LU102016B1 - Vaccines based on an antigen protein fused to a nanostructuring scaffold - Google Patents

Abstract

SARS-CoV-2 is the source of a pandemic viral disease affecting millions of people across the world and has claimed hundreds of thousands lives since its onset in late 2019. An effective vaccine should trigger formation of protective humoral and cell immune response against the viral components that will either inhibit viral entry into cells or kill virus infected cells. The present invention refers to the implementation of a vaccine comprising a nucleotide sequence encoding genetically fused antigenic protein domains with scaffolding polypeptides that self-assemble into soluble oligomeric nanoparticles. Nanoparticles comprise at least six copies of the antigen domain including e.g. receptor binding domain (RBD) or HRC domains or whole extracellular SARS-Cov-2 spike protein and are beneficial in comparison to monomeric proteins, due to increased avidity.

Description

Vaccines based on an antigen protein fused to a nanostructuring scaffold

FIELD OF THE INVENTION The present invention refers to a polypeptide comprising a genetically fused antigenic polypeptide domain with a scaffolding polypeptide domain that is configured to form a self-assembled nanoparticle, particularly a self-assembled soluble oligomeric nanoparticle, that comprises at least six copies of the antigenic domain. In another aspect, a DNA plasmid encoding protein antigen domains of the viral Spike protein of SARS-CoV- 2 genetically fused to a scaffolding polypeptide domain is provided, which may be used as a vaccine against viral diseases such as against Covid-19.

BACKGROUND OF THE INVENTION Covid-19 is a pandemic viral disease caused by infection with SARS-CoV-2 that affected millions of people across the world and claimed hundreds of thousands lives (7-3). This virus emerged in 2019 and triggered worldwide contagion as it spreads mainly through the respiratory droplets and aerosol. Since an effective treatment of the disease or spread of the virus is currently lacking, vaccination seems to be the best hope to stop the waves of infection affecting people throughout the world. An effective vaccine should trigger formation of protective humoral and cell immune response against the viral components that will either inhibit viral entry into cells or kill virus infected cells. Different platforms for introduction of viral components have been used, including inactivated or attenuated viral particles, isolated adjuvanted proteins, mRNA, plasmid DNA, non-replicating viruses, each of them with particular properties. The advantages of DNA plasmid delivery including low immunogenicity, cost-effective production, stability at ambient temperature without the need for a cold chain make it a suitable vaccine platform although no DNA plasmid vaccines has been approved (4, 5).

Antibodies should preferentially be focused to the domains and epitopes that can prevent LU102016 viral recognition of the receptor, viral fusion with cell membrane or hinder viral replication in other ways. The most suitable targets seem to be protein domains through which virus attaches to the cellular receptors such as the receptor binding domain (RBD) of the trimeric spike protein of the SARS-CoV-2, whose tertiary structure in the complex with ACE2 receptor has been determined (6, 7). Masking binding epitope by the antibodies prevents viral binding to the receptor and infection of target cells. Indeed RBD has been used in several vaccine candidates against SARS-CoV-2, similar as before for the related pathogenic coronaviruses (8, 9) and monoclonal antibodies against the RBD have been effective in therapy (70, 11). In addition to the RBD, Spike protein has other domains that are involved in the fusion with human cells, such as the HRC domain that is not involved in recognition of the receptor protein but plays a direct role in fusion. This domain could be very interesting as a vaccine as this segment is highly conserved among coronaviruses in contrast to the RBD, therefore vaccine based on HRC could be used against multiple coronavirus types, such as for example SARS-CoV-2, SARS-CoV, MERS-CoV and other emerging viruses of the same type. HRC, also called HR2 domain has been used to prepare antibodies to neutralize viral infection. However, bacterially produced denatured HRC peptides have been used that generated relatively weak immune response in comparison to the RBD (72, 13).

The ability of viral proteins or its domains to induce formation of antibodies depends on the structure and size of antigen. Viral surface proteins are typically presented to the host in the form of nanoparticles tens of nm in diameter that present tens of copies of viral proteins. Affinity maturation, class switching and memory cell formation take place in germinal centers inside lymph node follicles (74), therefore transport of protein antigens to lymph nodes is preferable in comparison to the insoluble aggregates at the site of injection. It has been shown that cells respond better to particles that present multiple copies of the antigen in comparison to the monomeric proteins, due to the facilitated entry of the particles above 20 nm to the lymph nodes, clustering of B cell receptors on B- lymphocytes but also due to the increased avidity of multimeric proteins in comparison to protein monomers (75-18). It has been shown that nanoparticles above 50 nm are retained longer inside lymph node follicles and are presented on the dendrites of follicular LU102016 dendritic cells (79). The majority of vaccines in current Covid19 clinical trials are based on full length spike protein (20-28). In this case, antibodies against diverse surface exposed epitopes of the Spike protein are generated; some of them may not prevent recognition of the ACE2 receptor or fusion.

Moreover, antibodies that do not prevent viral entry may even facilitate viral entry into the cell through an antibody dependent enhancement mechanism (ADE), most likely mediated by the Fc domain of antibodies and Fcy receptors, as shown before for SARS CoV and MERS CoV, as a highly undesirable property of a vaccine (29-31). Therefore focusing immune response to the receptor binding domain (RBD) of the Spike protein may increase the probability of inducing neutralizing antibodies.

It has been shown that RBD as an immunogen indeed induces formation of neutralizing antibodies (24, 26) Presentation of the target antigen domain in the multimeric form may augment cellular response and formation of antibodies.

This could be accomplished by chemical conjugation of a viral protein domain to the nanoparticle or by a genetic fusion to the scaffold-forming polypeptide.

Examples of attachment of immunogenic domains to the virus-like capsule are structural envelope proteins of bacterial, plant or animal viruses of such as Qf, HPV, JCV, HBcAg, cowpea chlorotic mottle virus capsids (32) and many others, nonviral protein compartments such as ferritin, lumazine synthase and encapsulin (17, 33-36) and de novo designed protein or DNA cages(37—43). An important issue of this strategy is that antibodies or T cell response may also be targeted against the scaffolding protein, which could impair the efficiency of the subsequent immunizations with the same vaccine type or it could eliminate cells that produce the components of scaffold proteins in nucleic acid-based vaccines (44)(45). Implementation of the smallest scaffolding proteins could therefore represent an advantage.

The size of the scaffold that forms nanoparticles is typically on the order of 100-150 amino acid residues (e.g. for ferritin, QB, lumazine synthase). On the other hand fusion of peptide tags that induce formation of large amyloid fibrils comprising peptide antigens has also been used for the generation of vaccines (46, 47). In this case, the amyloid or helical assembly-promoting short peptide tag induced formation of long insoluble fibers. The addition of peptide antigens decorated those fibers with T or B-cell LU102016 targeting epitopes (47-49). Proteins domains could however only be incorporated into the amyloid fibers by a combination of amyloidogenic peptides and folded protein domain with attached longer domain that by itself was not prone to aggregation but was incorporated into the amyloid fibers (50). The antigens must reach lymph nodes where maturation of the adaptive immune response takes place (32). Virus like particles with sizes below 500 nm can traffic through the lymphatic system and can be taken up by antigen presenting cells such as dendritic cells, therefore large insoluble aggregates are not optimal as they remain in the tissue and only degradation products can reach lymph nodes where the maturation of antibodies and class switching takes place in cooperation between follicular dendritic cells B- and T-lymphocytes.

Foldon is a peptide from a T4 bacteriophage fibritin that has a strong propensity for trimerization (57, 52). Fusion of a 27-aminoacid residue foldon peptide to a protein domain can direct the trimerization of an antigen, which increases its size and presents it to the B—cell receptors in form of a trimer that may increase the response. Indeed fusion of an RDB domain to a foldon peptide induced formation of trimers of RBD and has been used as a vaccine against the SARS-CoV-2(24). In this structural arrangement, the size of a protein particle is about 60 kDa and the complex has on one side exposed a trimeric foldon that is strongly immunogenic (52).

A short peptide comprising 24 amino acid residues from the viral beta-annulus protein from tomato bushy stunt virus has been shown to spontaneously form nanoparticles measuring approximately 40 nm in diameter (53). This peptide has been used to attach different cargo molecules, from DNA to peptide domains (54, 55)(56). Beta-annulus peptide, however, has not been used for fusion with large folded protein domains or for vaccination. Vaccines comprising fusion of protein antigen and scaffolding protein have been in most cases used as isolated proteins injected into the patient but have not been used to encode nucleic acids to enable production of the immunogen in the body.

SUMMARY OF THE INVENTION

The present invention refers to a polypeptide comprising a polypeptide antigen domain LV102016 genetically fused via a flexible polypeptide linker to a self-assembling polypeptide scaffold, wherein the self-assembling polypeptide scaffold is configured to form a self- assembled nanoparticle comprising the polypeptide antigen in an oligomerized state, 5 wherein the number of polypeptide antigen domains in the self-assembled nanoparticle is equal or more than six, and wherein the self-assembling polypeptide scaffold comprises the following domains: a core oligomerizing domain based on packing based on hydrophobic amino acids, beta sheet forming peptide segments, or clusters of aromatic residues comprising at least two phenylalanine residues; charged solubility and repulsion enhancing residues preferably comprising 1-6 residues of the same charge, and optionally at least one oligomerizing domain configured to present protein antigens defined oligomers comprising, for example, two, three or four copies.

Moreover, the present invention refers to a nucleotide sequence comprising a coding sequence for the polypeptide according to the invention, optionally incorporated in a delivery vector such as a plasmid, a linear or circular nucleic acid or a virus. In a further aspect, the present invention refers to a protein comprising the polypeptide according to the invention. In a still further aspect, the present invention refers to a vaccine comprising the nucleotide sequence optionally incorporated in a delivery vector or the protein according to the invention.

Particularly, a subunit vaccine comprising a genetic fusion of a selected polypeptide antigen domain with a scaffolding domain, particularly a self-assembling polypeptide scaffold, that induces formation of soluble particles of oligomers of the antigen domain in six or more copies per particle is provided. The invention refers to the combination of a polypeptide antigen with oligomerizing scaffolding domains where the scaffolding polypeptide is a short preferably less than 30 amino acid long hypoimmunogenic peptide. Preferably, the stoichiometry and/or structure of the oligomer does not have any substantial impact on the polypeptide characteristics. A preferred embodiment of this invention is presented in Figure 1: The scaffolding domain, i.e. the self-assembling polypeptide scaffold, is composed of the following functional segments:

1. Core oligomerizing domain that can induce formation of oligomers, 2. Solubility enhancing and repulsion domain that can maintain the solubility of the nanoparticle in a micellar arrangement, 3. Oligomerization domain that can maintain defined oligomers of LU102016 the antigen domain, such as e.g. in a trimeric cluster. Between those domains short linker peptides comprising preferentially from 0 to 6 amino acids, preferentially selected from glycine or serine residues, are located.

Core oligomerizing domains are selected from hydrophobic amino acid residues, beta strand forming peptides or multiple copies of short beta sheet forming peptides connected by linkers of short peptide comprising at least two phenylalanine residues that have propensity for oligomerization. Example of the multiple beta sheet forming peptides are segments from the beta-annulus peptide (53) or combination of dry zipper peptides (57).

The core oligomerizing domain can e.g. be composed of a cluster of hydrophobic amino acid residues that form a core resembling molten globule with not necessarily defined tertiary structure. These residues are preferentially aliphatic amino acid residues such as Leu, lle, Val, Ala that are hypoimmunogenic. The second type of core oligomeric cluster relies on beta sheet forming segments that are composed of short, preferentially 5-20 amino acid segments and preferentially from 1-5, preferentially to 3 beta sheet forming segments. The beta-annulus peptide comprises 3 beta sheet forming segments linked by flexible linkers to enable unhindered packing. The third example of core oligomerizing domain are clusters of aromatic amino acids, preferentially at least two Phe residues that have been shown to form oligomers (64, 65).

Solubility enhancing and repulsion domain is preferably composed of 1-4 charged amino acid residues such as Glu, Asp or Lys, Arg of the same type so that they induce repulsion between polypeptide chains and lead to the formation of micelles.

Defined oligomerization domains are composed of peptides that form defined oligomers such as preferentially dimers, trimers, tetramers that are required to form defined protein antigen epitopes such as in viral proteins. Those defined oligomerizing domains can be selected from examples in the literature such as the trimerizing foldon peptide or defined parallel homodimeric, homotrimeric or homotetrameric coiled coll peptides (58, 59).

The polypeptide sequence according to this invention comprises the polypeptide antigen genetically fused via a flexible polypeptide linker to the self-assembling polypeptide scaffold that causes oligomerization of the polypeptide antigen on the self-

assembled nanoparticle, i.e. that is configured to form a self-assembled nanoparticle LU102016 comprising the polypeptide antigen in an oligomerized state, wherein the number of polypeptide antigen domains in each self-assembled nanoparticle is equal or more than six and where the scaffolding polypeptide comprises a core oligomerizing domain based on packing based on hydrophobic amino acids, beta sheet forming peptide segments or clusters of aromatic residues comprising at least two phenylalanine residues; charged solubility and repulsion enhancing residues preferably comprising 1-6 residues of the same charge, and optionally at least one defined oligomerizing domain configured to present protein antigens defined oligomers comprising preferentially two, three or four copies.

The core oligomerizing domain and charged solubility and repulsion enhancing residues can be located at the amino-terminal region of the polypeptide, at the carboxy- terminal region of the polypeptide or in the center of the polypeptide adjacent to the antigen domain, preferably between two antigen domains.

Moreover, the present invention provides an implementation of a vaccine that comprises a nucleotide sequence that codes for the polypeptide antigen domain that self assembles due to the fused scaffolding domain and is able to generate strong response and neutralization of viral infection with a scaffold domain to enable formation of particles comprising six or more copies of the antigen domain par particle.

Small monomeric protein domains typically exhibit weak response of the humoral immune system, which is strongly improved by the present scaffolding domain.

Further, the invention provides combinable vaccination compositions for use in therapy, particularly for applying to a subject in need thereof two or more vaccination treatments using the same target protein domain in each vaccine composition that is in each vaccination combined with a different scaffold domain to minimize the formation of immune response against the scaffold.

Weak immune response against the scaffold is beneficial and is minimized by the small length of the scaffolding amino acid sequence and hypoimmunogenic amino acid composition.

In one embodiment, the present invention refers to vaccine compositions against infection with a virus SARS-CoV-2, where the target viral domain comprises RBD or HRC domain from the viral spike protein while the scaffold polypeptide domains are preferably composed of the foldon peptide to which two domains of the RBD or HRC are fused to the N- and C-terminus, or beta-annulus peptide or an icosahedral cage-forming lumazine LV102016 synthase. By this means, increased immune response in comparison to isolated domains RBD or trimerized RBD or bacterially produced denatured HRC is provided, because the antigen domains are presented in multiple copies on protein particles self-assembled by the scaffolding polypeptide domain. This disclosure surprisingly provides an additional improvement for efficient vaccines which improvement is based on different combinations of the target protein domain with different scaffolds so that the response is boosted at subsequent immunizations only against the target protein but not against the scaffold.

Figure legends Figure 1: The concept of designed soluble oligomeric protein vaccines according to the invention. A selected polypeptide antigen is genetically fused to the scaffolding domain that contains the core oligomerizing domain, charged solubility and repulsion domain and optionally defined oligomerizing domain to present protein antigen as monomer or a defined oligomer at the surface of a soluble oligomer. Figure 2: Molecular models of differently scaffolded RBD domain with number of RBD domains per particle larger or equal to six (in brackets) (A); Scheme of RBD-scaffold constructs (B). Figure 3: Expression of RDB protein domain fused to different scaffolding domains produced in plasmid-transfected mammalian cells and detected with ELISA (A,C) and WB (B). Supernatant of HEK293 cells transfected with indicated construct was harvested 3 days post transfection and the presence of differently scaffolded RBD domain variants was detected with anti RBD antibodies (A,B) or a combination of anti S2 and anti hexa- histidine HRP conjugated antibodies (C). Figure 4: Characterization of RBD-BAN protein, isolated from supernatant of Expi293F cells. SDS-PAGE analysis confirmed the purity and size of isolated protein (A), while DLS proved the formation of soluble protein oligomers (B).

Figure 5: Scheme of immunization and sample collection from mice.

RBD vaccines were LU102016 administered into BALB/c mice in the form of combination plasmid DNA, complexed with transfection reagent at defined time intervals.

Blood was drawn before each boost immunization to determine specific antibody titers.

At the termination mice spleens were harvested fur further experiments.

Figure 6: Titer of total IgG antibodies against the RBD for different scaffolded RBDs and scaffold alone.

Mice were immunized with different combination of RBD plasmid DNA, complexed with jetPEl-in vivo transfection reagent.

RBD specific antibodies rose from prime to first and second boost.

Higher end point titer against RBD was observed in scaffold RBD vaccines compared to RBD alone.

Figure 7: Titer of total IgG antibodies reacting with a SARS-CoV-2 Spike protein for different scaffolded RBDs and against immunization by the scaffold.

Mice were immunized with different combination of RBD plasmid DNA, complexed with jetPEl-in vivo transfection reagent.

SARS-CoV-2 Spike protein specific antibodies rose from prime to first and second boost.

Higher end point titer against SARS-CoV-2 Spike protein was observed in scaffold RBD vaccines compared to RBD alone.

Figure 8: Formation of different classes of antibodies against RBD for different scaffolded RBDs and immunization by the scaffold.

Mice were immunized with different combination of RBD plasmid DNA, complexed with jetPEl-in vivo transfection reagent.

Titers of IgA, IgM, 1gG1, IgG2b and IgG3 against RBD protein were higher in scaffold RBD DNA vaccines compared to RBD DNA vaccine alone.

Figure 9: Weak formation of antibodies against the scaffolding domain of the RBD- scaffold constructs.

Mice were immunized with different combination of RBD plasmid DNA, complexed with jetPEl-in vivo transfection reagent.

Titers of antibodies against B- annulus or foldon scaffold were observed only in some tested animals.

When performing switch immunizations (prime and boost immunization were different) antibody titers against B-annulus or foldon scaffold were lower.

Figure 10: Cytotoxic T cell killing from immunized mice against cells expressing viral S protein.

Mice were immunized with different combination of RBD plasmid DNA,

complexed with jetPEl-in vivo transfection reagent and at the end of the experiment LV102016 spleen was harvested.

The cytotoxic effect of isolated CD8+ T cells was higher in RBD- scaffold DNA vaccines compared to RBD DNA vaccines alone.

Figure 11: Scheme of neutralization assay based on Spike-ACE2 interaction.

Virus entry depends on the interaction of virus S (Spike) protein and host receptor ACE2. When neutralizing antibodies are present in immunized mice sera, they bind to Spike and inhibit its interaction with ACE2. Unbound Spike proteins are washed away before detecting ACE2-bound Spike proteins with Streptactin-HRP.

Figure 12: Neutralization assay based on Spike-ACE2 interaction.

Sera of mice immunized with DNA vaccines comprising scaffolded RBD are capable of inhibition of Spike-ACE2 interaction.

Constructs encoding scaffolded RBD are more potent than RBD in inducing neutralizing antibodies.

Figure 13: Neutralization of Spike pseudoviral entry into cells by generated antibodies from RBD-scaffold DNA immunized mice.

Sera of mice immunized with DNA vaccines comprising scaffolded RBD are capable of neutralization of Spike pseudovirus entry into cells.

Figure 14: Titer of total IgG antibodies reacting with a SARS-CoV-2 Spike protein for different scaffolded HRCs.

Mice were immunized with different combination of HRC plasmid DNA.

Higher end point titer against SARS-CoV-2 Spike protein after prime immunization was observed in scaffold HRC vaccines compared to HRC alone.

Definitions The term vaccine as used herein refers to a preparation introduced into the body of human or animal to stimulate active acquired immunity to a particular infectious disease.

A vaccine may comprise protein components that are based on the sequence of selected viral proteins.

The term scaffold as used herein relates to a polypeptide that triggers formation of a self-assembling oligomeric structure, composed of three or more copies of the scaffolding polypeptide and oligomerizes the polypeptide antigen domain to which it is LU102016 genetically fused to in order to present multiple copies of the protein antigen per each particle.

The term Spike as used herein relates to the Spike glycoprotein of SARS-Cov-2 (UniProt: PODTC2) which attaches the virion to the cell membrane through interaction with the host receptor and mediates fusion of the virion with cellular membranes.

The term RBD as used herein relates to the receptor binding domain of Spike glycoprotein from SARS-Cov-2 encompassing amino acids 330 — 521. This region of the Spike protein mediates binding to human ACE2 receptor.

The term HRC as used herein relates to the alpha helical domain of Spike glycoprotein from SARS-Cov-2 encompassing amino acids 1128 — 1210.

The term ferritin as used herein relates to Helicobacter pylori-bullfrog hybrid ferritin encompassing residues 2-9 of bullfrog ferritin lower subunit (UniProt: PO7797 with mutation N8Q) and residues 3-167 of H. pylori nonheme ferritine (UniProt Q9ZLI1 with mutation I7E). The term foldon as used herein relates to the C-terminal domain fibritin of bacteriophage T4 which in its native state forms a trimeric B-hairpin propeller and can be used as an artificial trimerization domain.

