CDR regions is identified by homology with the previously published immunoglobulin sequences.

All of these sequences are reported in the sequence list at the end of the description. In addition, there is shown in Figure 3, the amino acid sequence according to the 1-letter code, of the V _H and V _L for RS-348, _RS-18E2,. RS-2 EB and RS-255. CDRs are indicated and underlined and are given in Figure 4.

In addition, the sequences of the V _H chains (heavy variable chains) and V _L (light variable chains). Antibodies RV-138 and RV-133 are given, according to the 1-letter code, in Figure 5.

The sequences of the V _H and V _L chains of the RV-238 anticoprs are given, according to the 1-letter code, in FIG. 6. The CDR sequences are underlined in FIGS. 3 to

6.

For the RS-348 monoclonal antibody, the amino acid sequences of the heavy chain (H) CDRs 1,2,3 are referenced, respectively, under SEQ ID No. 1, 2.3, and those of the CDRs 1.2 , 3 of light chain (L) under SEQ ID No. 4,5,6.

For the RV-138 monoclonal antibody, the amino acid sequences of the heavy chain (H) CDRs 1,2,3 are referenced, respectively, under SEQ ID No. 13,14,15 and those of the CDR 1,2, 3 of light chain (L) under SEQ ID No. 16,17,18. For the RV-133 monoclonal antibody, the amino acid sequences of the heavy chain (H) CDRs 1,2,3 are referenced, respectively, under SEQ ID No. 19,20,21 and those of the CDR 1,2, 3 of light chain (L) under SEQ ID No. 22,23,24.

For the FV-238 monoclonal antibody, the sequences or amino acids of the heavy chain (H) CDRs 1,2,3 are referenced, respectively, under SEQ ID No. 43,44,45 and those of the CDR 1,2, 3 of light chain (L) under SEQ ID No. 46,47,48.

For monoclonal antico ps RS-18B2, the amino acid sequences of CDR 1,2,3 of heavy chain (H) are referenced, respectively, under SEQ ID No. 25,26,27 and those of CDR 1,2,3 of light chain (L) under SEQ ID No. 28,29,30. The V _H CDF3 of RS-18 E2 has the same sequence as that of RS-348 (SEQ ID No. 9 = SEQ ID No. 27). For the RS-2B8 monoclonal antibody, the amino acid sequences of the heavy chain (H) CDRs 1,2,3 are referenced, respectively, under SEQ ID No. 31,32,33 and those of the CDR 1,2, 3 of light chain (L) under SEQ ID No. 34,35,36.

For the RS-255 monoclonal antibody, the amino acid sequences of the heavy chain (H) CDRs 1,2,3 are referenced, respectively, under SEQ ID No. 37,38,39 and those of the CDR 1,2, 3 of light chain (L) under SEQ ID No. 40,41,42.

EXAMPLE 3 Anti-RSV Peptides Peptides of 20 amino acids corresponding to each of the 6 CDR regions of RS-348 and comprising amino acids of the framework region added to each end of the CDRs were prepared by synthesis. length or to facilitate synthesis. To obtain cyclized peptides, cysteine was added to each of the two ends.

The synthesis was carried out with a Milligen® 9050 automatic synthesizer, according to a solid phase method which uses amino acids activated by protected JSf-Fmoc esters, on a polystyrene resin (PEG-PS). 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. 20% piperidine in DMF was used for the N ⁰¹ deprotection steps.

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 have therefore could form disulfide bridges for peptic di cyclization.

The peptides were then recovered by precipitation in cold ethyl ether, centrifugation and repeated washing in ether. The precipitates were resuspended in distilled water.

The cyclic form of the peptides was obtained by spontaneous oxidation of the Cys thiol groups: an aliquot of

25 umole (1 mg / ml) deprotonated with NaOH (final pH = 8 to 8.5) was kept overnight with vigorous stirring.

The linear form of the peptides was obtained by maintaining the protonation (pH = 5.5 to 6.5) and, in the event of insolubilization, by mixing with degassed P BS (pH = 7.4) under nitrogen bubbling so as to prevent cyclization. The peptide solutions are then quickly frozen.

The sequences of the synthesized peptides homologous to

6 CDs of the RS-348 monoclonal antibody are reported in the attached sequence listing. The sequences referenced under SEQ ID No. 7,8,9 represent, respectively, the sequences of the peptides

PEP1H348, PEP2H348, PEP3H348, i.e. the sequences of the synthetic peptides constructed by homology with the CDRs

1,2,3, respectively, of the heavy chain of 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 synthetic peptides ^• constructed by homology to the CDRs

1,2,3, respectively, of the light chain of RS-348. In addition, there is shown in Figure 7, the sequences of these synthetic peptides according to the 1 letter code.

Example 4 Study of the Immunological Functional Properties of the Peptides of Example 3 - neutralization activity

Long strain RSV neutralization tests (subgroup A) were carried out by measurement of plaque reduction. 5 x 10 pfu / ml of virus were mixed for 1 h at 37 ° C. with a serial dilution of the peptides (from 15 μg to 0.875 μg) in cyclic or linear form.