The term lumazine synthase as used herein relates to the cage-forming protein lumazine synthase of bacteria Aquifex aeolicus (UniProt: 066529).

The term B-annulus (beta-annulus, B-annulus) as used herein relates to the 24- residue beta-annulus peptide originating from the tomato bushy stunt virus, which leads to icosahedral assembly.

The term pseudotyped virus SARS-CoV-2 as used herein relates to VSV-G virus, where surface G protein was replaced with SARS-CoV-2 Spike protein.

The term antibody as used herein relates to a protective protein produced by B lymphocytes in response to the presence of a foreign substance, called an antigen.

The term type of antibody as used herein relates to a protein (or protein complex) that includes one or more polypeptides substantially encoded by immunoglobulin genes or fragments of immunoglobulin genes. The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, LU102016 which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.

With respect to a pathological target such as a virus or an infected cell, the term "antigen" refers to a compound such as a polypeptide, polypeptide complex, glycoprotein, nucleic acid or the like, which elicits an immune response.

Organism, as used herein relates to any living organism.

The term immune system, as used herein, relates to an organ system in higher developed organisms composed out of specific cell subtypes, which act in order to eliminate foreign molecules from the organism.

The term immune response as used herein relates to ability of an immune system of any living organism to respond to administered antigen to formulate appropriate antibodies by antibody-producing cells, e.g. plasma cells in order to achieve a specific protection against any foreign pathogens.

The term immunization as used herein relates to administration of prepared vaccine into living organism or its body via oral or different parenteral inoculation routes, e.g. intranasal, intramuscular, subcutaneous, intradermal. The vaccine may e.g. be delivered via simple needle injection, inhalation or by the use of different traumatic or non- traumatic devices after vaccine administration. The first dosage of the administered vaccine into the organism is referred as prime and any following administrations of vaccines are known as boost.

The term mice as used herein relates to BALB/c OlaHsd mice, an albino laboratory-bred strain or any mice laboratory strain that is commonly used in immunological studies and immunization protocols, composed of immunization, appropriate blood draw and final termination of the study.

The term End point titer (EPT) as used herein relates to ELISA-based or any other experimental determination and calculation of specific antibodies towards different antigens. EPT is depicted as the final serum dilution or titer that present absorbance value above calculated cutoff value.

The term genetic fusion as used herein refers to the polypeptide or nucleic acid that codes for the polypeptide in a single chain that comprises polypeptide of two or more constituents that are consecutive or between them are short linker polypeptides that prevent steric overlap, typically comprising 1-10 small polar amino acid residues, typically LU102016 glycine or serine or similar amino acid residues.

The term cell, as used herein, refers to a eukaryotic or prokaryotic cell, a cellular or multicellular organism (cell line) cultured as a single cell entity that has been used as a recipient of nucleic acids and includes the daughter cells of the original cell that has been genetically modified by the inclusion of nucleic acids. The term refers primarily to cells of higher developed eukaryotic organisms, preferably vertebrates, preferably mammals. This invention relies also on non-vertebrates cells, preferably plant cells.

The term cells also refer to human or animal primary cells or cell lines. Naturally, the descendants of one cell are not necessarily completely identical to the parents in morphological form and its DNA complement, due to the consequences of natural, random or planned mutations. A "genetically modified host cell" (also "recombinant host cell") is a host cell into which the nucleic acid has been introduced. The eukaryotic genetically modified host cell is formed in such a way that a suitable nucleic acid or recombinant nucleic acid is introduced into the appropriate eukaryotic host cell. The invention hereafter includes host cells and organisms that contain a nucleic acid according to the invention (transient or stable) bearing the operon record according to the invention. Suitable host cells are known in the field and include eukaryotic cells. It is known that proteins can be expressed in cells of the following organisms: human, rodent, cattle, pork, poultry, rabbits and the like. Host cells may include cultured cell lines of primary or immortalized cell lines.

The term T cell, as used herein, relates to lymphocytes, the T-subset (e.g. CD4+ and CD8+ T cells) of white blood cells, a specific mononuclear immune cell population that interacts in the adaptive immune system by recognizing antigen peptides bound to major histocompatibility complex (MHC) molecules with a T cell receptor. Recognition of antigen peptides via a TCR activates signaling pathways, which result in cytokine signaling and a cytotoxic effect.

The term cytotoxic as used herein relates to cell destruction or cell killing by specific cytotoxic T cells, e.g. CD8 positive T cell subset via MHCI, bound to specific antigen. Antigen specific CD8+ T cell recognition of specific antigen bound to MHCI results in cell death activation and subsequent antigen-infected cell destruction.

The term specific lysis as used herein relates to calculated percentage of antigen- LU102016 infected cell death via antigen specific CD8 cytotoxic T cells. Percentage of specific lysis is calculated based on bioluminescence values of measured cells. Bioluminescence values are presented as Average Radiance (p/s/cm?/sr).

The term B cell, as used herein, relates to lymphocytes, the B-subset of white blood cells, a specific mononuclear immune cell population that interacts in the adaptive immune system by recognizing antigen peptides bound to major histocompatibility complex molecules with a B cell receptor. Recognition of antigen peptides via a BCR activates signaling pathways, which result in clonal expansion, transformation into plasma cells and subsequent antibody production.

The term nucleic acid, as used herein, refers to a polymeric form of nucleotides (ribonucleotides or deoxyribonucleotides) of any length and is not limited to single, double or higher chains of DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or polymers with a phosphorothioate polymer backbone made from purine and pyrimidine bases or other natural, chemical or biochemically modified, synthetic or derived nucleotide bases.

The term protein, as used herein, refers to the polymeric form of amino acids of any length, which expresses any function, for instance localizing to a specific location, localizing to specific DNA sequence, facilitating and triggering chemical reactions, transcription regulation, structural function, biological recognition.

The term recombinant, as used herein, means that a particular nucleic acid (DNA or RNA) is a product of various combinations of cloning, restriction and / or ligation or chemical synthesis leading to a construct having structurally coding or non-coding sequences different from endogenous nucleic acids in a natural host system.

The insertion of the vectors into the host cells is carried out by conventional methods known from the field of science, and the methods relate to transformation or transfection and include e.g.: chemically induced insertion, electroporation, micro- injection, DNA lipofection, cellular sonication, gene bombardment, viral DNA input, as well as other methods. The entry of DNA may be of transient or stable. Transient refers to the insertion of a DNA with a vector that does not incorporate the DNA of the invention into the cell genome. A stable insertion is achieved by incorporating DNA of the invention into the host genome. The insertion of the DNA of the invention, in particular for the preparation of a host organism having stably incorporated a nucleic acid, e.g. a DNA, of LU102016 the invention, can be screened by the presence of markers. The DNA sequence for markers refers to resistance to antibiotics or chemicals and may be included on a DNA vector of the invention or on a separate vector.

The term homologous sequences/fragments/proteins refers to the amino acid sequences of proteins/fragments, originating from the same or another organism, which show a good protein alignment with preferentially more than 70 %, preferably more than 80%, more preferably more than 90%, even more preferably at least 95% conserved primary structure in the alignment analysis. The term "homologue" refers also to mutant proteins, whose mutations minimally alter the function of the protein.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the provision of vaccines that comprise oligomeric polypeptide antigen domains, preferably more than three copies of the polypeptide domain from an antigen protein, such as for example but not limited to viral protein, fused to a self-assembling scaffolding polypeptide that defines the oligomeric state and the number of copies of viral protein domain in each vaccine particle, whereas the scaffolding polypeptide preferably comprises less than 30 amino acid residues. In one embodiment, the scaffolding domain is composed of the fibritin trimerization foldon peptide, preferably whereas an antigen domain is genetically fused both to the amino- and carboxyl-terminal end of the foldon peptide in the arrangement antigen- foldon-antigen. In a preferred embodiment, the self-assembling polypeptide scaffold is selected from a foldon peptide as displayed in SEQ ID NOs: 6 (amino acids (AA) 228- 256), 14 (AA 112-140), 36 (AA 246-274), and 40 (AA 112-140). The antigen domain is fused directly to the foldon or via a flexible linker peptide comprising typically 0-20 amino acid residues, where the linker preferably contains glycine and serine or threonine amino acid residues or other small hydrophilic amino acid residues. In this arrangement, each particle forms a trimer comprising 6 copies of the antigen domain. In one embodiment, the scaffolding domain is composed of the beta-annulus peptide containing 24 amino acid residues that has a propensity to self-assemble into several nanometer large particles comprising 60 or more copies of the antigen per LU102016 particle.

In a preferred embodiment, the self-assembling polypeptide scaffold is selected from a beta-annulus peptide as displayed in SEQ ID NOs: 2 (AA 26-49), 16 (AA 26-49), 38 (AA 146-169), and 40 (AA 144-167) or the corresponding homologous segments.

The scaffolding domain is fused to the antigen domain directly or via a flexible linker peptide comprising 0-20 amino acid residues, where the linker preferably contains glycine and serine or threonine amino acid residues or other small hydrophilic amino acid residues.

In one embodiment, the scaffolding domain may be composed of the lumazine synthase from Aequifex aeolicus that has a propensity to self-assemble into several nanometer large particles comprising 60 copies of the antigen per particle in an icosahedral geometry.

In a preferred embodiment, the self-assembling polypeptide scaffold is selected from a polypeptide as displayed in SEQ ID NOs: 8 (AA 224-377), and 20 (AA 15-168) or the corresponding homologous segments.

The scaffolding domain is fused to the antigen domain directly or via a flexible linker peptide comprising 0-20 amino acid residues, where the linker preferably contains glycine and serine or threonine amino acid residues or other small hydrophilic amino acid residues.

The polypeptide antigen domain may comprises a RBD or HRC domain from the Spike protein of SARS-CoV-2. Particularly, the polypeptide antigen domain may comprise the RBD domain displayed in SEQ ID NOs: 2 (AA 65-263), 4 (AA 227-399), 6 (AA 26- 224; 259-458), 8 (AA 225-377), 18 (AA 26-224), 22 (AA 43-241), 24 (AA 44-242), 26 (AA 44-242), 28 (AA 44-242), 30 (AA 44-242), 32 (AA 44-242) and 36 (AA 43-242) or the corresponding homologous segments.

In another embodiment, the polypeptide antigen domain may comprise the HRC domain displayed in SEQ ID NOs: 10 (AA 26-108), 12 (AA 26-108), 14 (AA 26-108; 144-226), 16 (AA 65-147), 20 (AA 177-159), 38 (AA 26-108) and 40 (AA 26-108) or the corresponding homologous segments.

In one aspect, the polypeptide of the invention comprises one antigen domain.

In another aspect, the polypeptide of the invention comprises at least two antigen domains, preferably 2 antigen domains, such as two RBD or two HRC domains.

The at least two antigen domains may be located at adjacent positions (i.e. antigen-antigen) or at separate positions such as separated by the scaffold domain, particularly by a foldon domain such as antigen-foldon- antigen.

In a preferred embodiment, the polypeptide antigen domain comprises a RBD LU102016 domain from the Spike protein of SARS-CoV-2 fused to a beta-annulus peptide, which is preferably configured to form a nanoparticle with six copies of the RBD Spike protein domain.

In another preferred embodiment, the polypeptide antigen domain comprises an HRC domain from the Spike protein of SARS-CoV-2 fused to a beta-annulus peptide, which is preferably configured to form a nanoparticle with six copies of the HRC Spike protein domain.

In another preferred embodiment, the polypeptide antigen domain comprises an HRC or RBD domain from the Spike protein of SARS-CoV-2 fused to an Aequifex aeolicus lumazine synthase, which is configured to form a nanoparticle, preferably a nanoparticle with at least six copies of the Spike protein domain.

In another aspect, the present invention provides a vaccine in the form of nucleic acids coding for a protein antigen-scaffold polypeptide formed through the genetic fusion of the antigen polypeptide with the scaffold polypeptide that forms nanoparticles comprising more than three copies of the polypeptide domain.

Functionally, nanostructured vaccine triggers stronger immune response than a monomeric antigenic polypeptide and induces weak response to the scaffold polypeptide that is fused to the viral polypeptide in order to assemble them in a nanoparticle comprising more than three copies of the viral polypeptide.

The embodiment of the vaccine can comprise different antigens and is represented by examples of the polypeptide domains of the Spike protein of SARS-CoV-2 protein, specifically the RBD domain (residues 330-521) or an HRC segment of the S2 domain (residues 1128-1210).

The examples described in more detail below are designed to best describe the invention. These examples do not limit the scope of the invention, but are merely intended to provide a better understanding of the invention and its use.

Example 1: Design of the HRC and RBD protein genetically fused to the scaffolding LY102016 self assembling polypeptides RBD domain of the Spike protein of SARS-CoV-2 encompassing residues 330 to 521 or an HRC segment of the S2 domain (residues 1128-1210) were selected as antigens for immunization.

Polypeptide scaffolds were designed in order to induce formation of oligomers of RBD or HRC aimed to present those domains at the surface of the generated polypeptide nanoparticles.

While the foldon peptide is often used to generate protein trimers, in this type of fusion the selected antigen is clustered in a trimeric form on one side of the complex, while the trimeric foldon is exposed at the other side of the trimeric nanoparticle.

The problem of exposure of the foldon to B-cell receptors and antigens was solved by fusing RDB or HRC domains to both the N- and C-terminal end of the foldon.

In this manner, a trimer is constructed that comprises six copies of the RBD or HRC antigen per particle with the small foldon peptide in the center, where it is protected from the recognition by antibodies.

The foldon peptide therefore represents 8% of the amino acid residues of the fusion construct in the case of RBD.

In the next type of a designed nanostructured RBD or HRC assembly, the selected antigen is fused to the 24-residue beta-annulus peptide originating from the tomato bushy stunt virus, where it leads to the icosahedral assembly.

In this manner, the beta-annulus induces the self-association of the antigen domains, where its structural model has been approximated based on the icosahedral symmetry of the parent viral scaffold.

According to this model, 60 copies of the antigen would be presented in the assembly.

However based on the particle size the isolated protein produced in mammalian cells the assembly may be even larger, which is beneficial for the presentation to cells of the immune system and formation of antibodies.

Beta-annulus peptide therefore presents approx. 16% of the residues and since it is engaged in the assembly, this domain is buried and weakly accessible to the antibodies.

Additionally, the beta-annulus peptide does not contain aromatic residues, with the exception of a single histidine residue, which makes it hypoimmunogenic, therefore resulting in the production of a low amount of antibodies against the scaffold.

Two additional scaffolded variants of the RBD and HRC were produced, one with a fusion of Bullfrog (Rana catesbeiana) and Helicobacter pylori ferritin that forms a 24-meric particle (60) and the second with Aequifex aeolicus lumazine synthase that forms an icosahedral assembly comprising 60 subunits.

Both ferritin and lumazine synthase have been used LU102016 before for the generation of vaccines, however, they have not been fused to the RBD and used as a vaccine for Covid-19. In case of those proteins, the fraction of the scaffold amino acid residues in the fusion protein is larger, reaching almost 50%, which also, in this case, remains buried in the core and protected from binding of antibodies.

Molecular modeling was used to generate the models and determine the length of the flexible peptide linker that is added between the scaffold and antigen domain in order to eliminate the potential steric hindrance of packing of protein domains.

In a similar way as for the RBD and HRC, the double N- and C-terminal fusion to the foldon could be designed for other protein antigens against viruses or other targets that present six copies of the domain in a single particle.

Genetic fusion with the beta-annulus peptide could also be used to design vaccines for other antigens.

While smaller peptides have been fused before to the beta-annulus peptide and produced in bacteria (55, 61, 62), according to the present invention, a novel genetic fusion of the beta-annulus peptide to the antigen for the production of vaccine and expression in mammalian cells is provided.

Introduction of the nucleotide coding sequence for the protein antigen-beta-annulus peptide fusion generates the vaccine that can be introduced into humans of animals.

Results: Molecular models of genetically fused RBD to scaffold domains.

Model structures, depicted in Figure 2 of designed nanovaccines were prepared by performing homology modelling with Modeller (version 9.23) (63). Structures PDBID: 6VW and PDBID: 6VSB were used as templates for the receptor binding domain (RBD). For the RBD-ferritin construct, composed of 24 domains, PDBID: 3EGM was used as template for the ferritin cage.

RBD-foldon-RBD was modelled as a trimer based on the template PDBID: 1RFO.

For B-annulus-RBD, homology modelling was used to first construct a model of the trimeric subunit based on the structure of the tomato bushy stunt virus (TBSV) (PDBID: 2TBV). Twenty trimeric subunits were then assembled into a RBD- decorated protein cage by employing icosahedral symmetry characteristic for TBSV, resulting in a 60-mer with a diameter of approximately 26 nm.

Model of the design AaLS- RBD, composed of 60 subunits, was built by employing PDBID: 1HQK as template for the lumazine synthase scaffold.

Example 2: Design of a sequence of scaffold for soluble protein antigen oligomers LU102016 for vaccine According to the described principle, the soluble protein oligomers are composed of the core oligomerizing domain, charged solubility and repulsion residues and optionally defined oligomerizing domain (Figure 1). The core oligomerizing domain can be composed of a cluster of hydrophobic amino acid residues that form a core resembling molten globule with not necessarily defined tertiary structure. These residues are preferentially aliphatic amino acid residues such as Leu, lle, Val, Ala that are hypoimmunogenic. The second type of core oligomeric cluster relies on beta sheet forming segments that are composed of short, preferentially 5- 20 amino acid segments and preferentially from 1- 5, preferentially to 3 beta sheet forming segments. The beta- annulus peptide comprises 3 beta sheet forming segments linked by flexible linkers to enable unhindered packing. The third example of core oligomerizing domain are clusters of aromatic amino acids, preferentially at least two Phe residues that have been shown to form oligomers (64, 65).

Scaffolding peptides can be attached to the antigen domain either at the amino- or carboxyl-terminal end, but preferentially at the carboxyterminal, so that the oligomerizing peptide is formed last and the ribosomal synthesis is not hindered by the oligomerizing domain.

Results: Based on those principles the following scaffolding domains have been designed and have been fused to the RBD or extracellular Spike protein domain for vaccine against Covid-19: * MicIN: AAAVVVIIILLLGDD (SEQ ID NO: 41) * Micl: GS DDD G LLLIIIVVVAAA (SEQ ID NO: 42) + Mic2: GS DDDG ILILILILILIL (SEQ ID NO: 43) + Mic3: GS DDD G QQNNLLLLLLLL (SEQ ID NO: 44) + Mic4: GS DD SG IFFI (SEQ ID NO: 45) * D3zip1: GS VEALYL GSG NNQQN PVA LYQLEN (SEQ ID NO: 46)

Example 3: Preparation of DNA constructs for the HRC or RBD protein genetically “102016 fused to the scaffolding polypeptides In order to prepare DNA constructs, common biology methods known in the art such as: chemical transformation of competent E. coli cells, plasmid DNA isolation, polymerase chain reaction (PCR), reverse transcription - PCR, PCR linking, nucleic acid concentration determination, DNA agarose gel electrophoresis, isolation of fragments of DNA from agarose gels, chemical synthesis of DNA, DNA restriction with restriction enzymes, cutting of plasmid vectors, ligation of DNA fragments, purification of plasmid DNA in large quantities were used. The exact course of experimental techniques and methods are well known to experts in the field and are described in the manuals of molecular biology. All the work was performed using sterile techniques, which are also well known to the experts in the field. All plasmids, completed constructs and partial constructs were transformed into the bacteria Escherichia coli by chemical transformation. Plasmids for transfection into cell lines (animal or human) have been isolated using a DNA isolation kit that removes endotoxins. Results: All plasmid constructs were inserted into a pcDNA3 backbone downstream of a CMV promotor. A CD45 signal sequence was added N-terminally for the secretion of protein antigens from mammalian cells and a hexa-histidine tag was added to constructs for affinity isolation. Non-tagged constructs were prepared in parallel for immunization purposes. The RBD construct and fusion constructs were prepared using a synthesized gene fragment encoding the RBD domain (aa 330-521) or RBD domain fused to peptides (beta annulus, foldon) or polypeptides (ferritin, lumazine synthase). Constructs are listed in table 1; nucleotide sequences as well as corresponding polypeptide amino acid sequences in the sequence listing.

Table 1: Constructs encoding RBD and HRC-based nanoparticle vaccine Bro” No Lame or] ID NO ID NO backbone 5 [6 | RBD-foldon-RBD | pcDNA3 | Signal-sequence —RBD—foldon-RBD | TP [Smee [POW [Sorensen RED meme antes | synthase 9 [10 |HRC ~~ [pcDNA3 | Signal sequence — HRC__ |

HRC-ferritin pcDNA3 | Signal sequence — HRC — ferritin LY102076 HRC-foldon-HRC | pcDNA3 | Signal sequence — HRC — foldon — HRC B-annulus-HRC | pcDNA3 | Signal sequence — beta annulus — HRC pcDNA3 | Signal sequence - RBD 19 20 Lumazine pcDNA3 Signal sequence — lumazine synthase - HRC synthase-HRC Mic1N-RBD pcDNA3 | Signal sequence — Mic1N - RBD RBD-Mic1 pcDNA3 | Signal sequence — RBD — Mic1 RBD-Mic2 pcDNA3 | Signal sequence — RBD — Mic2 RBD-Mic3 pcDNA3 | Signal sequence — RBD — Mic3 RBD-Mic4 pcDNA3 | Signal sequence — RBD — Mic4 RBD-D3zip1 pcDNA3 | Signal sequence — RBD — D3zip1 Spike-Mic2 pcDNA3 | Signal sequence — Spike — Mic2 RBD-foldon-Mic2 | pcDNA3 | Signal sequence — RBD — foldon — Mic2 HRC-GCN4-B- pcDNA3 | Signal sequence —-HRC-GCN4-b.annulus annulus 39 40 HRC-foldon-B- pcDNA3 Signal sequence — HRC-foldons-b.annulus annulus Example 4. Characterization of RBD and HRC-based nanoparticles produced by human cells (western blot, isolation, SEC-MALS, GF) Mammalian cell line HEK293 and Expi293F were transfected with plasmids for vaccination coding fusion proteins of the RBD to the scaffolding domains in order to produce in cells the protein immunogen. Supernatants of HEK293 or Expi293F cells were harvested 3-5 days post transfection and analyzed with ELISA and western blot using anti-RBD antibodies to determine the expression and size of proteins (Figure 3).

Produced proteins were purified and characterized. The molecular weight of proteins was analyzed by the western blot, which confirmed the expected size of the proteins. Proteins were purified using chromatographic methods and isolated protein particles were analyzed using scattering methods. Purified RBD-beta-annulus protein (Figure was analyzed by the dynamic light scattering and demonstrated that it forms soluble oligomers in the range of 500 nm (Figure 4B).

Methods and techniques of cultivating cell cultures are well known to experts in the field and are therefore briefly described in order to illustrate the implemented examples. Cells from the HEK293T cell line were grown at 37 ° C and 5% CO». For cultivation, a DMEM medium containing 10% FBS was used, containing all the necessary nutrients and growth factors. Expi293F cells were cultivated in Expi293™ Expression Medium at 37°C and 8%

CO2 on an orbital shaking platform with shaking speed based on shaking diameter and LU102016 flasks’ size.

Results: HRC and RBD scaffolded variants were expressed in plasmid transfected mammalian cells as shown by Western Blot (WB) and enzyme-linked immunosorbent assay (ELISA) (Figure 3). It is clear from Figure 4A the appropriate size and purity of recombinant isolated RBD-BAN protein at 26 kDa.

Figure 4B shows the soluble protein oligomer formation in the range of 500 nm, as determined by DLS.

Example 5. Immune response in mice to immunization by the scaffolded RBD by DNA vaccine To test the immunogenicity of RBD or RBD-scaffold DNA vaccines female 8-10 weeks BALB/c OlaHsd mice (Harlan Envigo, Italy) were used for immunization protocols.

All animal studies were approved by appropriate government institutions taking into account all the ethical considerations regarding animal studies.

Laboratory animals were housed in IVC cages (Techniplast), fed standard chow (Mucedola) and tap water was provided ad libitum.

Mice were maintained in 12-12 hours dark-light cycle.

All animals, used in the study, were healthy; accompanied with health certificate from the animal vendor.

Immunization (Figure 5) was carried out under general inhalation 1,8% MAK isoflurane anesthesia (Harvard Apparatus). Animals were vaccinated with plasmid DNA (RBD, RBD- scaffold, scaffold vectors, empty pcDNAS3 vector), coupled with jetPEl-in vivo transfection reagent (Polyplus Transfection) with the N/P ratio 12. Each animal received a total of 20g of designated plasmid DNA, complexed with transfection reagent with intramuscular injection.

Vaccine (prime) was administered using 30G needle into m.tibialis anterior after appropriate area preparation.

First boost was administered 2 weeks later and same was done for the second boost.

One day before each boost, blood was drawn from lateral tail vain using Microvette 300 (Sarstedt). Two weeks after the second boost the experiment was terminated.

Final blood was taken and also spleens were harvested from animals.

Mouse sera were prepared by centrifugation of blood samples 3000RPM/ 20min at 4°C.

In mouse sera specific anti-RBD and anti-Spike SARS CoV-2 total IgG were determined by ELISA test in order to test the immunogenicity of designed RBD DNA vaccines.

Also specific different classes of anti-RBD antibodies were determined.

In different experiment switch immunization was performed, where prime and first boost LU102016 was carried out with RBD DNA, connected with different scaffold in order to lower anti scaffold total IgGs, e.g. prime was carried out with B-annulus-RBD and for the boost RBD- foldon-RBD was used and vice versa.

ELISA tests were performed to determine End point titer. High binding half-well plates (Greiner) were used. According to desired total IgG determination, appropriate recombinant protein was used for ELISA plates coating; e.g. to determine specific anti RBD total IgG recombinant protein his-RBD was bound to plates. To determine specific anti-Spike SARS CoV-2 total IgG recombinant his-Spike SARS CoV-2 protein was used for coating of the ELISA plates. In the experiments, where total IgG against scaffold were measured foldon or B-annulus peptides were bound to ELISA plates. Recombinant proteins were coated in PBS buffer at the concentration of 60 ng of designed protein per well. Total volume of coated solution was 50 pl/well. Coated plates were incubated overnight at 4°C. Next day plates were washed with PBS+0,05 % Tween20 using ELISA plate washer (Tecan). Next, plates were blocked for 1h at RT with ELISA diluent (PBS+3%FBS) solution. Afterwards, plates were again washed. Then serial dilution of mice sera was added to plates, where each dilution presented a certain titer values. In the first row a 1:100 dilution was added, then a 3-fold dilution was performed with each row, resulting in dilution row (1:100, 1:300, 1:900, 1:2700, 1:8100, 1:24300, 1:72900, 1:218700). For mouse sera ELISA diluent was used. Mouse sera were incubated at 4°C overnight. Next day, plates were washed and afterwards goat anti mouse IgG (H+L)-HRP antibodies (Jackson ImmunoResearch), diluted 1:3000 in ELISA diluent solution. Plates were incubated 1h at RT. Next plates were washed. After the final wash, TMB substrate was added and the reaction was stopped with the addition of acid solution (3M H3PO4).

Absorbance (A450 nm, A620 nm) was measured by Synergy Mx microtiter plate reader (Biotek). Next End point titers were calculated. End point titer was determined as the dilution above the value of the cutoff.

From absorbance data of control animals (vaccinated with empty vector pcDNA3) the cutoff value was determined (Frey et al. 1998) by the formula: Cutoff = x + SD + f,

where Æ is the mean of absorbance samples, SD is standard deviation and f is the LU102016 standard deviation multiplier. For confidence level of 95% value 2,335 was used as the standard deviation multiplier. Graphs present values of calculated EPT; each dot represent single animal. Titers below 1:100 are considered as negative value and are not presented in the graphs, but are taken into account when mean is calculated. Results: Figure 6 shows end point titer against RBD antibodies two weeks after prime or boost immunization, determined in mice sera from RBD DNA, RBD-scaffold, scaffold or empty vector immunized animals. EPT after prime (left panel) is enhanced in animals, vaccinated in RBD-scaffold DNA vaccines (all different scaffolds) compared to RBD DNA immunized animals. The highest titer is seen in B-annulus RBD DNA immunized animals; approximately 2log10 higher. No antibodies against RBD were seen in only scaffold immunized animals. EPT after 15! boost (middle panel) are higher in all animals, still no antibodies are formed in animals, immunized only with scaffold vectors. Titer in animals, immunized with RBD-scaffold DNA increased. The same was observed after the 2" boost (right panel), where some antibodies were also formed in animals, immunized with ferritin scaffold or B-annulus. Further, some increase in EPT was observed in all animals, immunized with RBD-scaffold DNA vaccines. Clearly, all constructs, encoding for RBD- scaffold vaccines were more immunogenic as RBD DNA alone, suggesting higher immune protection against SARS-CoV-2.

Figure 7 shows end point titer against Spike SARS-CoV-2 antibodies two weeks after prime or boost immunization, determined in mice sera from RBD DNA, RBD- scaffold, scaffold or empty vector immunized animals. EPT after prime is enhanced in animals, vaccinated in RBD-scaffold DNA vaccines (all different scaffolds) compared to RBD DNA immunized animals. No antibodies against Spike SARS-CoV-2 were seen in only scaffold immunized animals. EPT after 15! boost are higher in all animals, still no antibodies are formed in animals, immunized only with scaffold vectors. Titer in animals, immunized with RBD-scaffold DNA increased. The same was observed after the 2" boost, where some antibodies were also formed in animals, immunized with B-annulus scaffold alone. Further, some increase in EPT was observed in all animals, immunized with RBD-scaffold DNA vaccines. Clearly, all constructs, encoding for RBD-scaffold vaccines were more immunogenic as RBD DNA alone, suggesting higher immune LU102016 protection against SARS-CoV-2. From Figure 8 it can clearly be seen that different subset of antibodies against RBD are formed in mice sera from RBD DNA, RBD-scaffold, scaffold or empty vector immunized animals.

This was determined after the 2" boost at the end of the experiment.

In all cases the titer of antibodies (IgA, IgM, 1gG1, IgG2b, IgG3) against RBD is higher in animals, immunized with RBD-scaffold DNA vaccines compared to animals that received only RBD DNA vaccine.

The ratio IgG/IgM is in favor of IgG.

In the experiment where switch immunization was carried out antibodies against scaffold proteins depicted in Figure 9 were detected.

Switch immunization (i.e. different RBD-scaffold for prime and boost immunization) was carried out to lower antibody production against scaffold peptides.

Control animals received only scaffold plasmid DNA.

Left panel shows total IgG against foldon, where right panel shows total IgG against B-annulus at the end of the experiment that is two weeks after the boost immunization.

Only two animals (immunized with foldon scaffold alone) produced antibodies against foldon.

In RBD-foldon immunization only one animal exhibited IgG against foldon.

In the case of switch immunization (prime with B-annulus-RBD DNA or RBD-foldon; boost with the opposite one) no animals reacted against foldon.

Similar was observed for IgG against B-annulus.

EPT of IgG against B-annulus was lower or absent in animals that underwent switch immunization protocol.

Example 6. Antigen-specific cytotoxic effect of RBD DNA vaccines immunized mice T cells To determine the antigen-specific presence of cytotoxic T-cells and its action, regarding cytotoxicity, mice spleens from RBD DNA or RBD-scaffold DNA immunized animals were harvested at the end of the immunization protocol.

Single cell suspension from spleens were obtained using tissue dissociator gentleMACS™ Dissociator, gentleMACS C tubes and MACS buffer according to the manufacturer’s instruction (Miltenyi Biotec). CD8+ T cell from spleen cell suspension were isolated using CD8a+ T Cell Isolation Kit according to the manufacturer's instruction

(Miltenyi Biotec). Cells were isolated based on negative selection using LS columns, LU102016 obtaining up to 108 of maximal number of labelled cells.

To determine RBD specific cytotoxicity mouse NIH-3T3 cells.

NIH-3T3 cells were seeded into 24-well plates (1*10*/well); next day cells were transfected with pCG1-hACE2 and pCMV-TMPRSS2 plasmids.

The next day, cells were infected with Spike pseudovirus.

Next day isolated CD8a+T cells (1*10*/well) were added in RPMI1640 cell medium.

After 24 hours, bioluminescence was determined using IVISIII (Perkin Elmer) after the addition of D- luciferin (500pg/ml), showing the state of RBD-specific cytotoxicity of CD8+T cells, isolated from RBD DNA or RBD-scaffold DNA vaccinated animals.

Bioluminscence values are presented as Average Radiance (p/s/cm?/sr), which were determined using Living Image® software.

From Average Radiance values (ARV) the percentage of infected NIH-3T3 specific lysis was calculates using formula: 9% specific lysis = 100% spontaneous death ARV - test ARV spontaneous death ARV — maximal killing ARV Results: It is clear from Figure 10 (left panel) that the higher cytotoxicity was observed in NIH-3T3 infected cells, which were treated with CD8+ T cells from mice that were immunized with RBD-scaffold DNA vaccines compared to RBD DNA immunized animals, implicating improved RBD-specific cytotoxicity potential of RBD-scaffold DNA vaccines.

Figure 10 (right panel) shows improved specific lysis of NIH-3T3 infected cells, when CDB8+ isolated cells from RBD-scaffold immunized mice were added compared to lysis of NIH-3T3 cells treated with CD8+ T cells from alone RBD DNA vaccinated animals.

Mean % of all specific lysis off RBD-scaffold DNA vaccinated animals isolated CD8 cells exhibited more than 80% RBD-specific cytotoxic activity, compared to only RBD, where approximately 40% of specific lysis was observed.

Each dot in graphs presents spleen cells from designated animal that was immunized with appropriate RBD DNA or RBD- scaffold DNA vaccine.

Example 7: Neutralization of ACE2 spike interaction by generated antibodies SARS-CoV-2 entry into host cells depends on the interaction between virus Spike protein and human receptor ACEZ that is present on the surface of human cells.

Thus in vitro assay using isolated proteins can be used to follow the capacity of antibodies to block LU102016 Spike interaction with ACE2. First, ACE2-Fc (Genscript) at concentration of 2 pg/ml in phosphate buffer saline (PBS) was adsorbed to wells of ELISA plates at 4°C overnight. Serum dilutions were prepared in 1% BSA/PBS-T (1% bovine serum albumin in phosphate buffer saline with Tween 20) and incubated with Spike protein at final concentration of 0.1 ug/ml for 1h at 37°C. After blocking in 1% BSA/PBS-T for 1 h at 37°C plates were washed in PBS-T and serum- Spike samples were added to wells and incubated for 2h at room temperature. After wash the plate was incubated with streptactin-HRP (1:10000) in 1% BSA/ PBS-T for 1h at room temperature. After the final wash, TMB substrate was added and the reaction was stopped with addition of acid solution (3M H3PO4). Absorbance was measured by Synergy Mx microtiter plate reader (Biotek). The concept of neutralization test is schematically presented in Figure 11.

Figure 12 presents results of in vitro neutralization assay. Absorbance values were normalized to average maximal absorbance (100%, samples where Spike was added in the absence of serum) and average background value (no ACE2 adsorbed, no Spike present) using equation: Xsampie(%)=100*(Asample-Abackground)/(Amax-Abackground). Negative control samples (where one of the binding partners is absent) do not yield values above background demonstrating that non-specific binding is negligible.

Results: Mice immunized with scaffolded RBD DNA vaccines develop potent neutralizing antibodies when compared to RBD vaccine as demonstrated with the loss of Spike protein binding to ACE2, depicted in Figure 12.

Example 8: Neutralization of viral entry into cells by generated antibodies … Pseudovirus system based on vesicular stomatitis virus (Berger Rentsch and Zimmer, Plos One, 2011) was used to determine virus neutralization capacity of immunized mice sera. Plasmids and VSVAG*/G virus were provided by Stefan Pôlhmann. Pseudovirus preparation was described previously (Hoffmann et al, Cell, 2020). Briefly, HEK293T cells were seeded into 6-well plates (9*10*/well) a day before transfection with pCG1- — Spike/PEl mixture. The next day, cells were infected with VSVAG*/G virus in serum-free medium for 1h, after which medium was removed and cells were washed with PBS before complete medium supplemented with anti-VSV-G antibody (8G5F11, Kerafast) was LV102016 added to the cells. After 18h cell supernatant was centrifuged and cleared pseudovirus supernatant was aliquoted and stored at -80°C until neutralization experiments. HEK293 or Vero E6 were seeded (2.5*10*/well) a day before transfection with plasmids encoding ACE2, TMPRSS2 and Renilla luciferase. Immunized mice sera were preincubated with spike pseudovirus for 30min before addition to the cells. The next day, medium was removed and cells were lysed in Passive lysis buffer. Luciferin substrate was used to detect Firefly luciferase activity as a measure of pseudovirus infection and coelenterazine H to follow Renilla luciferase activity for determination of transfection efficiency and normalization.

Results: As shown in Figure 13, sera of mice immunized with scaffolded RBD DNA vaccines neutralize pseudotype virus infection of HEK293 cells that were transfected with plasmids encoding ACE2 and TMPRSS2. Mice sera from B-annulus-RBD DNA immunized mice exhibited the best neutralization effect compared to others.

Example 9. Immune response in mice to immunization by the scaffolded HRC by DNA vaccine To test the immunogenicity of HRC or HRC-scaffold DNA vaccines female 8-10 weeks BALB/c OlaHsd mice (Harlan Envigo, Italy) were used for immunization protocols. All animal studies were approved by appropriate government institutions taking into account all the ethical considerations regarding animal studies. Laboratory animals were housed in IVC cages (Techniplast), fed standard chow (Mucedola) and tap water was provided ad libitum. Mice were maintained in 12-12 hours dark-light cycle. All animals, used in the study, were healthy; accompanied with health certificate from the animal vendor.

Immunization was carried out under general inhalation 1,8% MAK isoflurane anesthesia (Harvard Apparatus). Animals were vaccinated with plasmid DNA (HRC, HRC-scaffold, empty pcDNAS3 vector) alone. Each animal received a total of 20ug of designated plasmid DNA as a prime vaccination using 30G needle into m.tibialis anterior after appropriate area preparation. Two weeks after the prime the experiment was terminated. Mouse sera were prepared by centrifugation of blood samples 3000RPM/ 20min at 4°C. In mouse sera specific anti-Spike SARS CoV-2 total IgG were determined by ELISA test in order to LV102016 test the immunogenicity of designed HRC DNA vaccines.

ELISA tests were performed to determine End point titer as stated in the Example 5.

Graphs present values of calculated EPT; each dot represent single animal. Titers below 1:100 are considered as negative value and are not presented in the graphs, but are taken into account when mean is calculated.

Results: Figure 14 shows end point titer against Spike SARS CoV-2 antibodies two weeks after prime immunization, determined in mice sera from HRC DNA, HRC-scaffold or empty vector immunized animals. Clearly, all constructs, encoding for HRC-scaffold vaccines were more immunogenic as HRC DNA alone, where HRC-ferritin exhibited best action, suggesting higher immune protection against SARS-CoV-2.

References LU102016

1. Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727-733 (2020).

2. Wu, F. ef al. A new coronavirus associated with human respiratory disease in China. Nature 579, 265-269 (2020).

3. WHO cononavirus disease (COVID19) situation report.

4. Prather, K. J., Sagar, S., Murphy, J. & Chartrain, M. Industrial scale production of plasmid DNA for vaccine and gene therapy: Plasmid design, production, and purification. Enzyme Microb. Technol. 33, 865-883 (2003).

5. Racz, R., Li, X., Patel, M., Xiang, Z. & He, Y. DNAVaxDB: The first web-based DNA vaccine database and its data analysis. BMC Bioinformatics 15, S2 (2014).

6. Wrapp, D. et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science (80-. ). 367, 1260-1263 (2020).

7. Shang, J. et al. Structural basis of receptor recognition by SARS-CoV-2. Nature 581, 221-224 (2020).

8. Dai, L. et al. A universal design of betacoronavirus vaccines against COVID-19, MERS and SARS. Cell (2020). doi:10.1016/j.cell.2020.06.035

9. Ma, C. et al. Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments-The importance of immunofocusing in subunit vaccine design. Vaccine 32, 6170-6176 (2014).

10. Wang, C. et al. À human monoclonal antibody blocking SARS-CoV-2 infection. Nat. Commun. 11, 1-6 (2020).

11. Wu, Y. et al. A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2. Science (80-. ). eabc2241 (2020). doi:10.1126/science.abc2241

12. Wabl, M. & Steinberg, C. Affinity maturation and class switching. Curr. Opin. Immunol. 8, 89-92 (1996).

13. Maity, P. C. et al. B cell antigen receptors of the IgM and IgD classes are clustered in different protein islands that are altered during B cell activation. Sci. Signal. 8, 1-16 (2015).

14. Bachmann, M. F. & Jennings, G. T. Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat. Rev. Immunol. 10, 787-96 (2010).

15. Lôpez-Sagaseta, J., Malito, E., Rappuoli, R. & Bottomley, M. J. Self-assembling protein nanoparticles in the design of vaccines. Comput. Struct. Biotechnol. J. 14, 58-68 (2016).

16. Bachmann, M. F. & Zinkernagel, R. M. NEUTRALIZING ANTIVIRAL B CELL RESPONSES. Annu. Rev. Immunol. 15, 235-270 (1997).

17. Zhang, Y.-N. et al. Nanoparticle Size Influences Antigen Retention and Presentation in Lymph Node Follicles for Humoral Immunity. Nano Lett. 19, 7226-7235 (2019).