Monolayers of Hep-2 cells on 6-well plates were then infected. Neutralization was measured, for each concentration of peptides tested, when a reduction of plaques of 50% is observed and is expressed in average log per quantity of peptides.

No toxicity of the synthetic peptides was detected. The neutralizing activity appears particularly high with the peptide SEQ ID No. 9 (PEP3H348). It is observed that the peptide is presented in cyclic or linear form. The linear peptide has, however, neutralizing activity in a wider range of concentrations. The peptide SEQ ID N ° 9 (PEP3H348) therefore reproduces in neutralization the specificity of the subgroup presented by the antibody of which it wishes (RS-348) (specificity for the subgroup A of RSV; no neutralization of the strain 9320 of VRS subgroup B).

The neutralization results obtained with the peptide PEP3H (SEQ ID No. 9) are reported in Figure 1 where the

% inhibition of the infectious power of the virus is given on the ordinate and the amount of peptides is indicated on the abscissa, (- - for the cyclic form of the peptide, - D - for the linear form). On the other hand, the study of the capacity to neutralize a strain of subgroup B shows that none of the peptides SEQ ID No. 7 to 12 exhibits a strong neutralizing activity on this subgroup. These results indicate that the peptide homologous to the CDR3 of the heavy chain of RS-348 (SEQ ID No. 9) is strongly neutralizing, that it also carries a specificity of subgroup (A) and that the conformation imposed by the cyclization does not influence the specificity of this activity. - Merger activity

Fusion tests of cells infected with RSV of Long strain (subgroup A) were carried out in the presence and in the absence of synthetic peptides (PEP1H348, PEP2H348,

PEP3H348, PEP1L348, PEP2L348, PEP3L348) derived from the six CDRs of the RS-348 monoclonal antibody (sequences of these peptides: SEQ ID No. 7 to No. 12).

Hep-2 cells are first infected with vi us (5 x 10 ³ plaque forming units). Six hours later, amounts ranging from 0 to 15 μg of synthetic peptides were added to these infected cells.

An inhibitory activity against the fusion of cells infected with RSV has been observed in particular in the presence of the peptide PEP3H348, (SEQ id No. 9) (inhibition of 25% of the fusion in the presence of 60 μg of PEP3H348).

The peptides PEP2L348 (SEQ ID No.11) and PEP3L348 (SEQ ID No.12), on the other hand, stimulate the fusion of infected cells, when administered in linear form, and do not exhibit this fusion-stimulating effect when 'they are administered under the same conditions but in a cyclized form. The binding of the peptides PEP2L348 and PEP3L348 to the RSV fusion protein F therefore seem, when administered in linear form, to enhance the fusion activity of this protein. The conformation of these peptide sequences is an important element of this effect.

None of the synthetic peptides tested gave rise to cytotoxic effects.

It therefore appears that the activity of the FRS fusion protein F can be modulated, that is to say stimulated or else inhibited, by simple association with small peptide sequences, and thus lead to an increase or else to a decrease in RSV infectivity. The CDR3 of the V _H heavy chain variable region of the antibody RS-348 is capable of inhibiting viral infection of RSV in vitro. It is therefore possible to inhibit the infectivity of RSV using a peptide corresponding to a single CDR of a neutralizing antibody. This result also indicates that the

V _H CDR3 is a major part of the antibody determinant

RS-348 involved in the vi rus -anti body interaction. This CDR3H

(and the peptide PEP3H derived) carry the same specificity of subgroup in neutralization as the antibody of which it desires (RS-348).

- Passive immunization of mice (protective effect).

Infection four hours after intranasal instillation

A preparation of peptides, monoclonal antibody, or PBS (control) was administered nasally to batches of 10 E & lb / c mice. The animals were infected 4 hours later intranasally with the Long strain of the respiratory syncytial virus diluted in EME medium.

Five days after exposure to RSV, the lungs of each mouse were homogenized and the rate of RSV infection measured in plaque forming units (pfu).

The results indicate that the protection by passive immunization is total with the antibody RS-348 and zero with the control PBS.

Significant protective power has been observed with synthetic peptides homologous to RS-348 CDRs (SEQ ID No. 7 to 12), especially with PEP3H, the synthetic peptide homologous to CDR3 of the heavy chain of the RS-348 antibody. (SEQ ID No. 9), as indicated in table 1 below under: Table 1

In this table 1, the decrease in virus titer in the lungs of mice was calculated as follows: (logio ^means' of pfu per gram of mice lung tissue) - (logio using pfu per gram of tissue of lungs of mice having received a dose of molecules to be tested). The mean virus titers are statistically different from those of the control mice.

Infection 24 hours after intranasal instillation

We report here the results of in vivo tests obtained with the peptide PEP3H348 (SEQ ID N ° 9) in linear form. The same protocol can however be followed with other peptides.

Four groups of 7-8 B mice ^! VLB ^/ c 10 week old females (IFFA / Credo, L'Arbresle, France) were used. These animals weighed approximately 20 g each. Fifty microliters of

PBS (phosphate buffer) or ascites fluid containing either RS-348 antibody (1/25 dilution; 5.4 μg Ig), or linear peptide derived from CDR3H348 (PEP3H348 SEQ ID No. 9; 140 μg) were inoculated intranasally, under Retamine-xylamine anesthesia, in each mouse of the first, or respectively of the second group. The mice of the third group were each inoculated in a comparable manner with a peptide

(NEDFGLLGTTLLNLDAG SEQ ID No. 49) derived from the amino acid sequence 60 to 75 of the protein VP6 of Rotavirus. This third group of mice therefore serves as a peptide control.

Twenty-four hours later, the mice were inoculated intranasally, under a second anesthesia, by

3.75.10 ⁴ of VRS Long strain diluted in Basai Medium Eagle.

Five days after infection, the mice are sacrificed and their lungs harvested. The RSV titer of the homogenates of lungs, diluted to 1/10 (mass e / volume), is then measured by plate test with Hep-2 cells after coloring with neutral red. Viral titers are expressed in plaque forming units (PFU) per gram of tissue. The significance of the differences between groups is checked using multiple comparison tests (Duncan, Scheffé, Student-Newman-Keuls and Tukey-Kramer).

The statistical results obtained with these four tests are in agreement with each other. A single dose of 140 μg of PEP3H348 (SEQ ID No. 9) has thus been shown to be effective in preventing infection with RSV. In fact, intranasal administration of PEP3H348 (SEQ ID No. 9) twenty-four hours before infection caused a significant reduction in the virus in the lungs of mice infected with RSV.

Under these conditions, the viral titer in the lungs is reduced by a factor of 2.3 logio. With the antibody RS-348, a reduction of a factor of 1.56 log 10 was measured. No significant difference could be measured between PEP3H348 and the complete RS-348 antibody. The peptide used as a peptide control (SEQ ID No. 49) did not cause any reduction in the folding of the RSV. All the statistical tests lead to these same conclusions (a classic α level of 1% has been chosen). The results are presented in Table 2 below. Table 2: passive protection against RSV infection after intranasal instillation of PBS, RS-348, PEP3H348 (SEQ ID No. 9) linear, or of a control peptide (SEQ ID No. 49).

Reagent instilled Hub viral titer Decrease

24 h before infection (+ _ standard deviation) mean of

(μg / mouse) in the lungs, viral titer of mice pre-treated in

⁽ logio. lungs (logio)

PBS 3.26 + 0.43

RS-348 (5.4) 1.70 + 0.85 1.56 PEP3H348 (140) 0.95 + 1.02 2.31 Control peptide (140) 3.33 + 0.27

^a The mean viral titers in the tests with RS-348 and PEP3H348 are statistically different from those obtained in the PBS and control peptide tests (multiple comparison tests).

To verify the absence of residual neutralizing activity which could interfere with the harvesting of the lungs, a lung treated with PEP3H348 was mixed (1/1) volume / volume) with an infected lung which did not receive any peptide. No neutralizing activity was obtained.

Thus, the resistance of the lung pretreated with PEP3H348 to RSV infection is not due to a residual neutralizing activity in vitro.

It is therefore the first demonstration that a simple CDR can prevent the progression of an RSV infection in vivo. Until now, prophylaxis studies of RSV infection have only been carried out with whole Ig or fragments Fab. In addition to the ease of production (simple synthesis), the products according to the invention also have the advantage of avoiding secondary allotypic immune responses.

EXAMPLE 5 Therapeutic Tests in Mice

Six batches of each 10 10-week-old female deKLE / c mice were used. Each animal weighed about 20g. Each of the mice was inoculated intranasally with 10 pfu of VRS Long strain diluted in Bffi medium. 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 heavy chain of RS-348, (SEQ ID No. 9) in linear form at a rate of 70 μg per mouse, or

- intranasal inoculation of PEP3H (SEQ ID No. 9) in linear form at a rate of 140 μg per mouse,

- intranasal inoculation of PEP3H (SEQ ID No. 9) in cyclic form at a 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.

All inoculations were performed under keta ine / xylamine anesthesia. A day later, all the mice were sacrificed and their lungs harvested. The RSV concentration of the homogenates of the lungs was measured by plate test with Hep-2 cells and by neutral red staining.

The average decrease in RSV concentrations measured for each of the therapeutic treatments tested was calculated as follows: (average log of pfu per gram of lung tissue from experimental control mice) - ((lloogg mmooyyeenn ddeess ppffuu ppaarr gpara ggrraammmmee dd <e lung tissue from the mice tested). SUMMARY OF SEQUENCES

The sequence SEQ ID No. 1 is an amino acid sequence of a heavy chain CDR1H348 of an anti-RSV monoclonal antibody (RS-348).

The sequence SEQ ID N ^c 2 is an amino acid sequence of a heavy chain CDR2H348 of an anti-RSV monoclonal antibody (RS-348).

The sequence SEQ ID No. 3 is an amino acid sequence of a heavy chain CDP3H348 of an anti-RSV monoclonal antibody (RS-348).

The sequence SEQ ID No. 4 is an amino acid sequence of a light chain CDR1L348 of an anti-RSV monoclonal antibody (RS-348).