18. Mullard, A. World Report COVID-19 vaccine development pipeline gears up. Lancet 395, 1751—

19. Kruse, R. L. Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China. F7000Research 9, 72 (2020).

20. Corbett, K. S. et al. SARS-CoV-2 mRNA Vaccine Development Enabled by Prototype Pathogen Preparedness. bioRxiv Prepr. Serv. Biol. (2020). doi:10.1101/2020.06.11.145920

21. Mercado, N. B. et al. Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques. Nature 1-11 (2020). doi:10.1038/s41586-020-2607-z

22. Yu, J. ef al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science (80-. ). 6284, eabc6284 (2020).

23. Jackson, L. A. ef al. An mRNA Vaccine against SARS-CoV-2 - Preliminary Report. N. Engl. J. Med. (2020). doi:10.1056/NEJMoa2022483

24. Smith, T. R. F. et al. Immunogenicity of a DNA vaccine candidate for COVID-19. Nat. Commun. 11, 2601 (2020).

25. Zhu, F.-C. et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet 6736, 1-10 (2020).

26. Folegatti, P. M. et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS- CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 1-13 (2020). doi:10.1016/s0140-6736(20)31604-4

27. Fu, Y., Cheng, Y. & Wu, Y. Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools. Virol. Sin. 12250, (2020).

28. Wan, Y. et al. Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry. J. Virol. 94, (2019).

29. Liu, L. et al. Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI insight 4, (2019).

30. Kanekiyo, M. & Buck, C. B. Virus-Like Particle and Nanoparticle Vaccines. Human Vaccines: Emerging Technologies in Design and Development (Elsevier Inc., 2017). doi:10.1016/B978-0-12- 802302-0.00003-0

31. Choi, B. et al. Effective Delivery of Antigen-Encapsulin Nanoparticle Fusions to Dendritic Cells Leads to Antigen-Specific Cytotoxic T Cell Activation and Tumor Rejection. ACS Nano 10, 7339- 7350 (2016).

32. Kamp, H. D. et al. Design of a broadly reactive Lyme disease vaccine. npj Vaccines 5, 1-10 (2020).

33. Kanekiyo, M. et al. Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies. Nature 499, 102-6 (2013).

34. Swanson, K. A. et al. A respiratory syncytial virus (RSV) F protein nanoparticle vaccine focuses antibody responses to a conserved neutralization domain. Sci. Immunol. 5, eaba6466 (2020).

35. King, N. P. et al. Computational design of self-assembling protein nanomaterials with atomic level LU102016 accuracy. Science (80-. ). 336, 1171-1174 (2012).

36. King, N. P. et al. Computational design of self-assembling protein nanomaterials with atomic level accuracy. Science 336, 1171-4 (2012).

37. Xu, C. et al. Design of a hyperstable 60-subunit protein icosahedron. Nature 535, 136-9 (2016).

38. Ljubetië, A. et al. Design of coiled-coil protein-origami cages that self-assemble in vitro and in vivo. Nat. Biotechnol. 35, 1094-1101 (2017).

39. Lienert, F., Lohmueller, J. J., Garg, A. & Silver, P. A. Synthetic biology in mammalian cells: Next generation research tools and therapeutics. Nature Reviews Molecular Cell Biology 15, 95-107 (2014).

40. Veneziano, R. et al. Role of nanoscale antigen organization on B-cell activation probed using DNA origami. Nat. Nanotechnol. 15, 716-723 (2020).

41. Ueda, G. et al. Tailored Design of Protein Nanoparticle Scaffolds for Multivalent Presentation of Viral Glycoprotein Antigens. 1-30 (2020). doi:10.1101/2020.01.29.923862

42. McCluskie, M. J. et al. The effect of preexisting anti-carrier immunity on subsequent responses to CRM 197 or Qb-VLP conjugate vaccines. Immunopharmacol. Immunotoxicol. 38, 184-196 (2016).

43. Da Silva, D. M., Pastrana, D. V., Schiller, J. T. & Kast, W. M. Effect of Preexisting Neutralizing Antibodies on the Anti-tumor Immune Response Induced by Chimeric Human Papillomavirus Virus-like Particle Vaccines. Virology 290, 350-360 (2001).

44. Espacenet — search results.

45. Hudalla, G. À. et al. Gradated assembly of multiple proteins into supramolecular nanomaterials. Nat. Mater. 13, 829-836 (2014).

46. Rudra, J. S. et al. Self-assembled peptide nanofibers raising durable antibody responses against a malaria epitope. Biomaterials 33, 6476-6484 (2012).

47. Rudra, J. S. et al. Responses to Peptide Self-Assemblies. ACS Nano 1557-1564 (2012).

48. Wu, Y., Kelly, S. H., Sanchez-Perez, L., Sampson, J. H. & Collier, J. H. Comparative study of a- helical and B-sheet self-assembled peptide nanofiber vaccine platforms: influence of integrated T- cell epitopes. Biomater. Sci. 3522-3535 (2020). doi:10.1039/d0bm00521e

49. US20160074509A1 - Methods and compositions related to immunogenic fibrils - Google Patents.

50. Berthelmann, A., Lach, J., Gräwert, M. A, Groll, M. & Eichler, J. Versatile C3-symmetric scaffolds and their use for covalent stabilization of the foldon trimer. Org. Biomol. Chem. 12, 2606-2614 (2014).

51. Sliepen, K., van Montfort, T., Melchers, M., Isik, G. & Sanders, R. W. Immunosilencing a highly immunogenic protein trimerization domain. J. Biol. Chem. 290, 7436-42 (2015).

52. Matsuura, K., Watanabe, K., Matsuzaki, T., Sakurai, K. & Kimizuka, N. Self-assembled synthetic viral capsids from a 24-mer viral peptide fragment. Angew. Chemie - Int. Ed. 49, 9662-9665 (2010).

53. Nakamura, Y., Yamada, S., Nishikawa, S. & Matsuura, K. DNA-modified artificial viral capsids self- LU102016 assembled from DNA-conjugated B-annulus peptide. J. Pept. Sci. 23, 636-643 (2017).

54. Matsuura, K., Watanabe, K., Matsushita, Y. & Kimizuka, N. Guest-binding behavior of peptide nanocapsules self-assembled from viral peptide fragments. Polym. J. 45, 529-534 (2013).

55. Matsuura, K., Ota, J., Fujita, S., Shiomi, Y. & Inaba, H. Construction of Ribonuclease-Decorated Artificial Virus-like Capsid by Peptide Self-assembly. J. Org. Chem. 85, 1668-1673 (2020).

56. Colletier, J.-P. et al. Molecular basis for amyloid- polymorphism. Proc. Natl. Acad. Sci. 108, 16938-16943 (2011).

57. Ciani, B. et al. Molecular basis of coiled-coil oligomerization-state specificity. Proc. Natl. Acad. Sci. U. S. A 107, 19850-5 (2010).

58. Woolfson, D. N. The design of coiled-coil structures and assemblies. Adv Protein Chem 70, 79— 112 (2005).

59. Kanekiyo, M. et al. Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor- Binding Site. Cell 162, 1090-1100 (2015).

60. Matsuura, K., Mizuguchi, Y. & Kimizuka, N. Peptide nanospheres self-assembled from a modified B-annulus peptide of Sesbania mosaic virus. Biopolymers 106, 470-475 (2016).

61. Matsuura, K. Synthetic approaches to construct viral capsid-like spherical nanomaterials. Chem. Commun. 54, 8944-8959 (2018).

62. Eswar, N. et al. Comparative protein structure modeling using MODELLER. Curr. Protoc. protein Sci. 50, 2.9.1-2.9.31 (2007).

63. Colombo, G., Soto, P. & Gazit, E. Peptide self-assembly at the nanoscale: a challenging target for computational and experimental biotechnology. Trends Biotechnol 25, 211-218 (2007).

64. Gradisar, H. et al. Similarities and specificities of fungal keratinolytic proteases: comparison of keratinases of Paecilomyces marquandii and Doratomyces microsporus to some known proteases. Appl. Environ. Microbiol. 71, 3420-3426 (2005).

5.88 2 :@ listi PO05527 744 D898 - 25.08.2820 - sequence listing A Es Alarm md Tove $3 doy od AE Phares <EAB> NALIOHAL INSTITUTE OT CHEMISTPY : ; x 3 pan § © $3 . « Se AR Yarrcines hacarl an an antican aeat ais Seas Se à nnnnctreuetiondhne SALE Vatcines Based on an antigen protein fused to a nanostructurin 8 Coa A

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ggteoccaaat aa 792

<218> 2

<211> 263

<212> PRT

<213> Artificial Sequence

<488> 2

Met Thr Met Tyr Leu Trp Leu Lys Leu Leu Ala Phe Gly Phe Ala Phe

1 5 18 15

Leu Asp Thr Glu Val Phe Val Thr Gly Ile Asn His Val Gly Gly The 28 25 38

Gly Gly Ala Ile Met Ala Pro Val Ala Val The Arg Gln Leu Val Gly

48 45 Ser Ser Gly Ser Gly Gly Ser Ser Gly Ser Gly Gly Ser Ser Gly Ser 50 55 60

Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala The

65 7e 75 89

Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys

85 sg 95

Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe 188 185 118

Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr

115 128 125 Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gin 138 135 148

Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu

145 158 155 160

Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu

165 178 175

Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg 188 185 198

Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr

Page 2

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D88 - 35.98.2820 - sequence listing(P065527744) attgaaaage ttctgaatga gcagelgaac aaagaaatge aatcatcaaa ceotttatatge 788 agtatgetect cotggtgita cactcactca ctegacgety cagetttett tettttegat 848 Cacgcagcce asgaatacga gcacglgaag aageolgatta tatttettaa tgaaaataat see gttecagtec agttgacate aatttcagce ceggageaca aatttgaggz geotcactcaa 968 attittcaaa aagcttacga acacgaacag catatatcez aaagtataaa tastategig 1828 gatcacgcga Tasagagcaa agatcatgen accttcaact ttectgcagts gtacetgget 1068 gnacaacatg agçaggaget attetttaag gatatacteg acaagatcga actgatigse 1148 aatgaaaace acggecttta cttggcagat caatatgtca aaggaatage taagtetaga 1288 asgagttaa 1289 <218> 4 <211> 482 <212> PRY <213> Artificial Sequence 488> 4 Met Thr Met Tyr Leu Trp Leu Lys Leu Leu Ala Phe Gly Phe Ala Phe 1 5 18 15 Leu Asp Thr Glu Val Phe Val Thr Gly Pro Asn Ile Thr Asn Leu Cys 28 25 38 Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala 48 45 Trp Asn Arg Lys Arg Tle Ser Asn Cys Val Ala Asp Tyr Ser Val Leu 58 55 68 Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro 65 78 75 88 Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr ala Asp Ser Phe 85 28 95 Val Ile Arg Gly Asp Glu Val arg Gln Ile Ala Pro Gly Gin Thr Gly 180 185 118 Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Page 4

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LO LAS LED Aon Qlv Val ST aly Cha Aeun Sus Tur Dhe Una lau ale Can Tur Sly ADI ALY VOX VIN LY MRE ASS LYS HVT FRE PDO LES dn oe PVTTOALY TS “OI + CLR ing iu 155 Sa TF or Frere PES Roe Tee TAN ema EL A ei - Noe VAT NET Rie Sho fin Dey Thee Som Riu Wal fiv Tue in sen aps Any Vim fn ti ifs FIR QAR FPO IR ASN GLY Val UGLY 1yP GUN FPO Tyr APE Val Val vai GN DEAN sat LFI LA A2 Ÿ gate Cons Sa Nee 3 5 spas = © x J Er oy Sn x Lai Sen Dey fin L'an foes Hage Ain Dir AT: Than ni Muro Hi Das Yonge LEU SEP FRE Gal LEU LOU HIS AL Pro ala hr val LYS GLY Pro Lys "IN ER SR PER Lay LAD A888 SE en en en 7 PEL et man € ELU A PE vi = ; A AS ary fete Soe fair Shas aay Shay Wie Any Sole Min Dhe ser are Aes GAY SEP LGIV Ser Gy LAU SEP Gin Val arg Gin Gin Fhe Ser LYS Asp yey JR yp se px IAD SRE NAG LED L348 2353 ZA ay pu, 3 . Cot om N fn Ù : pu A end ~~ pr © Tin fu fac msi L'air Acs Sis Sn ia Noy Paver fi Mat Shs Toes oe LAE DAU LYS LOU LOU ASH OIL Gin Val ASN LYS Liu Met Gin Ser SE! ~ An ane

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RAT TID REE NN 385 318 315 328 xx es N Vase AT + ~~ Lis oy ~~ Lad a = ny = ++ tion Din Siw HIRES AST ey Tarps fo Far Mayo Sas me L3G te sun Sag AN EN Ir LAE FIR GAN LYS ALS TYP Glu HIS Glu GLN HIS Ale Ser GLUu Ser Lie aan yea sen FAD 330 355 fe An TT Ad NORA Wer AV Tre [ire Cam AA LEY on AT ew Tha eal ; a cn 0 x An Aer WS ; Tin x Seven Ta Ages LS ART = Plan DNS AST KEN LIE Val ASD HIS AIS 118 LYS DOM LVS ASD HIS Ala nr Fhe VAN sax “ue 348 345 358 Now ia Ÿ ne SO TT ae ay hr NX fey AY m PS ae FY RA PS à FY SN ar * X Acn Pha lou In Trn Tee Wal Als SF Ma Mio OT As SF Val fau ASN PRE LOU LAN ITD VD val Add GLU wan HIS GLU LIU Gly oval LOU see money FR. 325 SE 355 Sa lle Aou Ta à . a Pace TY en SLR A ae WY oo a x Ana RE Bahn lye Ash Tle [au Aon ye Tila S90 fau Ta Sy Ack Tu cn Ride FER LYS ASP LES LOU ASE LYS LAE al LOU 118 GLY ASN Wild ash nis FE. yy son

E SY FW SRE SA S382 S88 EN en ara oo HRI + Fags >

DEG - 25.98.2828 - sequence listing(POS5527744) Gly Leu Tyr Leu Ala Asp Gin Tyr Val Lys Gly Tle Ala Lys Ser Arg 38% 358 395 see Lys Ser <218> 5 <211> 1377 <212> DNA <213> Artificial Sequence <228> <221> CDS <222> {1}. .{1377) <488> 5 atgaccatgt acctgtggct gaagetgotg gcottegget tcgceotttet ggacacagag 5e gtgttcetga ccggccacaa cattactaat ttetetccat toggpgaagt gttcaatgce 120 actagsttcg catcagteta tecotggaat agaaagegca ttteccaactg tetggcotgac 188 tacagcgteec tetacaatte cgectottte tctacgttta aatgttacgg cgttagtcec 248 accaageteca atgactigty cttcacgaac gtatacgcgg acagctttet aataaggget 300 gacgaaglec gacagatcgc toogggicag acaggcaaga tcgccgatta taattacaaa 368 cttectgacg acttcacage ttecgtaatc gectggaaca gcaacancet ggattecaag 428 gtgggcggca attataatta teotttacagg etttteccgca anagcaatîtt gaaacctttt 486 gagagagaca taagcacgga aatctaccag gcaggoteca ceocottgtaa cggggtigaa 548 ggattcaact gctactttee acttcaaage tacggatice agccanccaa cggagtoggt 600 taccaaccat accgegttgt ggttetgtct tttgagetgt tgcacgctec ggcaacagte 568 tecgetecce aagotagteg aggetectegg tacattoctg aggogoccag agacggacaa 728 gcgtatgtcc gaasagacge Tgaatgggta cteottgagca catttetgez ttetggceec 788 aacattacta atttetgtec attcggggaa gtettcaatg ccactagett cgcatcagte 846 tatecetsga atagaaageg cattitecaac tgtgtgzctg actacagegt cotetacaat 288 Page 6

; . SO ORAN TE ede vee DST BETA AN nan an ER Para sequence listinoe{DSRSSOTTAA) DOB - 25,88,2020 - sequence lista IE (PUSSSe; FAR &- + 4 = Ju ay wt Pnnatapbbas nue sien ote ve RCOCRATET + San Fey a ott * oO a m cmp gg pe gd An mod ee ogy Saat eds arco ao caccasuet castgactis FEH YCLRCCOTCTE TCLICLACHLL Lagatgttac ggogttagte ceoaccsaget caatgactte Lt x $ i gens 55 me J 4 FAY AN 3 8-4 PAIE ~ Tatasrpes FORE Re TE otTantanooce Ss er ste aren en eek een oscagate 128 THHSTTSRnRSSS apotataneor SS AD AO UT SV ae EEE PFuraotlHooëtu HD NN LECTTCACHES aCETaTaCEC SEaCagqiTl SLasLdaZSE EUEacgasgl CCSSCHN X ; ç y nym on dere ing nn AGN 3 ze ; avccran ratogscerat tatanttarıa ancttecton conettenen TE SCTUCESSUC agadaggeas gatogccgat SL ai RES ER LS RS late ELLLLERELL aHdU4EELGE FAaUCECCEaY LotddtLaïad Al CT se ES & $ ce Bee Te OPN ES ET EY oN be at a ad 4 AN fa bn pap gas pale ay a Je on ane amr robe m SETA SN SS FPTosattess sprotooorgo cantatas Sieh gotteoçetan troceotopaa cagcancane cetrtoosasti OF SESFUESECER CootTALAgt LE ESTLSCE Lada TCEUOTEEan CaZCaaldat CYSSatleCa SZFUNSSCEE © a fed 20 ++ TTSSTTONOS CATANDORPD TR tatetttacn see ber cSannnoppnet Froeannnet4 ttragarars catTaaëgcace 1288 LATCLTLaCà SECTTULCCE Caadagrlaat CUTZanacott Tigagagaga cataagcace ç peut Pa pueveyéeE pe en es a ony he ES on oy + bep as ds ES NYE fo gas Es oy pn NOOO ROOST ene ee eb end one rer ey ey td er racoattean etsotne PES TAJJATOTIACS nocscagcocte cnacrceottrtot aacospop HA dodahnokLLdo LER ASS g gad LLLakLL HERE Lal ili HL SOLRSSS iy SSR LE Lng Laat or an prt on oy mn pede dee AT FE x Season tt craoeenneos ancoosanten ath ace anes a+ arcsspeti 1328 ceacttoans octarsosatt censor aney Raccçoonoteceo oo = gall GLOULELELE A3 ARS SEGEL SCLACHEGTT CCagllaady SACSSSEUCE gtlaccaace ataccgce + + ay aw en sun 3 5 3 Rafe de od ee gttorncoet regosanens Tetvorantes sonatas 1377 Grteosttsteot OR ya ottorpneget crogpcaacag teotecoote u caaataa 137; ÉLESVLOLEE CUTTTIRARCU EUCECOCECT CUggliaacag TOTECEETCN CAR RAA =

CLAS RH yey) ATO

SY ANS SÉLL> ASS Da DRT CLE4> NT STD Arti DIE Cannes SEES Artiticiai SEOqUENCE ANE = <i> 6 5 a CE : + § N : i An Dha Av Dkn ATs Din Met Thr Mot Tyr fou Tro Lou Lys Len [ou Als Phe Gv Dhe ATa D ha Met Inn Met 1yP LoU IPOD Led Lys Leu Leu Als Fhe Quy Phe Ala Phe % = “en + i > 16 is ; ot “x 7A TNE Lied Theme oO) Das Acy TT Than Sow !mis See {pu Aon Thy So Wal dhe Val Thy Siwy Brn Acn Tin The As: Leu CVS LEU ASD INT LAU Val Phe val ink Gly Fro Asn Lie Ihr Asn Leu {OO Pr sù “ae Ar Ze FER Sy A S30 £2 Ÿ — vi Siv Siu Val Phe Acn Ala The Aro Pho Als Cap Wal Tus Als ~~ fw ae i + Ya Fe EY EY vu Ü = * Asso Na A = = Se TY Le FPO PRE GIV DIU Val PRO ASH AL] nr APE PRE ALS Ser Val IVP Al nv A SE 40 45 5 \ TY eo Pape Wal Aa few Tun Car WURST San Tan Acn Are Tue Anne Tia an Aen Ov Via Ain Aan ay SOY fini Leu PRD ASH APS LYS APE LL© Ser ASH LVS Val Alla ASD Tyr der Val Lau En re ga SW 22 Gt ï uy D SS Ti BA Sr Ph Ya Yar WaT Can Des Tur Acn Ram Ala Tar Dhe se The Pha Lve Swe Tur Cv il Sa à Dr IvT ASN Ser Ala ser Png Ser Ihr Phe Lys Cys Tyr Gly Val Ser Pro * e.g Da 5 oa Ti sa AK TEA FR sa 5 A A BY ‘ ~ ox J al Tun Aa Aen Coe Da Th 8 cs Lois Aun Aon ag Sus Pho The Ach Wal Tr Ada Asn sai ans RAM LYS LEU ASH ASD LOU LYS PRE nr Ash val Tyr AIS Asp ser Phe “ ee ne Qu Ba SE 8 SE SS “ ; | ; ç x PRE an ex an mn SL, Au Than AT Wal TI cs Biv Agen Gln Val Are Gin Tle Ala Bra Sw Gin The Sv al Tle Arg Gly Asn Lu Val Ars Gin e Ala Pro Gly Gin Thr el Val Lie APE LLY ASD GIU Val APE Gin LIe Aid PO Gly Gin in X Co 145 + an eh ite

AC LED ALE 5 x RU A Pass Avr Tum we fan Den À Ln An Dhe T H pa 7 On VS Cea es AT 4 Ace sx Ay sr ; e Ie x A y Dina T GW vs LYS LLC AIS ASD IVT ASH HYP LYS LOU FPO ASP ASP PRE INT aly Lys au x anse ++ AO 35

LAD AL RECA a 7 Page /

32245 NANTES A AN SE yA Liv eg Boob Sever DORER VTT AY ST no SETA - cantience Tietinoe/N 5055237744) MS - AD ES AREY SSOQUENCE J1STINE(\FEVDDE J ; Vial Ut Us Aen ; - pe ase x Eau eur can Sau Asn Ser ve Wal Giv Giv Asn IE Toa AU + Pm Sen Can Acn Acn tas Asn SO as Jal Gly Gly Asn Val Le 3 IPD ASH DEP ASIN ASH LEU ASD DEP LYS val 3 X Val 240 ALS IPD ASH SEP ASH Af? Li i 3 a an ane + SA RAR TTR Le 134 155 APRES ASK 4530 FAR : e Ç A. Tarr Tue Den Dha Tv § a 5 Aro us Saar Aon SID WG FED MR pe Kansas rm Tim Arey fans Da Aro ù LA met ASH AUS LYS TU HR T Vi Asn LV LEU IVT AY # LEU FIL OM BLY 5 SEP ASN LOL X FV RST \ 3 2 HE “ 7 ge 4 An “Et A 148 158 155 168 LED La AD a LE 1 À TI Sor Thr Glu Tie Tver Sin Ala Gly Ser The P ro Cvs 3 Ars As € 5er Tr 3 2 2 Ay =) ca JAN DS tit X + y Glu Arg Asp fie Set INT QLU LAC IVT OURS Ada Way QE È } UAW RUE ASP > 3 Ce J. ay Ter aa 17 TE 176 LED

AD AN : AL ELA Ps Tas - ot £ A Parc Tue Rha Den leon Gin Cor, Tyr fiv Asn Gly Val Gla Gly Phe Asn Cys Tyr Phe Pro Leu Gin Ser Tyre di y ASH BLY Val al Gly PRO ASH LYS TYP FRS À X “ N Ss NEY

TRS ANAL TON SE Tu lug ASS oe ~ - N gant vied Arad > Q ~~ Val Sly Tur Sin Dea Tye Arg Wal Wal wal Pilar er Dies Thien Aan Hiv Wal Sy Tues Ain FULDA AE Vos Vos vos Phe Gin Fro Thr Asn LAY Val uly yh adn MO > Ë Amar se Dan au FE a 205 195 288 285 AA a 20 . ~ : ee oy Svan fae x a CE D Ava The Wal Sug Gly Dra ua 3 Eos is US {au Tan Mic Ala Den 81a Thee fal vs Siv Pro Lys Leu Ser Phe Glu Leu Leu His Ala Pro Ala Ihr Val (ys Gly X oy ey ex 4e SR 20 218 SL. SL LAW ALS £4 - ox + x tre Acn Te Un ; 3 "x e Siv Tur Tle Bea alu Ala Pro Arg Aco Oly Gin JE Coen Sar Ser Se At vr Tie Pro Glu Ala Pro Arg Asp Glv Gin GAY ser Gly Gay Ser G AY IVP Le PPO QIU AIS PPT ë ; X ka bi ar Po = m ; i. x a AA 22 pas JAH 225 238 235 24€ a £3 ç i N Ti Dal oeags - i a Sly Trn Wal fon oan Sar The Pha [ou Ain Tyr Val Are Lvs Asp Gly Glu Trp Val Lou Leu Ser INT PIE LOU Aka 3 VE Val APE LYS ASD ULY Wild Pg Voili LOU LEON ai * oF cs oC ee Cx “see En 24! ANS L200 ats Je) LN 3 X N TT The Asn Leu {vs Pro Phe Gly Sly Val Phe Sly Sen Sly Bra Asn Tie They Asy EU LYS MED HIRE BY LAU Vai yng GLY SEP GLY FPO AST O LL© iin Ash LOU LYS FTC FA X “ “ oy on am aa 268 365 278 a WF Ha NSLS 1 A 38 AT Sar Val Tyr Als Tro Asn Aro Lys Are Tle ; Thor Amey Din AT- an Wa ; Ata ; Ac 5 Lys Are Ie Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp ASN Arg Ly ë ASH Add IN PR > See ge NO YEE “a, IE SD 2 22 EST LI Wal A7 A Ter Ser Val Leu Tyr Asn Ser Ala Ser Phe e Ave en PSE f a An “sr te fn sait sp Asn r= Ala Ser Pha per Ann LA fe [id ASD IV oF Se LE O5 MSI JC! SET ASR LYS Val Ald ASD YP SEP Val LOU FW x on ae N

LAA ane ve a FOR ess HET au at NS | 1 ; «| D The Tue lan Aen Acc Tan vi ya { Ue TYE Sl Val Ser Peo The (vs Leu Asn Aun | su Lar Thin Dhe {us ve Tyr ALY Wald at PERS ad LY LEM RoE AS LTV DEFINE FRE LYS LYS PVP LAY Val Der ! X HEU 249 NE 358 385 335 315 340 Sh JAW - T ! A A DPho Wal Tia Are QT i Ac Sin Cvs Phe Thr Asn Val Tyr Ala Asn Ser Fhe Val Tlie Arg Giv As SOSE Lys FRE RP ASN Val yr ALS ASP Ser rne val 8 X { ” ” oy Sag TRE 325 Aa DAI fo Jl SIG 5 ï vl Ne 1 = TT; Ain Aan Ter Aon FR x en x Opa Av din The Oa bw Tia Ala Ass Tyr Asn Val Ang { in ] LES À Lei "Fo LL ALTE ES AN LVS we ANS MAR FAS vow Sa Val ARE Gin 116 AIS Pro Lay Lin nr aly LA { 3 = ; a 7 N THE 348 345 SI Dépt aE 5 pi 3 x tnt Tin Ag Trn Aen Can i + Agr Pha The Gly Tugs Wal Tis Ala Ten Acn Say Tyr Lvs Leu Pro Asp Asp Phe The Gly Os Val Ils Ala Trp Asn bei TYP LYS LOU PPO ASD ASE FR® INP ly LYS va { 5 = “er aan ren see Sea 185 355 350 307 i A 3 3 Val aiv fiv Asn Tvr Asn Tye Lau Tyr Are A5 Asn Leu Asp Ser Lys Val Guy Gly Asn TyP Asn bye LOU Ty APR Asn Asn Leu Asp ser LYS Val aay GAY X X 3 Ë . oy yr + AL 275 3,2 BED A i a | Den Dhe iy Aro Asn T HES = ap T = p 5} = Lys Ser Asn SH vs pri ‘he D APS ASD ILE SEP IM Leu Phe Arg Lys Ser Asn Leu Lys Pro Fhe Gag Arg Asp ld LEU MRE APS LYS 2 X seen © Fosse 8 tou RS tad

Dan er An Ana ns bene oer a ae OA RN MAD an AS IRIEL moses TY ofan DROLET AA BEE - £5.08, ddl SÈQUENCES LISTINE( FEEL 2443 Ie XR cou SEA 385 358 395 489 pnt x + ra a a x oo x Lu LU A» FAT RU LL N vai a tt Ÿ > AEE Tr Ain fiv Sen The se Er Acr fdas Ya) Shaw AL tas Siren GAL OLIS 1VYP VIN ALS GLY DEP PT Fre LVS ASS Gay val Gil Gly Fhe Ae STOR AE 455 4318 415 Agen Owe Tur Dho Des lan On Cap Tus Aile Oa Min Sea The Sows Avr ASH LYS TYP MNO Pg LOU Gin Ser tyr Gly Fhe Gdn Fro Ihr Asn Gly ATO ae aa 478 Go Sad Wat 2e Thee De pures Torre Amer Wad Wad weal Yow Se Sue oY Saar 1 2 ; N N a Fri pee Yasım Apo fm Adm in + mit ar FE a > 38} » oar Val Quy IYP Gan Pra tyr Arg Val val Val Lou Ser Phe Gig Leu Leu ane ARR Aa 435 A448 445 Wie Ata Dra Alan The Val Sue Tr Mon | WS PS AL FU ALLG TR val LYS Uiy PTU LYS Ase SOIR SI 23 AREA - CALE #

PNR PURE ST ; TY PES LAL ALT SEY FINA

SELL DAN SUI RN By Etant Carnsanen

SAL APLAITILCILDSI SEGQUONCE SION LEAD SDDT TE REL LUD

AEE TY SN É AR SEN SDS î ÉTATE SELL Ar LAD 8 TRO > Ss SGA 3

LAE J stottraetot tteohbsesptoest spetoscteteo ototrraoses nototrareon Come es Ne ome an Ain LLCESEL SELBER BULECULELE RLRACLANCE agigudalda {oaddaddad D oo pa Ay ES ES SN SE ex = PTS PRÉ INT pee on ay ewe gee ee an on an gn nny ole Lan an de ns aus abe ale le dope une an ae Pr rrr ae ss CACS ASS ACT vhaochunoTtToo oTrapotaee SRSENTTARAOTSR ay TotTotoes STTSSSUOAan YORE Lali diliall BORSUSELSRS SUCHEN aaiatiadia SLTLELELCC att ggggaa LE orotteants reacstacsobt cppntenots tatarcatanna atacannaırın 86abtbersrsse Sa B«ELLLGAdLE CLLoOCLONGAL CNCATLANL(LE LOLSCELSE]d atafdaagly catividaad AS PaotTaetaenaêpte ae asaave art A au pape ds abs as on padi eg en mn ewe de ey gn SAN To co 5. TRSROSSOT of +. sa + os ++ + Vue Tann ya SAN RESTE dCLAlASCEL CCLCLACdat TCCECOCCEX TCTCLA£Ett Logsatgttac DÉS gorottanots grrarrnneet rnateontho tosttenena arcohatarcer vconrnsest+r+ Aa SSL Lea NN EIN SAT AF CEST S FA AS AT At OT SSATASCTTT SLR RSR SSSR IG LE EURE SH LEM LALELEQ CLEO LOU RS SGAGCO Shiu ER pures amy mn be ny sa awe one ey Fre ow ey a NES Ee Nav ep A PU A pw A an Par A neg ane ape on AAN ye mn ew san ga ma ae PE gm ane ges gar gms she NEN ctastTanvoo otonconnot seoseanate sptercoscocote ACT OS an paTrorsronst DH x) Se € si 5 eal Seda LS Fa edie any oy SC EAU ASS Ar ES & pa nes EH SOLGGORRS SES QO HV OVER LL REN 9 EEE OR HR LA EN ES ws LAN Sa an ida au, eu Beale Lan an a way ems gen alana dn gm dee gem ans PEE me ES on mn a IN EW Nr a eae ay eg Ba gr pw er ana or ew ay a oa PET A Aw am en en en ANN Tabtaattacss NAST Sr TON POT AU EU NE Oa OCTO AN CAS SAT an° SAA SEAT fac Tila CHACLYCACA gETVECETad TCBCOTUEEAn cagcaascaac Had mr ew ui de aa gmt mm ew NT TAT SES" Ne eng EN cde snide mode dhe an an gn a ET prin dd ene en yey eT my yi NIE SPY SSR Tr ANSTOSSCSOS AST Tat TATEOTTTACA OFT Trees SAaxasgrant SLES LARSSLLLLE SRSSRSE SSSR Lagi LA LOC lal LL VOL BEL LLLLLLE NR TO ee my en gn ened ab Ee Te NE er Sen am amy ee en ew an eye pins my encge an Jus us gee ae my ant ne gn an ew man ge dae gar pau an am am gen ges oleae sh Fl ode oy my gm en PE FON ONT atoms S oma Pome Ae meray ety Sacer etot May LL sda ti VIFAarAaArAaES SETS SEAT TS! SAU HSSCT t Ca oO & SE LLRREHEELL LL LARGE GRGES LOLOL aLy SOHLE 7 SES Se CAES SD Ne LL LEN LAER SEER ay an on aw ET ETE eu tw np erp eT tei ee ple gr en he A oy end oy a an ge ay eb de gen gE en an wa ea ge ant SOD sacooootto napopattran otortactbt Soar CAS @oTarggat Soar o ane? £048 GAL REREV LE GORRAL LL A a CL SL acttt cctacttcaaa SE LOCAL L eK bete, PE ENST NANTES er eee an en re ima en an an ang rhe wn an am ane am nee crn snr papa ie an fe meer coo Rs afm ln Fo pg oy sp ann oh ev A a ES sen OO ee FRETS aay at ass as otoottreotot a Sant STTSCPSCOS Su AACEEAFTUCE EULaACCHACT. DUSCCEHCEULT SURACUTOLET CTTITSagct SLiglalipin Dr Serocvrpnnprap Reh ocoat oe Sa mor Tera bene bands ereverort serdar orer es as Sd THE COSCANCTAN ï Toi So CANASET ONE VE AS 5 SUSUT AR : BETON ASS Fa, MAS SCO Whigs SK Lada = EYHSH 05 Lol HELARLE SEN MB € AR OK SENS IFoo owen ON Tage 9 Ï SRE oF

DAG - 25.88.2028 - sequence listing{PRO5527744) tatgagggga agoigacgge tgaggggttg agettcggca teglogeaag cagettcaac 788 cacgctetgg tagacagatt gettgagget gcaatcgatt gtatagtgcg acatggagsc 848 cgggaggaag acatcacact cgtgcgcgta cegggtaget ggganattee tgtagcegee 388 ggagaacteg caagaaagga ggacategac geggttatag ccattggggt ceottattegc 968 ggggraacge cecactttga ctatategea tcagaagtet ctaaaggtet ggctaacott 1828 agceoteogaac tcagaaagce cataacttte gotettatla cagetgatac cctegagcag 1688 gccattgagc gggcaggtac caagcacggt astaageget gggaagctge actcagegea 1140 attgagatgg cgaatctgtt taagagcctg cgetaa 1176 <218> 8 211» 381 <212> PRY <213> Artificial Sequence <409> 8 Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln (ys His 1 5 18 15 His His His His His His His Gly Gly Ser Gly Ser Gly Pro Asn Ile 38 Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala 48 45 Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp 58 55 68 Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr 65 78 75 8a Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr 85 98 95 Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gin Ile Ala Pro 188 185 118 Gly Gin Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp 115 128 325 Page 18

FEN SE AS Tans NNT Gn ge Md edd er FS DISASTER A AN Af I. AR ni FEARS ~ VDS PETITE! DORE STAR LOS ES LDL SSQUENCE LISTINE(FPGOSD2// 44} N EN x Pho The Sle Sue Wal Tia Alla Tem Acs Cam Aen Aen fan fom Cem} vse FRS INT Lay LYS Val Lig A1a IPD ASN ser Ash Asn Leu Asp Ser Lys oF oF : wo “TA ne An Jo ASS LS Val Gly Glv Asn Tyr Ash Tye Lou Tyr Arg lou Dhe Arg lye San Aon VOL WAY WAY Moi TED ADI YE RRL TYE APE LOU PRE APE LYS REP Asn oa 45 Ar s’en 165 AS ADS Low En Else DNA BRL PAL AUS ALL ee eed mL en Paca CT Ne ~~ Pont + Af Wray Phan sin Abo fan ia Sars The fiss Tia Than Sy AY sy Shae EU LYS PPS FRR GU APE ASD 116 sar ine QIU Lie Tyr Gin Ala Guy FEN Ta FR

AD A LED Corn FRA Dre er Aa A AR em. mmm “i « ~~ = ~1 = N Saar Thr Dra Ove San Shy Val Sis fie Oha don Due Trans Dha Dee Say SEP INRP FPS LYS ASN LAY Val DIU Gy Fhe Asn Cys Tye Phe Pro Leu

AOS TN TE TR SIE + QE is LS AT oF En nt SNL eal su = ee oe oN fo CT SY “+ my = hi Sin San Tyr Site Dias Sin Deen The Aen Av Sa ROOTS Tare 8 y Rey Taw MAT SEP SVP RY FRE ON FPD IND ASH GAY Val Guy Tyr Gin Pro Tyr

SON SRR YON

AT LD LBD a a tia) Na Re N ; 5 a vai a X X N53 x = x a Ade Annee Wad Vind Ada) oes ae Sin NU ue bers Foe Ie AT a Dan A rN Thy am im APE VIL val Val Leu SEP FRE Glu LOU Leu HIS Ala Pro Als Thr Val SA se EEE SARE das LL Se ~ Page ma. em = oy = ~~ “x = - RE “x "x Fu Rly Din bw Siang fuir Can Sv Caux Shae Sar me Uma Tay T2 TY LYS GAY orl LYS wd) WAY SEP GLY DOM GlY Lay Ser her div Gin Lie sea SN seu TA

LAT I LAD SA Taran Tai Ver base Vans iver AY rn Ste Boer: Agnes Dh SU La ow Vea oan + Ye ; qi RS ; à entt Len Am = [EE So A Mage oT Ds Soon Yee (NE OGIU way LYS LEU INT ALS QU GLY LEU Arg Phe div Lie Val Ala sar see see FAN SEY si

LAS LD ESS Sar Arg Phe Agn Hic Ala lan Val don Ans lan Wal Og ATv Ala Tila Ser ARE Kine ASH His Ala Leu Val Asp Arg Leu Val Glu Gly Alas lls

SES ER TH S68 SBD 278 Asn Cvs Tle Val Arc His aly Sly Aro Ol Sn Aen Tia The Pan Wal ASF LYo RAS Val AS TRS Bly wry APS wil LAU ASD 118 INT Lay val RR. oes sen Pe) à BA AS - LES su LS Ars Vaï Den S910 Saar Tan Sir TA Dan WaT ATs ATS SUR Ter Yon AU AVE Val Pro aly SEP IPD Glu Lie Pro Val Als Als Gly Glu Leu Als

EN SE A 239 285 388 \ ; J | - A Cee FA + 7 ~~ Crm € oo . Aro ye Hi Aen Tin Aon ATa Wald Ther ATa Tha mT Wim Y fans Th Annee AVE LYS LIU AS POLAR ASS ALS Val AXE Aa 148 LL) Val LOU 118 APE ae SA san sue 385 318 315 328 ~~ AT om vu Ta PESTE ; + "a x e x List € ; AN faits Ain rs 3e Mie Da Sow Tees Tle AY Cay STs Lin Ten 2e PL: SAN Aid INRP PFPO HIS FNS ASE Tyr Lie Aia der Glu val Ser Lvs Gly SE san op ILD 22% 332 nas AT = Ken Sog © be FEN ae 4 eas Re asus TN ay xx si a ar SR AL ST DEE NAS eur gras à Mi Seo | arg Ds Tia ke ire Sha fm LEU Ala ASN Lal Ser Leu Glu Lau Ai SO LYS PPO lig INT png Gly val san “au EN

TAS A IES

IA SEED BOR ex Pinus ATX Ann I N TLL ee CT or ~~ a 7 x vi Tim Tie Alm S 5 Th oan 1 s Min ATX PT MT Amey AT AS Thier Dre LAD HT AIS ASP nr Leu GLU DIN Als lig Glu Arg Ala Gly Thr Lys Ser “een sex 555 SE 30D NAS oe WL . X ~~ “+ Hm AN = x on aN . x “x = Lis € ivy Norn we ST Tran Tr Ala ATs tas Sas T= TT Cas Mat AY a TAS LLY ARR LYS Gly IVD Lil ALS Ala Leu Ser Ala Lie Glu Met ALS RN oy son SED So

DGG - 25.98.2028 - sequence listing(P605527744) Asn Leu Phe Lys Ser Leu Arg 385 358 <218> 9 <211> 327 <212> DNA <213> SARS-CoV-2 <228> <221> CDS <222> (3)..(327) <488> 9 atgaccatgt acctetggct gaagectgete gecttecgget tcgeeotttet ggacacagag £8 gtgttegtga coggegtegt gateggeatt gtgaacaata ccgtgtacga coototgeag 128 cecgagctez acagecttcas agaggaactg gataagtact ttaagaacca cacaagecee 188 gacgtggace tggecgatat cagcggaate aatgecascg tcgtgaacat ccagaaagag 248 atcgaccgge tgaacgçaget ggccaagaat ctgaacgaga gectgatega cotgenagaa 368 ctggggaagl acgagcagta catctaa 327 <218> 18 <211> 108 <212> PRY <213> SARS-CoV-2 <400> 10 Met Thr Met Tyr Leu Trp Leu Lys Leu Leu Ala Phe Gly Phe Ala Phe 2 5 ie 15 Leu Asp Thr Glu Val Phe Val Thr Gly Val Val Ile Gly Ile Val Asn 28 25 38 Asn Thr Val Tyr Asp Pro Leu Gin Pro Glu Leu Asp Ser Phe Lys Glu 48 45 Glu Leu Asp Lys Tyr Phe Lys asn His Thr Ser Pro Asp Val Asp Leu 58 55 68 Gly Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gin Lys Glu 65 78 75 se Page 12

DEG ~ DS AR PAS cemeteries Ut etre à DODD VTT AN Les 2 WSL, SG - SEQUENCE LISTINE(FUE SA AR Tia An Aro an dan Oto Val Ala ve Ach ap Asn Alu Sar Say Tie Die Asp arg Leu Asn Glu Val Als Lys Asn Leu Asn Glu Ser Leu Ile or a. Ne 8% ag 95 Ana 1. eu PULL à PULL à - mx J. x = ; sn Ta On Ars boa AN are Siw à TES Tay TY = ASD LE Gn LU LOU DIV LYS IVPT Qiu Lan yy olde Aa “ar