The sequence SEQ ID No. 5 is an amino acid sequence of a light chain CDR2L348 of an anti-RSV monoclonal antibody (RS-348).

The sequence SEQ ID No. 6 is an amino acid sequence of a light chain CDR3L348 of an anti-RSV monoclonal antibody (RS-348).

The sequence SEQ ID No. 7 is an amino acid sequence of a synthetic peptide (PEP1H348) derived from a heavy chain CDKL of anti-RSV monoclonal antibody (RS-348).

The sequence SEQ ID No. 8 is an amino acid sequence of a synthetic peptide (PEP2H348) derived from a heavy chain CDR2 of anti-RSV monoclonal antibody (RS-348).

The sequence SEQ ID No. 9 is an amino acid sequence of a synthetic peptide (PEP3H348) derived from a heavy chain CDR3 of anti-RSV monoclonal antibody (RS-348).

The sequence SEQ ID No. 10 is an amino acid sequence of a synthetic peptide (PEP1L348) derived from a light chain CDR1 of anti-RSV monoclonal antibody (RS-348).

The sequence SEQ ID N ^c ll is an amino acid sequence of a synthetic peptide (PEP2L348) derived from a light chain CDR2 of anti-RSV monoclonal antibody (RS-348). The sequence SEQ ID No. 12 is an amino acid sequence of a synthetic peptide (PEP3L348) derived from a CDR3 light chain of anti-RSV monoclonal antibody (RS-348).

SEQ ID NO: 13 is an amino acid sequence d ¹ a heavy chain of a monoclonal antibody CDR1H138 anti FW (RV-138).

The sequence SEQ ID No. 14 is an amino acid sequence of a heavy chain CD 2H138 of an anti-I monoclonal antibody (IV-138).

The sequence SEQ ID No. 15 is an amino acid sequence of a heavy chain CDR3H138 of an anti-IV monoclonal antibody (FV-138).

The sequence SEQ IP No. 16 is an amino acid sequence of a light chain CDR1L138 of an anti-FV monoclonal antibody (FV-138).

The sequence SEQ ID No. 17 is an amino acid sequence of a light chain CDR2L138 of an anti-RV monoclonal antibody (RV-138).

The sequence SEQ ID No. 18 is an amino acid sequence of a light chain CDR3L138 of an anti-FV monoclonal antibody (FV-138).

The sequence SEQ ID No. 19 is an amino acid sequence of a heavy chain CDRLH133 of an anti-IV monoclonal antibody (RV-133).

The sequence SEQ ID No. 20 is an amino acid sequence of a heavy chain CDR2H133 of an anti-IV monoclonal antibody (FV-133).

The sequence SEQ ID No. 21 is an amino acid sequence of a heavy chain CDR3H133 of an anti-IV monoclonal antibody (FV-133).

The sequence SEQ ID No. 22 is an amino acid sequence of a light chain CDKLL133 of an anti-IV monoclonal antibody (IV-133).

The sequence SEQ ID No. 23 is an amino acid sequence of a light chain CDR2L133 of an anti-IV monoclonal antibody (FV-133).

The sequence SEQ ID No. 24 is an amino acid sequence of a light chain CDR3L133 of an anti-IV monoclonal antibody (FV-133). The sequence SEQ ID No. 25 is an amino acid sequence of a heavy chain CDR1 of an anti-RSV monoclonal antibody (RS-18E2).

The sequence SEQ ID No. 26 is an amino acid sequence of a heavy chain CDP2 of an anti-RSV monoclonal antibody (RS-18E2).

The sequence SEQ ID No. 27 is an amino acid sequence of a heavy chain CDP3 of an anti-RSV monoclonal antibody (RS-18E2).

The sequence SEQ ID No. 28 is an amino acid sequence of a light chain CDR1 of an anti-RSV monoclonal antibody (RS-18B2).

The sequence SEQ ID No. 29 is an amino acid sequence of a light chain CDR2 of an anti-RSV monoclonal antibody (RS-18E2).

The sequence SEQ ID No. 30 is an amino acid sequence of a light chain CDR3 of an anti-RSV monoclonal antibody (RS-183E2).

The sequence SEQ ID No. 31 is an amino acid sequence of a heavy chain CDR1 of an anti-RSV monoclonal antibody (RS-2B3).

The sequence SEQ ID No. 32 is an amino acid sequence of a heavy chain CDP2 of an anti-RSV monoclonal antibody (RS-2B8).

The sequence SEQ ID No. 33 is an amino acid sequence of a heavy chain CDR3 of an anti-RSV monoclonal antibody (RS-2E8).

The sequence SEQ ID No. 34 is an amino acid sequence of a light chain CD RI of an anti-RSV monoclonal antibody (RS-2B8).

The sequence SEQ ID No. 35 is an amino acid sequence of a light chain CDR2 of an anti-RSV monoclonal antibody (RS-2B8).

The sequence SEQ ID No. 36 is an amino acid sequence of a light chain CDR3 of an anti-RSV monoclonal antibody (RS-2B8).