A LES RER oye Lal¥> LL Loy eg Oe Sa Qt LAA Soi

HR NALA <Ildx DNA 142 Apt dal Canpanse AA ArtiTictai SEQUENCE 228»

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DRG - 25.98.2820 - sequence listine(F895527744) <218> 12 <211> 286 <212> PRT <213> Artificial Sequence <488> 12 Mat Thr Met Tyr Leu Trp Leu Lys Leu Leu Ala Phe Gly Phe Ala Phe 1 5 18 15 Leu Asp Thr Glu val Phe Val Thr Gly Val Val Ile Gly Ile Val Asn 28 25 38 Asn Thr Val Tyr Asp Pro Leu Gin Pro Glu Leu Asp Ser Phe Lys Glu 43 45 Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu 56 55 68 Gly Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gin Lys Glu 65 78 75 88 Ile Asp Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile 85 98 a5 Asp Leu Gin Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Gly Ser Gly Ser 188 185 118 Gly Glu Ser Gln Val Arg Gln Gin Phe Ser Lys Asp Ile Glu Lys Leu 115 128 125 Leu Asn Glu Gln Val Asn Lys Glu Met Gin Ser Ser Asn Leu Tyr Met 138 135 148 Ser Met Ser Ser Trp Cys Tyr Thr His Ser Leu Asp Gly Ala Gly Leu 145 158 1355 160 Phe Leu Phe Asp His Als Ala Glu Glu Tyr Glu His Ala Lys Lys Leu 165 178 175 Ile Ile Phe Leu Asn Glu Asn Asn Val Pro Val Gin Leu Thr Ser Ile 188 185 138 Ser Ala Pro Glu His Lys Phe Glu Gly Leu Thr Gin Ile Phe Gin Lys 185 288 285 Ala Tyr Glu His Glu Gin His Ile Ser Glu Ser Ile Asn Asn Ile val 218 215 228 Page 14

Ras se AS Ana SR ; RER NA . 75 AR 978028 © carmisnrce Tietino/DAATTI7TAM 00 L288, CE SOQUENCE LS FOOD EA fem Wis ATs YIiQ lors © : N wl A st sf 3 Asn HIS Ain Tip | ar bye Aghn Wig Ain Thy Pha Agen Dho Im x ASD HLS ALS LAG LYS 28r LYS ASD HIS ALS ihr FRE Asn Pie Leu Gin se 5 355 a se san dé ÉD AD A 48 Wom Teen AP AU a J : + = . - Tern Tus Un AT à fr Ten MY 5 Tar ANT La UT sa Adal 8 à ï = Ten Tat fal Ain ii Ain Ma gs ta ES tua ES EE Foal tai Bin fare Acer Tige PR OIVP Val ALS LAW UID HIS GLU ALU QIU Val LOU FRE LYS ASD Lae 3 + “ae “La ser 245 250 255 Kar Asa Pace TR x ; x = i. ; N . {ais Aon ue Thay Vey Tous Ther Tw Ao oon fem Wie AT ï + ï ou Asn Ly Tiley Gin Laits a GIy Aon Gin my Hi SEY air Tur | an LEU ASD LYS LAS Lid LOU 2128 © LY ASS iu ASH HIS QGIV LOU yr LOU ey au on ge " EN “ yng

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CLE 25318 CDS SA + LAD ay NL SAN fe NM A ; PAST <222> {1}..{6813 = A x € oS TREN SR Laas AS vw ee ee ert rer ewe oy ep de ey or Tne 5 A ntosreatet me ot Toot gaagrtorty geretteragged TrasetTTroT pone es mn STUSTRCCATEY SCL EUEELC FRAT secte 8 TTOFECY SEO TTStT Sopararsuaep Si > 5 N saa ugly LAL LL X Zi LoL Lg = © Sit SN S 8 SER HEARLLECLE BLECHE LEERE LLLCL Ral QLIEGE SG et o+ + © et OR Coo ï ot set oo a troorastt stannranta rrototnron ceptetosno TONER ELELLLE\HS CCUSECELLEL S9(CESCatL gugaadaata CCgUgtladga COCLCTECSE Land = que an une aura dhe gan en ay gn may gee RE & $ oer eran eye rr apanpeeesas susenaseRs pat ; ; FON Sn arascettenn agaogoganasts patanotast ttancocasesn ~ ne er = TDi SUCPASCE : scaëe RAR AYSSORAI ÿ so, ST art TUTAATAACCDA CACSNATEON SC 188 BSR aCagaiidan agapffaadyg gataagiady tiaagaacca cacaageree ixg saroteoass Trporontat sassopnante eue eon 4 $ 8 gacoteracec tggpcgatat cagoggaate satecrasveor togteaacat Coagaaagan 248 Ë ÉSRBRSLE LREELES LOL CONCHEHGSGLE dalgl lal LCR Eag Cat Cesgass Eds 240 rode en TN Sa TET En er oa oY eT er er en : : Abe ONCE Tey +*ssnoonanpseot ESS NNT Sham asa oe carn ; tee SRE stogaceoges tTranscrasot gpecaagaat cteaacracra pecteantorpa cotrcaanas 358 HILRACCEEC TEdGCRoESL BECCaagaat CUEdalSagd Eclt£attëa ceotgcaagca 388 he EY SY ee + + + styéporoanot aroascanpta ratenootaot pronoortrto ania mg eae + = er SUSE R(HEAECAETa COUCHSLoNt SSoOSSSICTLE SStaloattl0 TSaggcsece 368 EREERAGE Hola LEER SELL BEREAEHELCLYE HELA atill THagELECLL SOY YN EI ED Senf at rr en en a oN NS SR Fy en cond ç 3 € 3-4 Lead RONSROSOAI Anett at Sconassones potoanstooe TachettisÖnas eu ran as 8 ane ACC garpcetatet gassagac erivnateoeo tTacteotteaër cacatiuete AFH SORGEN ARLHLOLEL LUHIGHEHAD RELROOLESS ESEL LESSK CoOCATLLCTLE Sou Satay race Tretoesnteses scattoteo ; to oped 8 Tatty ogra tTretpatereoo rattotonne natarrotot naroarretet RE Sa LLL AR RA Li Hed TET CATTOT OA satz oo où ASN + En ACE BERLIN LEERE LER LadligtRadl QULALLSLES RA S ER Ss Ë Au po le or oy ny vy a ed gn vy a enr 5 ; x x. rtecacnoot Franscacon nPtorataso taeda anos BE un . A "TEgaca ASSTHRPOAn actgoatass tact NASR SOC ACSASAND Sooo garats Ge (UERACAECT TCadAGagEe octgpatagsg TaAcCTTTHaga acdacadaag COCCSSCETE 548 SN que ue be em a ew ge ane ay + 2 = parctanere atateagoons natenstoss aoecobe obo JR _— £ oo FattotpPPP > HLATLASCEF AA COIN ES sopotrooton acateocaras noncateosags OA BR TEENS aLa2LCoONCHE dalLodtg££ SSCEUCEUSa atatddagas agagatlgac So roprtoenneseo nosteoperran gnaatetons : cA 5 & ropcotonarpe nootooccnn gnatetonne gapnocrton tTronsetoc: ny ge oy ay de ne ae ge Ses L HS LNGULS GERNE Saad LELERGAL NORMES List LUE SUCTECA SFJACTEOSS Hrd BE = X SEES KAHN Ragas eG SORGE LEER VOS

DOG - 25.08.2028 - sequence listing(P665527744) <218> 14 <313> 226 <212> PRY <213> Artificial Sequence <460> 14 Met Thr Met Tyr Leu Trp Leu Lys Leu Leu Ala Phe Gly Phe Ala Phe 1 5 18 15 Leu Asp Thr Glu Val Phe Val Thr Gly Val Val Ile Gly Ile Val Asn ’ 28 25 38 Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu 48 45 Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu 5e 55 69 Gly Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu 65 78 75 84 Ile Asp Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Lau Ile 85 98 95 Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gin Tyr Ile Gly Ser Gly Gly 188 185 118 Ser Gly Tyr Ile Pro Glu Als Pro Arg Asp Gly Gln Ala Tyr Val Arg 115 1328 125 Lys Asp Gly Glu Trp Val Leu Leu Ser Thr Phe Leu Gly Ser Gly val 138 135 148 Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu 145 158 155 168 Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His The 165 178 175 Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser Val 138 185 198 Val Asn Ile Gin Lys Glu Ile Asp Arg Leu Asn Glu Val Ala Lvs Asn 195 288 285 Leu Asn Glu Ser Leu Ile Asp Leu Gin Glu Leu Gly Lys Tyr Glu Gln 218 215 228 Page 16

DOG - 25.08.2028 - sequence listing(F865527744) Tyr Ile 225 <218> 15 <211> 444 <212> DNA <213> Artificial Sequence <228> <223> CDS <222> (13..(444) <488> 15 atgaccatot acctotgect gaagetoutg goottoggot tegcotTtel ggacacagag se Etgttegtea ceogpcatass Tcacgtesse grascogece etgcastaat ggeacoagtt 128 gctetgacee gaclagctest aggaagiict SSSaZCSNCE ECtecagcss aagoggagst 388 tetagtggtt cagteogtgat cggcattetg sacoataces tgtacgacec tetgcagece 248 Hagctpgaca gcticaaaga ggaactegat aaglacttts agaactacac aagoooogas 388 Etgnacctgz ecgatatcag cygaatcaat gcocagegteg tgaacçcatcca gaaagagate 368 gacoggoiga acgagelgge caagaateotg aacgagagec tTgategacot gcasgaacte 428 gesaagtacg agcagtacat ctaa 444 <218> 16 x211> 147 <2132> PRY <213> Artificial Seguence <488» 16 Met Thr Met Tyr Leu Trp Leu Lys Leu Leu Ala Phe Gly Phe Ala Phe i 5 18 15 Leu Asp Thr Glu Val Phe Val Thr Gly Ile Asn His val Gly Gly Thr 28 25 38 Gly Gly Ala Ile Met Als Pro Val Ala Val Thr Arg Gln Leu Val Gly 49 45 Page 17

DEO - 25.98.2029 - sequence listing(PBBE527744) Ser Ser Gly Ser Gly Gly Ser Ser Gly Ser Gly Gly Ser Ser Gly Ser 58 55 59 Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gin Pro 65 78 75 89 Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His 8h se ss Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser 188 185 118 Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala Lys 115 128 125 Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu 138 135 148 Gin Tyr Ile 145 <218> 17 <211> 675 <212> DNA X213> SARS-Cov-2 <220> <221> CDS <223> (1). .(675) <408> 17 atgaccatgt acctgtggct goagotectz goottegget tecgcotttet ggacacagag 69 gigttcgtga ccggcoccaa cCattactaat ttetgtccat toggggasgt ettcaatece 128 actaggttez catcagteta tgestggaat agassgegea tttecaactg tgtgsctgac 188 tacçagegtec tctacaattc cgactctttc tctacgttta aatgttacgg cgttagtacc 248 accaagetca atgacttgtz cttcacgaac gtatacgcsg acagctttet astaaggggt 386 gacgaagtee gacagatege teocggetcag acaggCaaga tegecgatta tTasttacaaa 368 ctteeotgace acttcacagg ttgcgtaatec geootegaaca geaacaacct ggattecaag 428 gtgggeggca attataatta tetttacagg cttttecgca aaagclaattt gaaacetttt 488 Page 18

SANTE ASS à à À 0 Le - Veen DANN AAN PRE SE A9 YN CAN EET TR Piatt ings PRESS ITAL Dg - 25.98.2838 - Saguenee LIST IR PEED 0L +E LAGS AD > i a 3 meer ert an Sc oooot aan TAR ; Seas teen repebtTotans coos aaa AB cega satctaccas geoapgetoca gocottetas crppottran ï ry ER a que bunosanegen natotneccans À GNECLSLS {UTLEY aa SS S TATATIACACD Trnoracoon AATTTATCAY ÉCARENCTCLA 8 £888 ZaaiidiEa OQ SAAR ELD LI TY Ga Ne La bey = se HRHRGESHALE VOOR 5 © pets am ne nee San 2 SHEATTES AOFFPANSPAN saoaote oot san 3 i Rade A my ended em a Een on er er sy Ae à ATEN S da CESANTIOSPT VE Fo dr ge N ne op gee afi ng aa ITT IRIE Lal Egat ul EL CHAN HH SEATLLSGCT ECTACTTITCC acttcssage Tacggattee à 8 BEARLLY FEQTULRACT SCURCLELCC acttce ES SE Ë “© 2 3 A nSHpEÈSs roe ane nade SHB i fed 3 cobb ebay ob bb oaaore tod EE NN OYE De ocascarte SHH 2 “at neporoettot+ pobtteototet TTT OAT LEALOLALALAL BRL OLE Tacrcaaceat nrrorottot oo CYSTCT TTTESSCTET TECACE £8 ë LACCAACLaY JCCECEULEU SE UTCTETC LEGECLE & X ey = 675 torootrrrepa astan CECHSTCCCS aatas LRMRE 44 LS Qa

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CATHY AN 3 § AY Db Sv Pha Ala Dha i i T i i Lys Leu Lou Ala Phe Gly Phe Ala Phe ae had qe AA ey * i. Soest Ta NOTE X x, = Yoana LOU Als he GAY ie ALA ; Met Ihr Mot tyr Lou Ti FLEW LYS LU LOU Add 3 PEL ON > i ; ne = “ea 15 3 3 ig JE _— we vw = VER YU mes ur - i Fan 5 PU Dee Atn Tia The Ass | pu Owe ani ~~ Fa 3 Shen VERT They Ta Deen Asn HES 3515 ASH LOU LYS Pr Am Vins SN tra Aal PE VAI Far sa 05 “PO AST LLR 391! ASN 3 LEU ASP AP Qiu val PRE val ny Lay * - 25 38 28 Lh Sr £33 £3 T ï Ts WaT Tare AT A - x i Arg Phe Ala Ser Val Tver Ala au Jo Val Pha Aen Als The Ans Dhe Ain Noy fai hy Ala Pro Phe Gly Glu Val Phe Asn Ala Thr Arg ! He ALY SEP Val X FPS PRE dy Gail Val Fe ASN AIS ihr Arg “ A ve ST £35 35 ia +. x a e Aor Duc Wal alas Aon Tu 58 er Val i eu I Sam Are tue anses ia Sean AH À WS ddd Mla Ahly EE] RIN vous MA DE N APE ; APE lig AS VS Var Ald 3 1PD AST APE LVS APE 218 Der Asn Oy i } } DS CS 58 SD Bu Di Bh = Fu PEU ne MAT Teen Dan . ~ wb mu tas Pace Vas alae Wiad Ca Pro T { Ser Ala Ser Pha Ser Thr She | VS LAS FAY JAV Vas ST! fi Tyr Asn Ser Ala Ser Pha Ser Thr Phe Lys Cvs Tyr SG AN VE + Va ASS LANCE HAS 2 . La J a. 20 SR va FE sa DD 0 fn ß Pa N Am Acs Soe Sha x Rn : Sue Rha The don Wal Tvr Als Asn Sap Fhe En go Pages Ÿ ens Agn Acn ! mit Suc Sm Tnt ASH Val DVI ALS ASH SE! +) 11 LYS Leu ASH ASD LEU LYS FRS INT Asn À X SE 85 Se >> + > ; x - Zn m0 Sn Plan Tar ; a inl A ST Tie Ala Pra Sly Sin The Ow | or ~~ or Fad Ame oT ey im LA Fo GIV GAIN If Ay Aden À FA Avery SET Am Tan Vind A yrs sin fle Ala Pro Glu Sin i § \ Joa Sa ASS Lait AS wid So # 5 MAT SAS ARS 5 3 Val lis Ar 5 RLY ASD LIU Val APS ©

LG AFD ; Pro Asn Aso Phe The lv Cvs 3 à N Tyr Asn Turn Lvs eu Pro Asn Asp Fhe Thr Gly CVS x ec Tle AY Aor Tiers AH VIS NS TOI | POS AST ASD ne tait 32% X Lys Lie Ala Asp Tyr Asn Tyr Lvs Leu Pry { i = + i Lo ae “Se Te ii LE 125

LAS EEA ils Lo fy enw x A. & : Vat Qu Av Ack € + Ma X or Acc Tan awe fal Sly Glv Asn Val Il Ala Tro Asr ar Asn Asn Leu Asp Ser Lvs VOX ALY AY Ahn Val Yle Als Tern Asn SEP ASH Asn LOU ASS 2 LYS GA X 3 VOL AAC FANS ONE PAST 25 “A

RN YER 138 LID SL 136 A32 î N cer De Ds i pi Sar Acn Lau Lye Ren Tha T i Tyr Arg Lou Phe Arg Lvs Ser Asn Leu Lvs Pro Phe Tyr Asn Tyvr Leu Tyr Arg Lou Phe Ars Lys Ser Asn Leu Lys Tyr Asn Tye Leu Tyr Arg Leu Phe Arg Ly 3 CE , “ ? N AO : Ton jun Ne 158 Lah i168 TAR Lot de 2 HS te ï : co & Ti tee rie ; . . oY fT oe oY ar The Des Due u .. TI Sas TY oe Tarn fal AT Aix Ke: yy Fld LW Ss oY Naver Aer TTa Con The Stay En TAFT Lin Aia Gly Sey Th Fri Lys Lit Arg Asp Ile ser Thr Gly Ile 7 VIP Gdn X 34 APE AST LS RER EY. 185 178 isd 435 RA

DO8 - 25.08.2828 - sequence listing(P695527744) Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly 189 185 198 Phe Gin Pro Thr Asn Gly Val Gly Tyr Gin Pro Tyr Arg Val Val Val 195 208 285 Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys 218 215 220 <218> 19 <211> 788 C212» DNA <213> Artiticial Sequence <228> <223> CDS <222> {1)..({788) <400> 18 atettecgtet ttetggteet gctgectetg gteteccagce agtetcagat atatgagsgg 68 aagctgacgg ctgaggggtt gaggtteogge astogtegoaa gcagettcaa ccacgetetg 128 gtagacagat tggttgaggg tgcaatcgat tatatagtgc gacatggagg ccgggçaggaa 388 gacatcacac tegtgegegt accgggtage tgggaaatte ctgtagecge cggagaacte 246 graagaaagg aggacatega cgoggttata gecattgges teottattez cogggcaacg 388 teccactttg actatatege atcagaagte tetaaaggte tegctaacot tagoctogaa 368 ctoagaaage ccataacttt coptettatt acagetgata ccoctggagca ggocatigag 428 cegecageta ccaagcacgg tastaagggg tEsgaagctg cacteagege aattgagatg 288 gegaatotgt ttaagagcet gcgcggtagt getagtagta gcegaagtat cotgatcggc 548 attetgaaca ataccgtgta cgaccctctg cageccgage tegacagctt caaagaggaa 588 ctggataagt actttaagaa ccacacaage cccgacgtgg acctgggega tatcagcgga 668 atcaatgecca gegtegtgaa calocagaaa gagategacc ggctgaacga ggtggecaag 728 aatctgaacg agagcctgat cgacctgcaa gaactgggga agtacgagca gtacatetaa 780 <218> 28 Page 28

SY NE AS ES 4 4 Las ; DSH. 28 88 20008. cesnnanre TUtetino{DAAEEVTTANN Los £3.08, Jue sequence isting (POGS5277443 SYN SOS 5 © > ve LR)

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A AE 48 45 Tia Aen Fue Tle Wal Ame Me Au a oy ~~ a z Tig Asn VS Tip Mal Ape Has falas ft Anse Sir Sr Aucun Tia Thy à mt ASP LYS LE Val APE HIS LAY Lily APE QU QIU ASD 218 inh LEU a ye 58 en an 2 ci Par Ow Leet SE 4 ; Vat Arg Val Des Su Cas Ten Miss Tin D Vim) yl AT ex = Val Arg Val Pro Gly Ser Ypn Qu Tie Pro Val Ala Als Gly Slug Lau 8 È WAY SEP IPD Lal LG PPD VAL ALS Ald AV LDAU LOU Se “ea op Go iw ES se #2 £2 SE AY on Re a J . ; . AIR ane lue Siar Aow Tin Noe wy A + vs D eu AY x EN CU Cy Ain Arg Lys Glu Ash Tie Ash Ala Val Tie Als Tie S1v Val Leu Tia APE LYS Gall ASE 118 ASD ALS Val 118 ALS LAS Gly vail LOU LIE a. hs Fh Cr SS 3e 85 Arg Glv Ala Thr Pro His Phe Acn Tur Tle Ala S Alu Val < Au DAY Aaa HP Pro Hs Phe AS Tuer im Ain tan Gin Fal Sens us 8 y ia in PO OHIS PRE ASD TYP LL Add DARK Glu Val DEP Lys “FAST 5 3 bed TN TA 16 YN 4% a