The sequence SEQ ID No. 37 is an amino acid sequence of a heavy chain CDR1 of an anti-RSV monoclonal antibody (RS-255).

The sequence SEQ ID No. 38 is an amino acid sequence of a heavy chain CDR2 of an anti-RSV monoclonal antibody (RS-255).

The sequence SEQ ID No. 39 is an amino acid sequence of a heavy chain CDR3 of an anti-RSV monoclonal antibody (RS-255). The sequence SEQ ID No. 40 is an amino acid sequence of a light chain CDR1 of an anti-RSV monoclonal antibody (RS-255).

The sequence SEQ ID No. 41 is an amino acid sequence of a light chain CDR2 of an anti-RSV monoclonal antibody (RS-255).

The sequence SEQ ID No. 42 is an amino acid sequence of a light chain CDR3 of an anti-RSV monoclonal antibody (RS-255).

The sequence SEQ ID No. 43 is an amino acid sequence of a heavy chain CDR1 of an anti-RV monoclonal antibody (RV-238).

The sequence SEQ ID No. 44 is an amino acid sequence of a heavy chain CDR2 of an anti-FV monoclonal antibody (FV-238).

The sequence SEQ ID No. 45 is an amino acid sequence of a heavy chain CDR3 of an anti-RV monoclonal antibody (RV-238).

The sequence SEQ ID No. 46 is an amino acid sequence of a light chain CDR1 of an anti-FV monoclonal antibody (FV-238).

The sequence SEQ ID No. 47 is an amino acid sequence of a light chain CDR2 of an anti-RV monoclonal antibody (RV-238).

The sequence SEQ ID No. 48 is an amino acid sequence of a light chain CDR3 of an anti-IV monoclonal antibody (IV-238).

The sequence SEQ ID No. 49 is the amino acid sequence 60-75 of the protein VP6 of Rotavirus.

LIST OF SEQUENCES

(1) GENERAL INFORMATION:

(i) DEPOSITOR:

(A) NAME: University of ≥mrgogne (B) FUE: Esplanade Erasme (C) CITY: DIJON

(E) COUNTRY: FRANCE

(F) POSTAL CODE: 21000

(G) TELEPHONE: 03 80 39 50 00

(ii) TITLE OF THE INVENTION: New means for diagnosis, prevention and treatment vis-à-vis contaminations or infections by viruses with mucous tropism.

(iii) NUMBER OF SEQUENCES: 49 (iv) FOFME DECRYPTED BY COMPUTER (A) TYPE OF MEDIA: Floppy disk {B) COMPUTER Iffl 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 () TYPE: amino acid

(C) NUMBER OF STRANDS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: 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: both

(ii) TYPE OF MOLECULE: peptide (iii) HYPOTHETIC: NO (iv) ANTI-SENSE: NO

RECTIFIED SHEET (RULE 91) ISA / EP (v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CD 2H3 8

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 2:

Val Ile Trp Ala Gly Gly Gly Thr Leu Tyr Lys Ser Ala Leu Met Pro 1 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: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR3H3 8

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 3:

Asp Pro Asp Tyr Tyr Asp Asn Tyr Phe Tyr Ala Met Asp Tyr 1 5 10

(5) INFORMATION FOR SEQ ID NO: 4:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 17 amino acids (B) TYPE: amino acid

(C) NUMBER OF BRENS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide (iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR1L348

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 4:

Lys Ser Ser Gin Ser Leu Phe Asn Thr Arg Thr Arg Lys Asn Tyr 1 5 10 15

Leu Ala (6) INFORMATION FOR SEQ ID NO: 5:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 7 amino acids (B) TYPE: amino acid

(C) NUMBER OF STRANDS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR2L348

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 5:

Trp Ala Ser Thr Arg Asp Ser 1 5

(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: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR3L348

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 6:

Lys Gin Ser Tyr Asn Leu Phe Thr 1 5

(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: both (ii) TYPE OF MOLECULE: peptide

(vii) IMMEDIATE SOURCE:

(B) CLONE: PEP1H3 8

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 7:

Cys Gly Phe Ser Leu Thr Asn Tyr Ala Val His Trp Val Cys 1 5 10

(9) INFO MATIONS FOR SEQ ID NO: 8:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 19 amino acids (B) TYPE: amino acid

(C) NUMBER OF STRANDS:

(D) CONFIGU ATION: of the two

(ii) TYPE OF MOLECULE: peptide

(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: both

(ii) TYPE OF MOLECULE: peptide

(vii) IMMEDIATE SOURCE:

(B) CLONE: PEP3H3 8

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 9:

Cys Ala Arg Asp Pro Asp Tyr Tyr Asp Asn Tyr Phe Tyr Ala Met Asp 1 5 10 15

Tyr Trp Gly Pro Gly Thr Cys 20 (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: both

(ii) TYPE OF MOLECULE: peptide

(vii) IMMEDIATE SOUP:

(B) CLONE: PEP1L348

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 10:

Cys Lys Ser Ser Gin 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) CONFIGU ATION: of the two

(ii) TYPE OF MOLECULE: peptide

(vii) IMMEDIATE SOURCE:

(B) CLONE: PEP2L348

(xi) DESCRIPTION OF THE 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) INFORMATION FOR SEQ ID NO: 12:

(i) CHARACTERISTICS OF THE SEQUENCE:

(A) LENGTH 18 amino acids (] __) TYPE: amino acid

(C) NUMBER OF STRANDS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide (vii) IMMEDIATE SOURCE:

[B) CLONE: PEP3L348

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 12:

Cys Tyr Tyr Lys Gin Ser Tyr 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 BRENS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide (iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO (v) TYPE OF FRAGMENT: internal (vii) IMMEDIATE SOUP:

(B) CLONE: CDR1H138

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 13:

Ser His Trp Ile Glu 1 5

(15) 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: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

<B) CLONE: CDR2H138

(xi) DESCRIPTION OF THE 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) 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 both (ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOUP:

(B) CLONE: CDR3H138

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 15:

Glu Gly Ala Tyr 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: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(E) CLONE: CDR1L138

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 16:

Arg Ser Ser Gin Ser Ile Val His 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: both

(ii) TYPE OF MOLECULE: peptide (iii) HYPOTHETIC: NO (iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOUP:

(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 9 amino acids (B) TYPE: amino acid

(C) NUMBER OF STRANDS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO (iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR3L138

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 18:

Phe Gin Gly Ser His Val Pro Arg Thr 1 5

(20) 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: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOUP:

(B) CLONE: CDR1H133

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 19:

Ser Tyr Trp Ile His 1 5

RECTIFIED SHEET (RULE 91) ISA / EP (21) INFORMATION FOR SEQ ID NO: 20:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 17 amino acids (E) TYPE: amino acid

(C) NUMBER OF STRANDS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide (iii) HYPOTHETIC: NO (iv) ANTI-SENSE: NO (v) TYPE OF FRAGMENT: internal (vii) IMMEDIATE SOURCE:

(B) CLONE: CDR2H133

(xi) DESCRIPTION OF THE 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) 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: both

(ii) TYPE OF MOLECULE: peptide (iii) HYPOTHETIC: NO (iv) ANTI-SENSE: NO (v) TYPE OF FRAGMENT: internal (vii) IMMEDIATE SOURCE:

(B) CLONE: CDR3H133

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 21:

Ser Tyr Arg Asn Asp Asp Gly Tyr Tyr Ala Met 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: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE- NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

[B) CLONE: CDR1L133

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 22:

Ser Ser Ser Gin Ser Leu Val His Arg Asp Gly Asn Thr Tyr Leu His 1 5 10 15

(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: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

{B) CLONE: CDP2L133

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 23:

Lys Val Ser Asn Arg Phe Ser 1 5

(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: both

(ii) TYPE OF MOLECULE: peptide (iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR3L133

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 24:

Ser Gin Ser Thr His Val Pro Leu Thr 1 5

(26) INFORMATION FOR SEQ ID NO: 25:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 5 amino acids (1E§ TYPE: amino acid

(C) NUMBER OF STRANDS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

{B) CLONE: CDR1H18E2

(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) CONFIGU RATION: of the two

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOU RCE:

(9 CLONE: CD R2H18 E2 (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: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(E) CLONE: CDR3H18E2

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 27:

Asp Pro Asp Tyr Tyr Asp Asn Tyr Phe Tyr Ala Met Asp Tyr 1 5 10

(29) INFORMATION FOR SEQ ID NO: 28:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 10 amino acids (B) TYPE: amino acid

(C) NUMBER OF STRANDS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR1L18K

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 28:

Ser Ala Arg Ser Ser Val Gly Tyr Met His 1 5 10 (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: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR2L1812

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 29:

Asp Thr Phe Lys Leu Ala Ser 1 5

(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: both

(ii) TYPE OF MOLECULE: peptide

(iii) H YPOTHET I THAT: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR3L18E2

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 30:

Phe Gin Gly Ser Glu Phe Pro Leu Thr 1 5

(32) INFORMATION FOR SEQ ID NO: 31:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 5 amino acids (B) TYPE: acid in ine

(C) NO BRE OF BRINS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide (iii) HYPOTHETIC: NO (iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CD R1H2 B8

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 31:

Ser Tyr Asp Ile Ser 1 5

(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: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR2H2BB

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 32:

Val Ile Trp Thr Gly Gly Gly Thr Tyr Tyr Asn Ser Ala Phe

1 5 10

Met Ser

15 (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: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CD R3H2 B8

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 33:

RECTIFIED SHEET (RULE 91) ISA / EP Arg Thr Gly Thr Gly Pro Phe Ala Tyr 1 5

(35) INFORMATION FOR SEQ ID NO: 34:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 17 amino acids (B) TYPE: inborn acid

(C) NUMBER OF STRANDS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR1L2B8

(xi) DESCRIPTION OF THE 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) 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: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR2L2B3

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 35:

Leu Val Cys Asp Leu Glu Ser 1 5

(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: both (ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR3L2 B8

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 36:

Gin His Ile Arg Gin Pro Tyr Thr 1 5

(38) INFORMATION _t FOR SEQ ID NO: 37:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 5 amino acids (___) TYPE: amino acid

(C) NUMBER OF STRANDS:

(D) CONFIGU RATION: of the two

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOUP:

(B) CLONE: CDR1H255

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 37:

Ser Phe Gly Met His 1 5

(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) CONFIGU RATION: of the two

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOU RCE:

(B) CLONE: CD R2H255 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 38:

Tyr Ile Ser Ser Gly Ser Ser Thr Ile Tyr Tyr Ala Asp Thr Val 1 5 10 15

Lily 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: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOUP:

(B) CLONE: CDR3H255

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 39:

Ser Arg Leu Arg Thr Val Met Asp Tyr 1 5

(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: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR1L255

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 40:

Arg Ala Ser Gin Pro Asp Ile Gly Ser Ser Leu Asn 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: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR2L255

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 41:

Ala Thr Ser Ser Leu Asp Ser 1 5

(43) INFORMATION FOR SEQ ID NO: 42:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 9 amino acids (B) TYPE: amino acid

(C) NUMBER OF STRANDS:

(D) CONFIGU ATION: of the two

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR3L255

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 42:

Leu Gin Tyr Ala Ser Ser Pro Phe Thr 1 5

RECTIFIED SHEET (RULE 91) ISA / EP (44) INFORMATION FOR SEQ ID NO: 43:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 5 amino acids (B) TYPE: amino acid

(C) NUMBER OF STRANDS:

(D) CONFIGU RATION: of the two

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR1H238

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 43: sp Tyr Ala Met His 1 5

(45) INFORMATION FOR SEQ ID NO: 44:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 17 amino acids (B) TYPE: amino acid

(C) NAME BRE OF BRENS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOU RCE:

{B) CLONE: CD R2H238

(xi) DESC RIPTION OF THE SEQUENCE: SEQ ID NO: 44:

Val Ile Ser Pro Tyr Asn Gly Asn Thr Asn Tyr Asn Gin Lys Phe 1 5 10 15

Lily gly (46) INFORMATION FOR SEQ ID NO: 45:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 5 amino acids (B) TYPE: amino acid

(C) NUMBER OF STRANDS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

{B) CLONE: CDR3H238

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 45:

Leu Leu Phe Pro Tyr 1 5

(47) INFORMATION FOR SEQ ID NO: 46:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 11 amino acids (B) TYPE: amino acid

(C) NUMBER OF STRANDS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(E) CLONE: CDR1L238

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 46:

Arg Ala Ser Gin Glu Ile Ser Gly Tyr Leu Ser 1 5 10

(48) INFORMATION FOR SEQ ID NO: 47:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 7 amino acids (B) TYPE: amino acid

(C) NUMBER OF STRANDS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide (iii) HYPOTHETIC: NO (iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR2L238

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 47:

Ala Ala Ser Thr Leu Asp Ser 1 5

(49) INFORMATION FOR SEQ ID NO: 48:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 9 amino acids (B) TYPE: amino acid

(C) NUMBER OF STRANDS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide

(iii) HYPOTHETIC: NO

(iv) ANTI-SENSE: NO

(v) TYPE OF FRAGMENT: internal

(vii) IMMEDIATE SOURCE:

(B) CLONE: CDR3L238

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 48:

Leu Gin Tyr Ala Ser Tyr Pro Phe Thr 1 5

(50) INFORMATION FOR SEQ ID NO: 49:

(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH 17 amino acids (B) TYPE: amino acid

(C) NUMBER OF STRANDS:

(D) CONFIGURATION: both

(ii) TYPE OF MOLECULE: peptide

(vii) IMMEDIATE SOURCE:

(B) CLONE: Rotavirus VP6 seq 60-75

(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 49:

Asn Glu Asp Phe Gly Leu Leu Gly Thr Thr Leu Leu Asn Leu Asp Ala Gly 1 5 10 15

Claims

1. Peptides characterized in that they essentially consist of an amino acid sequence capable of recognizing, according to an antigen-antibody type reaction, at least one epitope of a virus with mucous tropism, implicated in infections caused by such a virus. 2. Peptides according to claim 1, characterized in that they are capable of exerting an activity of neutralizing the viral infection and, if necessary, of inhibiting the fusion between infected and non-infected cells, or between cells and virus, and / or to exert a protective effect by passive or active route and / or to inhibit the transcription of the mucous tropism virus. 3. Peptides according to claim 1 or 2, characterized in that they are capable of inhibiting an essential step of viral multiplication. 4. Peptides according to any one of claims 1 or 3, characterized in that they have a specificity of viral subgroup in neutralization. 5. Peptides according to any one of claims 1 to 4, characterized in that they comprise an amino acid sequence possessing the properties of a CDR of anti-virus antibodies with mucous tropism. 6. Peptides according to any one of claims 1 to 5, characterized in that they essentially comprise one or more amino acid sequence (s) which corresponds (each correspond) to that of a CDR of an anti- mucous tropism virus, such as a CDR of an anti-RSV antibody or an anti-RV antibody. 7. Peptides according to any one of claims 1 to 5, characterized in that they have antigen-antibody type properties with RSV. 8. Peptides according to claim 7, characterized in that they are capable of reacting with the epitope 205-225 and / or 255-278 of the F protein of RSV. 9. Peptides according to claim 7 or 8, characterized in that they are capable in vitro of exerting an activity of neutralizing an infection of cells by RSV, and / or of inhibiting the fusion between cells infected with RSV and uninfected cells, or the fusion between cells and RSV. 10. Peptides according to claim 7 to 9, characterized in that they are capable in vivo, in particular when they are administered intranasally, of exerting a protective effect by the passive route against an RSV infection. 11. Peptides according to any one of claims 7 to 10, characterized in that they correspond to, or constitute analogs of regions of CDR, and in particular of CDR3, of monoclonal antibodies with VRS specificity, of subgroup A or B 12. Peptides according to any one of claims 7 to 11, characterized in that they have a size between 5 and 50 amino acids approximately, preferably between 10 and 30 amino acids approximately. 13. Peptides according to any one of claims 7 to 12, characterized in that they correspond to the amino acid sequences SEQ ID No. 1 to SEQ ID No. 12 and SEQ ID No. 25 to SEQ ID No. 42 . 14. Peptides according to any one of claims 7 to 13, characterized in that they essentially respond to the amino acid sequences SEQ ID No. 3 or SEQ ID No. 9. 15. Peptides according to any one of claims 1 to 14, characterized in that they have antigen-antibody type properties with FV. 16. Peptides according to claim 15, characterized in that they are derived from antibodies capable of reacting with site III and / or IV of the protein VP6 of RV. 17. Peptides according to claim 15 or 16, characterized in that they correspond to, or are analogs of CDR regions of monoclonal antibodies with RV specificity. 18. Peptides according to any one of claims 15 to 18, characterized in that they essentially comprise at least one amino acid sequence chosen from the group consisting of the sequences SEQ ID No. 13 to SEQ ID No. 27, and SEQ ID N ° 43 to SEQ ID N ° 48. 19. Peptides according to any one of claims 15 to 18, characterized in that they are grafted in place of the CDRs of i munoglobulins IgG or IgA. 20. Peptides according to any one of claims 1 to 19, characterized in that they present in linear form or cyclized form. 21. Antibodies, characterized in that they are directed against the peptides according to any one of claims 1 to 20. 22. Nucleic acids characterized in that they comprise the DNAs comprising the genetic information corresponding to the peptides according to any one of claims 1 to 20, advantageously the DNAs capable of coding for the peptides according to any one of claims 1 to As well as the RNAs, in particular the mRNAs, and the corresponding cDNAs. 23. Transfer and expression vectors such as cosmid, plasmid, phage, animal or plant virus containing nucleic acids according to claim 22 and host cells containing such vectors. 24. A process for obtaining peptides according to any one of claims 1 to 20, characterized in that one operates by synthesis, or according to genetic engineering techniques using nucleic acids or vectors or host cells according to claim 22 or 23. 25. Diagnostic compositions, characterized in that they comprise for detecting the presence of a virus with mucous tropism, in particular of FV or RSV in humans or animals, - of at least one peptide according to any one of claims 1 to 20, or to demonstrate an immune response, of at least one antibody according to claim 21, or an equivalent ligand, the peptide, the antibody or the ligand, being associated with a marker for the detection reaction, such as a radiolabel or an enzymatic marker and, if appropriate, with a vehicle suitable for carrying out the diagnosis. 26. Method for in vitro diagnosis of contamination or infection by a mucous tropism virus, characterized in that it comprises: - bringing a biological sample, such as a body fluid, into contact with . for detecting the presence of the virus in humans or animals, at least one peptide according to any one of claims 1 to 20, or a diagnostic composition according to claim 25, under conditions allowing the detection an anti gene- anti co rps type reaction, or . to demonstrate an immune response, with at least one anti-peptide antibody according to claim 14, a ligand binding to the peptide, or a diagnostic composition containing them according to claim 25, and disclosure of the reaction produced when the viral antigen is present. 27. Kits for the diagnosis of contamination or infection by a mucous tropism virus characterized in that they comprise at least one peptide according to one ^" any of claims 1 to 20, or an anti-peptide antibody according to claim 21, or a ligand, and the reagents suitable for the detection reaction, in particular markers and solvents. 28. Pharmaceutical compositions having anti-viral properties, characterized in that they contain at least one peptide with anti-viral properties according to any one of claims 1 to 20, in association with a pharmaceutically inert vehicle. 29. Compositions according to claim 28, characterized in that they can be administered intranasally. 30. Compositions according to claim 28 or 29, characterized in that they have anti-RSV properties and contain at least one peptide corresponding to one of the sequences SEQ ID No. 7 to SEQ ID No. 12 and very particularly to the sequence SEQ ID N ° 9. 31. Vaccine compositions characterized in that they contain an effective amount of antibodies according to claim 14, directed against the peptides according to any one of claims 1 to 13, or of equivalent ligands in association with an appropriate vehicle.