HE ARS iv Leu Als Asn Leu Ser Lou Slug Leu Ares 8 D 1 Th DE 3 WAY Lm Ada Mal SELS SCI Lu A LEU Ary We Dey Tia The Dhe Say ¥ LRU SEE LRU WAN LOU ANE LYS MUD Lie int PRÉ Guy EEE 4 ON ) ta 2e axe 135 128 125 Wat Tia The Als Aes The Kan GOT = Al "3 n° A + ; Val Tig Thr la Asp Thy Lou Siu Sin Ala Tle Glu Are Ala Slv The i Ald ASE HNN LOU ad GAD ALS 118 QU APE ALS Lay ine ane ~~ 7 A PE ar TR ne 4 a0 Rial ADD Asp Yona LEIS #5 N ex oy Re . 3 tas LA Su Avy ue Av Tan 1 AT AT 3 & Fu Ele mn LVS HIS GIy Ash LYS SV Tm Si Ala Ain Leu Ser Als Tie a Mad ¥ Gly Asn Lys Giy Trp blu Ala Ala Leu Ser Als Ile Glu Met “ar "> TAR TO spe TR 145 158 155 168 m net 1 AE Ain A in Leu P ha face Can fa a ~~ ~ 0e > a x ALS Asn Leu Phe LYS Ser Lou Arg Gly Sar Sly Ser Gly Ser S N % + we AN Ma Ne he Se ha BS at Na à # x ; Nd FAN oY 4 WW © ap ALY ser SE OLY < LOU APE Gly SEP BLY SEP GLY 580 iy DE! aT = | TAK TN Tr

LON LA LS al Wal Tia Te Tia Val Ace Ree wi fend OW © Val Val Tie Lily Tle Val Asn Aun The Val Tye Aso Pro Lou § Tr Dre gd LE LLY LAS Var ASH ASN IND val TYP ASD Fro LOU Lin ¥ro aan YA "TON ne dak Lh 198 2835 AE Siu an fon Tarn She fue Alu Alt la À i T D { WEL LE ALD SET NY LY ETL Poy Aan ws Tr PDha ve Agn His LU LEU ASP SEP FIG LYS QU Gaul LOU ASD LYS IYP FRE LYS ASH HIS SO ET 7

TON SEAT VISE AWS Aha 285 a a Ea = a Fed § x Tian sn Daa cn Ua Rees Vence #00 on © AN _— TN Ser Spa Asn Val Asn Lou Sly Asn Tig se fiv Tis Acs AU S i NEY Pi > ASD x Lo 5; a) So AS Ar Fie CA fx à x FE = & ba Nh € O ASE Val ASD LOU Loy ABD LAS Der Luly 118 ash ALS ser SAR ae ia Yep © eue AM 225 2 aE = dk Law Cr RL A x nn. 4 . if Vim Aon Tin Se ase Sas TY Roa oa A 3 A SY Foam CE Vall Val ASR L418 Lit Ly siu Ile Asp Arg Leu Asn Glu val Ala Lys 3 SL ASN 118 Gin LVS Gil 118 ASD APE LOU Ash Glu val Ada LYS Base NA

AGATE AN Parga 31% ro = A ae de

DOG - 25.08.2028 - sequence listing(P995527744) 225 238 235 249 Asn Leu Asn Glu Ser Leu Ile Asp Leu Gin Glu Leu Gly Lys Tyr Glu 245 258 255 Gin Tyr Ile <218> 21 <211> 788 <212> DNA <213> Artificial Sequence <228> <221> CDS <222> {1)..(788) <488> 21 atgaccatgt accigtgpet gaagctgetg gceotteggeot tegcotttet ggacacagag se gtgttegtga ceggegecge cgcagtegta gtcatcateca ttecteccttcet cggggacgac 128 ggaagtecca acattactaa tttgtgtcca ttcggggnag tgttcaatge cactagette 180 geatcagtct atgegtggaa tagasagegc atttecaact ghgtggetga ctacagegte 248 ctetacaatt ccgcctcttt ctctacgttt aaatzttacg gegttagtec caccaagete 380 aatgacttgt gettcacgaa cetatacgcg gacagetitg taataag&gg tgacgaagtc 368 cgacagateg ctccggetca gacaggcaag atcgecgatt ataattacaa acttectgac 428 gacttcacag ettgegtaat cgoctggaac agcaacaace tegattecaa getesgcgge 488 aattataatt atctttacag gottticcgc aaaagcaatt tgaaaccttt tgagagagac 548 ataagcacgg asatctacca ggcagectec accecttgta acggeottga aggaticaac GO tgctactite cacticaaag ctacggatlic cagccaacca acggagtegg ttaccaacca 660 taccgegttg tggttetgtc ttttgagetg tigeacgote cggeaacagt ctgeggtece 728 saaggcggct ctggeggegg ctccggagge tetcaccace accaccacca ccaccactaa 788 <218> 22 <2ii> 259 Page 22 masa NE AO TINY em AA AE ev CDMS EY A AN AR LL ou as BE DES 2 carmiianss 18 et N Re DIiAatf UT AUS N OS AD, 05, 2026 sequence LISTINE(|PHSSS2 7744) das DET <été> HRA HR A pute a 0 X SA 3 Se ya PN SY 2 etd Et SE nd antianna “2435 APFTITICiai gushes «AREA su <ioë> 22 dinde CUT tac CT Re jee Taman} oe FE 1 mac AU Dies ace PAR AU. EY eg ee Mat pris MA SAP oan TEN boone FT à nt ar: Ai = un IS AS SRE ao: ds Met Ihr Met Tyr Leu Trp Leu Lys Leu Leu Ala Phe Gly Phe Ala Phe x © "ON TR X A ex HEN + 2 AY ÈS au An The Sir Val Dho Val The Tw Aa Ay AT 4 dad VAT wad Tp LEU ASE INT DLL Val PRO Val thr Gy Ala Ala Ala Val Val Val Tie A Se > Si pe TER LE pere Su To. ON N amr HE X © EY Le yr. Doe eu = EY pen ym nes TY ST by a A eur 5 nas Tia is ia à ais à DA sis San © nn St Tan are à Fa Yer Thu £ Fat DIE LAR LAE LOU LEU LOU AY ASD ASD GLY SEP FUG ASH lig ihr Asn LOU au AE AR 3 4 A > st = ALL LAN m a Ce fe md 2 Ban Sr +, Cove Ren Oho flv Tai Wad On Acn AT Thin Ans ho Ala Can fs à Vase LYS FTO FRE GLY QIU Val FRE ASN Ala nr Arg Phe Ala Ser Val hyd om "… J

SEX RE SER = +2 ve Am CF aa A. A rs or Apres TT. me ye ae eo es FA AT ~ Now yee Sea Vin N Tr Ï A AT tn, Ans Ÿ 3 as en “. Ng Fon Ain SE ss £a moi Ala PP ASH APE LYS APE Lie ser Ash LYS Val Ala Asp Tyr Ser Val J. en “x an DO 22 i Sr De Vars Ace Sa AT - EE I Covey Tag Maes oases fare tape TU Ne TO ea oan vase ff A » At EY IE an ce res SH A FE x VAs NF ss tan LOU TY ASH ser Aia ber Fhe Ser Thr Phe Lys Cys Tyr Gly val Ser ar An ar ss 38 a5 Pra The Lue lou don Agen Lau Sus PDho The Aen Wal Tur ATs Acn Soe FPS INT LYS LOU ASD ASE LOU CVS Kine Thr Asn Val Tyr Ala Asp Ser 188 TAN 118

LE ARS AAR Pha Wal Tle Aro ST Aen Sg Val Arg OTs Tia Alla Deas Ola ST The PRE Val 148 arg GLY ASE LAL Val Arg Gin Lie Ala Pro Gly Gin Tu HE Bu AE LAD LL Ld Jai] J vie \ CY A ges Tis Ace Vague à © 1 IS ne an As Di The 277 Siw ade Tin Adnan 2 wy Tage a REET Das Ÿ pti Ay Ken ACT Ase Voksen sir Gly LYS LI0 ALS ASD IST ASD Tyr LYS LOU Pro Asp Asp Png Ihr Gly ET) AN + LR 138 135 LEG Mare MATT ATT - TE an ae Rem Een ie Roos 1 ans ÊÂ be Ce 1 OST STs EUR» : Fon FS ay A CE LAr Ac, Ar > ~ Saar + § 5 : six LYS Val Lie ALS ITD ASTM DEP ASH ASH LOU ASD Sar Lys Val div Gly A } } 3 X 2 TR RER NN 2 SR 145 158 355 188 Agr Twe Agen Tur Tan Tur Aro Par Dha Ang uc Sar Ach Pau fe Des ASH TYE AST PVP LOU YT APE Leu Png Arg Lys Ser Asn Lou Lys Pro a TFN “TE 165 178 375 ha Qu Ars Ach Tla Sor The STi Tim Tur An Als Alu Car The Des FRS LAU APE ASD Lie ser Ihr Glu Lie TVA Gin Ala Gly Ser Thr Pro FIN 455 FOR iy LED IW pn . ~~ Teh em Des Dike No fase Tas 351 De Tas Tey Car Farm are Ace Shar Ais Sea 2 De Aon Pure Tur Dha Den lan ATH Can Tum LYS As GIY val Gly dy PRE Ash LYS Tyr Pig Pro Leu Gin Ser Ty

AOE SIAN SPENT

QE SEA SAN LED S40 28% FETs De Sins Dan The Acn Sw Wal Ta Tur lm Dia Tass Spey Wad ART GLY PROS LIN MPO IP ASH GAY Val Gly Tyr Gin Pro Tyr Arg Val val ie BER TE

LAW LAD É AXE Val Leu Sor Pho Gl Lau lan Mic Ala Ora An The Val Sus Oly Dee VOA LRA ON! PIS VMS AM LOS TES MA rE MAS TON Mold AVS Way NES

TN IH SRE TAD £2502 LH L322 LAER Page 93 rags >=

DOG - 25.08.2828 - sequence listing(P&85527744} Lys Gly Gly Ser Gly Gly Gly Ser Gly Gly Ser His His His His His 245 258 255 His His His <218> 23 <211> 783 <212> DNA <213> Artificial Seguence <228> <22i> CDS <222> {1}..{783} <4ge> 23 atgaccatgt acctetggct gaagctgctz gcetteggct tegceotttet ggacacagag Ga gtgttegtga ccggccacea CCACCACCHC caccaccacg goggetotgeg cggeggetce 128 ggsgectete ccaacattac taatttgtgt ccattesggg aagtettcaa tgocactagg 188 ttcgcatcag tctatgcetg gaatagaaag cacattteca actetetgec tgactacage 248 gtecetetaca atteegecte tttetctacg ttlaaatatt acgpcgttag Lcccaccaag 308 ttcaatgact tgtecttcac gaacgtatac goggacaget ttgtaataag gggtgacgaa 360 gtecgacaga tegetecssg toagacagee aagatcgccg attataatta caaacttect 420 gacgacttca caggttgcgt aatcgectgg aacagcaaca acctggattc Caaggtggac 488 ggcaattata attatettta caggettttc cgeazaagea atttgaaace Ct{tgagaga 548 gacataagca cggasatcta ccaggcagee Tccacccott gtaacgggot tgaaggatic 608 aactectact ttecacttca aagctacgga ttecagccaa ccaacggagt cggttaccaa 560 ccataccgeg ttgtgettet gtottttgag ctgttgeacg ctecggcaac aglotgeggt 728 cocaaageat cagacgacga cggactecte ctcatcatta ttgtegtegt ggcagctecg 788 taa 783 <210> 24 Page 24 isti PO@5527744) Dog - 25.88.2820 - sequence listing(

STD VE

SAL LO yey see C£td> FRE CY Art d ZELTE Coantuipnea <213> Artificial Sequence © ASN NA <asg> 24 . “x 1 x NL i : 3 :; Als Dha Alu Oha Alan Die A EX ; on Ve lys Lou leg Als Pha Sly Phe Ain tre ‘et Thy Met i A LOL TPE LEU LYS LOU LOA FA US si dy DONENS MAY A N Met Thr Met 7 VPT LOU Ti #OLTU LYS LOU LOU À 3 7 “ee I Ta VE 1 5 18 35 — ur . x 3 Cos La TT ï Fan” i fee" vi 7 Mig Wie Mig Mic Mig Hic bte J x FL bs X This d'u Mie te M: Mig OH 3 His His eu Asp Thy Gla Val Phe Va fir Gly HIS 1 FILS MAS HIS HIS OH Leu Asp Thy Glu Val Phe Val The GLY HIS HIS HL À a | ot AN >» “ee 29 28 25 38

LX * = Gly Ser Sly Gly Ser Pro Asn Tle The Asn a5 ENE ps : Een Fe. Sr == 17 Lae faits CIE a FPo Asn Lie vi ASH LS GAY GLY DEP DIV biy Gly Ser Gay GLY der Bro : HAS Gay Gly DEP DIV Liy © AN SE VAY dy il 5 si a8 AD 32 Aa Fa N = = o> A Faq 1 = Az vi A 3 Ee A new EY dee AT + cry NA 3 i ; D ea Ar Die Acer Ala he Arg Frs Ain Yo al = Ro x Tue FN Ey en Ra yes F wy Fon Hi A Da Ka TY Ai X i 3 Ala SEY vai RU CVS ‘po FE PLY LAU Val HITE ASTM ALES Li ATE ny LEU LYS FPD Phe Gly QIU Val Png asn Ala 8 , so

CE LE A Le 55 DS x ~ aT ATs Ace Tue Can : Tia Sor doy Cue Wal Ala Asn Tyr Ser ae Re TT ae Aon Ang fue Ang Tin Sor Aun vs jai Ala Asn PAY Ser Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn lys À p 8° so x => RS - sn ) we RE te va ae 39 + ~~ La A > i enw on Tas Vie en A - De Can The Dba Due 6 RES Tes Sl Fal red 1 Tyr Asn Ser Ala Ser Dhe Ser The Pho | ss Cvs Tyr Gly Val Val Let € N PT AST DOI Ald Hat SI Rly si MAS LY S À = 3 3 AL LEU X a ue 85 sa 9% ss vu A A 1 © Pha Thr Asn Val Tyr Als Asn Sap Br Thr Lvs Leu Asn Asp Leu Ovs Phe Thr Asn Val Tvi Aid ASD Ser Pro Thr LYS LEU ASH AS = LOU LY 3 PIC O INT MLN Ve > 3 SET FFO 3 { EE “an ta + eed ax 148 A As U ol] À 2 Val Are Sin Tie Ala Den Si 1 Sin Cap Pha Val Tia Aro Sly Aon dt fai APE Gun 118 ALS Pro FAY VAN ser Pie val lig Apg Gly Asp Glu Val Arg oi i 3 ” FEN aa 115 126 125 at RÉ EU we AY X + Asn Tr Lys Leu Pro Asn Asn She The su, Sas} o~ Pla Ala Aen Tur Aan T FEN AS LATA PEL ASS MS ES AN ihr Gly LYS Lie Ala Asp Tyr Asn Tye Lys Leu Pro Asg i p “ ; + Rex

N RY TER ann Sr 148 i38 135 14% An? NS 3 3 A A Leu Asn Ser Lvs Val lv 3 Cvs Wal Tle Ala Tern Acn Sor Asn flan | SL ASD SSP LVS Val ly Gy LYS Val Lie Ala 19D Asn ber Asn Asn Leu À Ï X X Cr € “LA TAN 158 155 AD tax ANNE ASS LAS Lust

LÉ i T A leu Dhas Ano | VE Ser Asn | eu 3 VS G1 AS Tyr dan Tyr Leu Tyr Arg Leu Phe APE LS OST ASH LEU LVS Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Ly 3 TLV ALR y A 2 ee

FE STE TER TF 175 155 i174 i i. J x ~~ Can Tin | a ~ > A YA fue Sin Ala Sly Son The f Di G1 Are Asn Tig gr The Glu Ile Tyr Gin Als Giv Ser Thy Wray DA 2 Si Aro Aucun Tin Car Ski Al LAS SE VIT Ara BLY 0 Pro FRE QU AI Ë AS OLIS SEP nF LAU LAG TN 3 “esp AO 18a 185 198 LORY wn id oe

AUS iv Val Glu Gly Phe Asn Cvs Typ Phe Pro Leu Gin Ser Pre CWS Asy S LV Va i AU QLV HE À i Yo i 3) AAT + rn ARS MAR a Pro {ys Asn Gly Val Glu Gay FRE AST LYS DV & 8 7 7 ene

NINN HAN 395 ce WONT 225 OU A } i ial on Typ Sin Bro Tyr Are Val U gi Phe Gin Pro Thre Asn Gly Val &ly Tyr Gin Pro Tyr Are Val Tyrp Gly Phe Gin Pro Thre Asn BLY Vad bly IVP Ldn PPt vi 8 Vi FAY THE VAS 3 » ’ 7 ; VS

TIN AA sit SAS SENS 318 É AS & 3 eg PAT Pise Ta 3 3 a El IN pa ATs Ther Wal ve iv 3 a N D$ Gly Le HEI Ee ES Ala Ren ya iy Val Wh Lay Lie D ONE te Key Pia Sis fau 1 ais MAS ALY FRO ALS Tn Wal LVS 3d Va Leu > “ne Leu HIS ALS FPO AI X 3 Val Val Leu Ser Phe Giu Leu Lou HM Dune VE

FORT LS

DOG - 25.08.2828 - sequence listing(P005527744) 225 238 235 248 Pro Lys Gly Ser Asp Asp Asp Gly Leu Leu Leu Ile Ile Ile Val Val 245 258 255 Val Ala Ala Ala 268 <218> 25 <211> 783 <212> DNA <213> Artificial Seguence C328» <221> CDS <222> (1)..(783) <488> 25 atgaccatgt acctetggct gaagetgetg gcottegget tecgcotttet ggacacagag &8 gtettcotga cecggecacca cceaccaccac CACCACLACH geggotetgg cggeggetec 128 ggaggctete ccaacattac taatttgtgt ccattegggg aagtgttcaa teccactagg 188 ttcgcatcag totatgegtyg gaataganazg cgcattteca actetgtege tgactacage 248 gtoctetaca attececete tttetctace titaaatgtt acggcgttag teccaccaag 388 ctcaatgact tetgeottcac gaacgtatac geggacaget ttgtaataag gggtgacgaa 368 ÿtccgacaga togetocggg tcagacaggc aagateogecg attataatta caaacttect 428 gacgactica caggtigegt aatcscctgg aacagcaaca acctggatte caaggtggec 480 Sgcaattata attatcttta caggcttttc cgcasaagca atttgaaacc ttitgagaga 548 gacataagca cegaaateta ccaggeagge tecacceott gtancggget tgaaggatte 609 aactgetact ttccacttca aagctacgga ttecagccaa ccaacggagt cgettaccaa G68 ccataccgeg ttetggtteot gtoitttgag ctgttgcacg ctecggcaac agtetgoggt 728 Cccanaggat cagacgatga tggacaacaa aacaacttec tgcteeotgct gettetgcte 788 taa 783 Page 26

Rn AN NE er DAATESTTAAN = tige Sa ste PRASRIT IAL SE AN ERY carsancae Te LIE NWR LS SSS) RET FR AD ‘aa aauenes Listing MAN ) VOD - 25.08.2020 SEGQUETICE si Rue ve <218> LAB 8 8 ax

SAL ARE

AAN BRT <éké> FR! a An Seal Cantanca <213> Artificiai Sequence ann se <isg> 25 * Pie N est Su Dia ATs Dha ; Leu Leu Ala Phe Gly Phe Als phe i Met Tyr Leu Trp Leu Lys Leu Lou Ala Phe Gly Phe Ala ! Met Thr Met ; Eu } SU LYS LEU LOU ALS 3 Met Thr Met Tyr Leu Ti © LEU Ly I 1 ’ 5 is Ne i > EUR i et + PE $ ds ee WS eo LIN eo Cra 234 Lie Se dis His Hig - € a? x el x SY MS FEY jt x MEY MIS His DAS \ Asp Thr Glu Val Phe Val Thr Gly His His His His His L Lou Asp Thy Qiu Val Phe Val Ti X ne L Ÿ yp 38 28 LQ ax - 2 5 Yia The Acn ; S ST Siv Cap Ora Ach Tia Fi AS! 3 si Sar Gly Gly Gly Ser Liv Gly Ser Prog Asn lis Thr Asn Hie Sv Sv San Sv Gly Gly Set aly Gly Se HIS GIV vi ÿ SCT GAY Wd > > . ’ 18 AN ; AM od 35 48 5 35 A ï "pe Arg Dhn Als Con Val DE Fly Glu Val Fhe Asn Ala Thy Are Phe Ala Ser Val ï a N 0 + Wa a 4 iy : vo à Toi ADS Da SR > a es Leu € VW Fro Fe SAN SAL Ou TE HAS LEW LYS PO FRE GAY a A = 58 55 se 2 2 7 ; . Tor © en en. Wal Alan Asm Tue Lar T3 Ser cn Cvs Va Ain Asn Tyr Se | T A Arg Lys Arg Ile Ser Asn {vs Val Als ASE VI Sf} Tyr Ala Troy Asn Are Lvs ANE L318 Her ASN LYS : FYE Ada IPD ARN AY ÈOLYS TE = ne : 78 iS de AS #2

SI FY ; - Ter Slew Usd ; + Ser Thr Pha Lys Ove Tur Gly Val , - Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys 1 vr Gly a * x N Vin Now Soy SNE IN a REL A NE Suit $ 1 A à Valk Leu DV ASH Hed Mla aad EID © ; Vas LOU yy MDN oh A on a . sa 55 eu ca ss ï - Ÿ 5 re. “I - Wal Tur Ala Aen { Asa Leu Cvs Phe Thr Asn Val Tyr Als Asn Ti i i u Asn Asn Leu (yr TIC OS RAT SME VOS IN ; Ser Pro Thr Lys Leu Asn Asp Leu € VS FHIG IN $ SET PPS ONE LYS LOU AS $ > sa 188 185 118

A AZ x PEN a ~~ Tia Als Dre Siw Sn 31 Glu Val Arg Gin Ile Ala Pro Gly Gln SS Pr Val Ile Are Gly Asp Gly Val Arg Gin Tie Ala | X ser 1e Fad LA 5 4 SAN dd Ned ail, A V8 * SS SEP FRE Val 118 arg Gay i LE 328 LED 115 ASR

EU N Des TH i D Acer Acn Dho Ths > ; “asus à c Loi Ben Aon Ace Pha Thi Ï Giv Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro ASD Asp Pas The ST | rg LIE AIS ASD Tye AS! iX LY TP GLY LYS ALLES Ad AS! 3 an pi 7 que TA î3E Lay 138 13% À A332 A5 - ; La AR. N A las Acer van Dre Wal GA 3 i 5 Ser Asn Asn Leu Asp Ser Lys Val GAY 31 Cvs Val Tle Ala Trp Asn Ser Asn Asn Leu As Boas LY 3 { Wr 3S FE woo <a a — SN Pe ES SE LAY LYS VL Lig A A "y 55 nd > 3 J qu 155 3 ; € Aa nt 145 10%

AS \ a Cap Ach lan us T Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys BN . Is fon Tass oa it App Leu Phe Ars LYS 56 3 Gly Asn Tyr Asn Tyr Lou Tyr Arg Leu S es CES as +78 175 155 LG a 03 Ty Tver Gin Ala Sly Ser Thre 51 À Asp Tle Ser Thre Glu Ile Tyr Gin Als Giy Ser in Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile 1 X 3 FOU FRE Gal AY EH ASP LL sen oo N 2e 158 188 255 + mt ~ Tver Phe Pro Lou Gin Ser 31 Val Glu Gly Phe Asn Cvs Tvr Phe Pro Leu Gln Sei Pro Ove Asn Gly Val Glu Gly Phe Asn Cys Tyr FI Pro Lys Asn biy Val Glu Gly 3 LS 3 EA 385 195 su aa Na 195 LGV x =, Tur Arg Val in Pro Thr Asn Gly Val ly Tyr Gin Pro Tyr Arg Val 3 pi S 3 ÿ EN ï {A € ï 5 {€ Sa de NY A = + A3 2m 5 = Tyr Gly Phe Gin Pro The Asn Gly Val NOS PET VLY FASO an 3 > a 218 235 225 LAW = TN ey an “eT Pare 27 Tags «2

DOS - 25.88.2828 - sequence listina(P8085527744) Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly 225 238 235 248 Pro Lys Gly Ser Asp Asp Asp Gly Ile Leu Ile Leu Ile Leu Tle Leu 245 256 255 Ile Leu Ile Leu 268 <218> 27 <211> 783 <212> DNA <213> Artificial Sequence <228> <221> CDS <222> {1)..{783) <400> 27 atgaccatgt acctgtgsct gaagcetgetg gactteggct tegectttot ggacacagag sg gtettecetga ceggccacca ccaccaccac Caccaccacg gcggcteteg cggcggetec 128 ggaggctete ccaacattac taatttgtet ccattegggg aagtettcaa tgecactagg 188 ttegcatcag totatgegle gaatagasag cgcattteca actgtetgge tgactacage 248 gtectetaca attecgeete tttetetacg tttaaatgtt acggeettag teccaccaag 388 cteosatgact tetgecttcac gaacetatac geggacagel ttetaataag ggetgacgaa 388 gtecgacaga togotocgge toagacagge aagatcgccg attataatta casacttect 428 gacgacttca caggitgegt aategectgg aacagcaaca acctggatic caaggtggsgce 488 ggcaattata attatettta caggecttttc cgeaanagea atttgaaace tittgagaga 548 gacataagca cggasatcta ccaggcaggc tecacccott gtaacggget tgaaggatte 680 aactgctact ttecacttca aagctacgga tteccagecaa coaacggagt cagttaccaa 668 ccataccgcg tigtggttet gtottttgag ctettgcacg ctecggcaac agtetgegat 728 Cecanaggat cagacgatga tggacaacaa aacaactige tectectgct gcottetectg 788 taa 783 Page 28 ener ye - Yi RAA PANNE I VTT A PLEA AL AR OO © NAAR PASTIANS MORAN S 2 SAS LOR - BD OS AL SEQUENCE LISTINE(FOGSSZ/ 744) KEN se <210> 28 24 4 à sn S31 R JEN ahd £00 TES pr

SELL FRE SDR Avi ZI al Comironsa L323 APTITICIEL Sequences < SLA IR RSS > Eel 3 = + + ; ix 8 Ÿ EM es Hu Day AT a Die Mat Thr Mat Tuy ag Ten lan uve [nn fau Ala Dia 2 y Pha Ala Pha Met Thr Met Tyr Leu Trp Leu Lys Leu Leu Ala Phe GLY Pog Ala Phe = a. “ + © “A {En i > 18 is À 2 oi PUR if à Di Lied CT Div Ne MWe ide Wee Lite dde te Eesti der The STi Wad DhA ws Vive Yer Lt 2 die His Mie Ms e Hig bits LEW ASD ny QU Val Phée Val tm LAY HIS HIS HAS HIS HIS HIS HIS + I. Py se a LE LSD 3 ; A = + 0 ue J ~~ ~ Ban Aen TI Thin Ans te Slve Oly Sor Av div Alu Yan Av Gly Sar Pro Asn Tis Thre fan BAS LY GLY SEP BLY dy GLY Ser Gly LLY Ser Pro Asn Ile Thr Asn se AS SEX 35 A + i al © =~ =" EE fed si Seay AT The Anse Dm AUS Can 147 foes 25 © Theres The Sie Ari Val Dia Son Ala The 3 ss pr Abs es Va LEU LYS FPO PRO GI1Y LAL Val Pha Asn Ala Thy Arg Phe Ala Ser Val La cr sa Sid 55 GG . = x © Tan - =. La x Taw Ney (He leve Ans Tin Rar Ace Sie Wad Ain Aon Tur Can crue AT as mx n Ars auc no Tin Tor Avr Durs al Ala Asn» ay set PP Atà IPD ASH APE LYS AI BAAR OUT ASS LYS Val Ad ASD PVP DE ; ’ ay yur = on op 2e “x an AR Te nu Hig Gi re ES se Val Leu Tyr Asn Ser Als Ser Phe Ser THe She Lue Cuve Ter Elu Val Vas LEW IYP ASN SeP ALS ber Phe Ser Thr Phe Lys (ys Tyr Gly val QT GE os SS > FR x. ; 2 à Le Dia The Acn Val Tuas ATA Ace ann Prey The Due lou Son Aon lan Swe Dla Ths Aon al [RYE AT: An SEP PRG INT LYS LOU Asn Asp Leu LYS Phe Thr Asn Val Tye Ala . ASE aoa aan TT

EC AEN AAR fn x we oe x «a mn TS AT Dees AS 0 we = Pl AS = pe Agnes Tae Age sa ag fat Anse An m $? à Den SE 85 ; Scan Ds fn à Im Anne ai ë à ta 3 vus Fe) ÿ SEM IN NL A x $ A SEP FRE val lig AI 5OGAY ARF BAW Vai APE ihn LISE ALS Fro LY wand An oy qa “TE AEE] SON AAD Sold X42 - x . J. N ae, 3 ; Lp ~ Rev Dies Thien Try su Yar TP ma AT Aan Tyr Asn Tur vs fau Pea dcr fan Sha The Thies Shr Dove a Ain Age AYE i a sr i ca Pro Asp Asn Ph En RP GAY LYS AID ALS ASD TYP ASH 1yP LYS LOU Pro Asp As PO FRO im en RAM AS 458 TAL À 38 ESS AE 23 LB ; - ; . - . Co = Dien AAN as FY Wal Tia Aa Trn Asn Can Acn Acn Por Aen Can 1 ase iad Shag ; Eve Wa a Ala pH Asn Sor Ay an 2 sn Ser ly fa Das Giy CyS val Lie Ala Trp Asn der Asn Asn Leu Asp Ser Lys Val Gly x MN a van “LE SE

A LUD VRR DE

LAS LS ASS AD - = | + ï x ; ax Amer lue Can Rew Ia Are AU Apr re Hoven Tus oan Tr” Arg lan Dha Sever | oars Sep Agn Lau Lvs Giy Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Ar E LYS SEP Asn LOU LYS & > 3 a Ay Wer TF 175 ASS 250 LS D Di Glu Arg Asn Tle Sar The An Tie Tur On ala Oty Sa p The FPS FRE GLU APE ASR Lie Ser ihr Gly Lie Tyr Gin Als div Ser Th qo sue an X ex SE ANS LD Re A ; x ~ N nn Ce SI A eed wl Aor Due Tur Dha Den Pau Ola Sass Dee Sire Ac Sw Wal fx iy Pad ts MMe Aan Taal HAY ATEN WEYL OR ts ir SEY FPO LYS ASH BAY val Glu 6 LY MAE AST LYS TVD FRE Pra LOU Gan DE! oo “ne

THR TAL IAT

LED AUG FA ; 4 x a Sa - ~~ > x | J ten fiv Val dv Tum An Den Tom Ame liad Tyr Gly Pha Sin Pro The Asn Ov Val alu Tue Sn Pen Tyr Arg Val TYP LLY PRE GIR Fro Ihr Asn Gly Val Gly Tyr Gin Pro Tyr Arg Val Dann T0 “AE MAS ta RS SF

DOB - 25.88.2828 - sequence listing(PBB5527744) 218 215 228 Val Val Leu Ser Phe Glu Leu Leu His Als Pro Ala The Val Cys Gly 225 238 235 248 Pro Lys Gly Ser Asp Asp Asp Gly Gin Gin Asn Asn Leu Leu Leu Leu 245 258 255 Leu Leu Leu Leu 268 <210> 29 <211> 759 <212> DNA <213> Artificial Sequence <>28> <2213> CDS <222> (1)..(759) <408> 29 atgaccatgt acctgtgget gaagetecte geeottegget tegoctitel ggacacagag 68 gtettcetga ceggecacca ccaccaccac caccaccacg gcggetotgg cggcggetec 129 ggaggctete ccaacattac taatttetet ccattesggg aagtgttcaa tgccactagg 188 ttcgcatcag totatgogty gaatagaaag cecattteca actgtetgec tgactacage 248 gtectetaca attecgeote ttteoteotacg tttaastztt acggcgttag tcccaccaag 308 cteaatgact tgtgottcac gaacgtatac goggacaget tiglaataag gectgacgaa 368 gtccgacaga tcegctecgeg tcagacagge aagatececcg attataatta casacttect 420 gacgacttca cagettgezt aatcgectgg aacagcaaca acctggattc caagetggec 488 ggcaattata attatottta caggetttte cgeaaaagea atttgaaace tttigagaga 548 gacataagea cggasatcta ccaggcagge tecaceeett gtaacgegot tgaaggatte 588 aactectact tteocactica aagctacgga tteocagccaa Ccaacggagt cegttaccaa 568 ccataccgeg ttetgettet grtettttgag ctettgcacg ctccgecaac agtetgeggt 728 Ctcasaggsa gcgacgacag cgggatitte tttatttaa 759 Page 38

Ran ae mie SOUSSE aS TN NY EN ES LE A a = ec CREAT TOE A AN DEAR pu LAS PENSER x SEN » 5 3 NY! ARK TTY Fate LS AD 085 ZOL0 - sequence LLSULNS (PESDI LS 248 3

TO TH SALE 3g $211 355 LAA ÉLb£ AND Dar Sen FRI AN ARTS oa wT NC TE Tae É F m SAN x ÿ os ray Lames CLE Artiticiai Seguengs + A SN So cit 26 N a ES : en z ... : - : n° veu, PE al Aa ui Mat Thr Mot Tur Lou Ten [an ie lan fau Ala Bho AT Dha Ala Dh oO MEL HHT PEL EP LOU IPD LeU LYS Leu Leu Ala Fhe Gly Fhe Ala Phe * o TA *E & 3 A AD ent es Au Thee AUT 18d Ye VET se oY ME ile MS 5 T5 07 5 Lit ee id. = AM Tr Fm Sr ; Tongs ai 15 LES = £ x = x py iY ad LEW ASP INP LAU Val Phe Val The Gly His His His Mis His His His “a a TD Li £23 > Las LA en 411 ey RL ea en STs Can Den Kan TT en Thies Ans HIS GAY iy SET Giy Gly GLY Ser Gly Gly Ser Pro Asn Tle Thr Asn 33 a a Poovey fe Dea PInoy Tr SUT er Wat he Now AY The se Dik AT — Laye Fmd EYL Ase SEY “vie iN y “ir sa sa Ac A1 Tin Aer 3 Ain [am Lun: LEW LYS FPS FRS Lay GIU Val PRE Ash AIS {Ahr Arg Phe Als Ser Val Ego oe ga Se 55 Hid Pas Ad Can Nom Amey Tare Arey TV oa SA As Swe VAUT ATT Ae wy Lau en YP ALS rp ASN APE LYS Arg Lie ser Asn Cys Val Ala Asp Tyr Ser “> rey oe se > NS $2 DF Aimy Lanta Tasse me ÂT- Lan CDR an Thm Shen Pare € ve van TEs SY Vay Lal tyr Ash SEP Ala ser Fhe Ser Tne Phe Lys Ovs Tyr Gly Val cr Da dE Xe Lad a hy 52 > #3 Lan Das The fare fai As fon ! nn vo Dh: Toren Au fe ivr ATT An SEP FRO INP LYS Leu Asn Asp Leu Ovs Phe Thre Asn Val Tyr Ala ASD TAN aan AA

AG ASS AL sp Phe Val Tle Aro flv Agen QTu Wal Arg Mn Tin Ata Des As Are ser Phe Val Lie Arg Gly ASP DIU Vol APS DIR Lig ALS Pre Lay Gin ++ FE 452

LA AAW LED They DT Le Tue THe ATVs Nowy Tir Acn Tran fase me Dar Aces Nem Man Wim Thy Gly Lys Lie Ala Asp Tyr Asn Tyr Lys Leu Fro Asn ASD Png IN Ln TIR 148 158 135 ay Giv {vs Val Tile Als Tro Asn Ser Asn don lou Aon Sap à vs Wal SAT ARYANS VAL AUT RAS THR S00 SCT ALN ASN LEU ASP SEP LYS Vad DAV 22 15% Lad 106 Ss A on Tara A ew Tow [J WL aa A veu 8 ae de Aves 8 von Css Ans Do tape [CRE vase à 5 Ya Som are Ars er She Are Dur LEY ë ~ Yon ; VAY ASR TYE ASTM YT LOU IYT APE LOU FMC APE LYS Ser Asn Lau LYS Ta x > £a APTE LO Lid Lid Dres Tha ATu Aro Aen Tia San The Sr Tia Tur On ATs fu Car The TS PRE GLU APE ASP Lie her Thr Glu Lie Tyr Gin Ala Gly Ser Thi +“ vien aor + EAN 1028 se ion

ASC AG AE Trey Owe Aon Oly Val alin aly Dha Acn Owe Tus Dia Den ods Oly Can FPS LYS ASH LAY Val Glu GLY Fhe Asn Lys Tyre Phe Pro Leu Gin Ser

SON SOA OD 325 286 285 Tir lu Dha Un One hr Aen Gly Wal Sly Tur Sin Des Tus Ars Wad PFT ORLY FRÉ LAD FRG INRP ASH GUY Val biy Tyr bin Pro Tyr Arg val “yen sai mt IT pq E va

SAG SAS LE fal a] Tu sde WY ¥ SH uh

DOS - 25.88.2028 - sequence listing({P005527744) Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly 225 238 235 248 Pro Lys Gly Ser Asp Asp Ser Gly Ile Phe Phe Ile 245 258 e218> 31 <211> 884 <212> DNA <213> Artificial Sequence <228> <221> CDS <222> {1)..(864) <400> 31 atgaccatet acctgteget gaagctectg gcctteggct tegeotttet ggacacagag 6e gtattcetga ccecggccacca ceonccaccac caccaccacg geggctetgz cggcggetec 128 ggaggctete coaacattac Taatttetet ccattegggs aagtettcaa tgccactage 188 ttecgcatcag tctatgestg gaatagaaag cgcattteca actgtgtgse tgactacage 248 gtectetaca attecgecte tttetetacg tttanatgtt acggegttag tceccaccaag 308 ctoaatgact tgtgettcac gaacgtatac gcggacagct ttgtaataag gggtgacgaa 368 gtcegacaga tegcteocggz tcagacagge aagatogecg attataatta caaactteet 4238 gacgacttca caggttgegt aatcgectgg aacagcaaca acctggatte casggtegge 480 ggcaattata attatcttta caggettttc cgcaaaagca atttgaaace ttitgagaga 548 gacataagca cegaaateta ccaggcagge Tccaclcoctt gtaacggggt tgaaggalte 680 aactgctact tteccacttca aagotacgga ttccagccaa Ccaacggagt cegttaccaa 668 ccataccgecs ttetgetteot gtottttgag ctettecacg ctecggcaac agteotgcggt 728 cocaaaggea gtgtteagge tetgtaccte gettecggta acasccagca gaaceecgte 780 gctetttace agctegaaaa ctaa 884 <218> 32 Page 32

. : A rym 28 list Pé05527744) DOS - 25.88.2820 - sequence Listing DL 244}

ST DEF

SALES ALY J, se

LLL MR STE Maat od AS NT CAN ren py oe CLASS APTITICIai SEGQUENCE AN ss CAGE 33 ay Ra & ayn ry 5 X N 7 AN 2, Frais ue PRE ae NL AU x him Mat Thr Mat Tur lan Ten lan faa lan [nu Ala Dia Sy Dha Ala Dhn Met Thr Met Tyr Leu Trp Leu Lys Leu Leu Als Phe Gly Phe Ala Pha . Ca + X 2 En À 2 AS 13 È pme Rom The NT ge Lin DT She bit This DT ide Meo Se Mie dite WSs Lite LEU ASE INT QIU Val Mie Val HP Gly PIS HIS HIS HIS HIS HIS HIS i 2 a ee sa ze SE se ax LS SE Le RL Ze N Base mn ER Can Den Aen Tin Tha Aen eo fa Any gui cary da ASE ë wily Lime wo PAY fu TRE Saar RE SCT x Ti Tr SN MAS BAY GAY SSP GIV GLY BLY SSP GLY GLY Ser Fro Ash lig {Ihr Asn si TER si a AE AR 53 pi A ; N ; Le ; ; - os a = fe trans sase Time Thao las Ass WaT Din Acn AT a Then Ares Pha Alix San Wal LEU LYS MP0 PRE BLY QIU Val rig Ash ALS in ANE (HS ALS DEP Val cn ges za D >> Ets Tan SY ow A ey Any À e ânes HT aan New free fn Aa Ars Tarn Dar Tare As [asa ë 3 Are Ny SOF m Rat 5 ad arm in A + on rx sa Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala ASH Tyr DOI > a 27 an ge 2e € ca oh A £5 se pres Ÿ Fr Term Ar © s AT- e + Mia Can CTE har ques Shawn Toews Far AF) Wa Pot Turm £ HS Narn Ain Saar Daa Soar The Dis Dar FRYE Tas SEX: fat VELL LEU TT ASN SEP AIS HOF PRO Har ine FRE Lys LYS Tyr biy Val er Am ue > À. ALN Xe sh > Uh ~ > vi : ; ~~ ae wi Der 4 > An Au Ca Prey Thee ase Toni Rew New Tamir Sire Dho Tie Ann trs Ty Ain Aon SEP FPO INT LYS LOU ASH Asp Leu (ys Fhe Ihr Ash val Tyr Ads Asp qe qa AA

LES AD LAS CS rad Tad oY ‘ oY UT fa Avner PET ae TH AY ee Tone St OT en Tin 23 Tin Ang Sv Acr Foxe fm Acer im Tip Airis Din - ar AN ser FRE Val Ale APE LAY ASH Liu Val arg Gin Lie Ala Pro Giy Gin

TE TIER ANE ALD dE AED - N A . At vi Lu so ture WY > AU + Aer Te Aer Tas fase 5 mac Une Rosen Aer Dig This TE qe tar sx im 7 ma Try Noy Teer Horse x vey fe £ nv Dia TS INE LAY LYS AIS ALS ASD ry, Asn Tyr LYS LOU Fro Asp Asp Phe Tig Fa TIRE TA ASS ASS 242 PU re 9 ~ Ram Vis AT- SF page Noe Tony Noon Ages Boy Ast a Sr WSs} A $ « az se ë i X ya ~ EN N ï nt À Fal cs 3 ses LÀ; LAY LYS val 138 AZ rp ASD Ser Ash ASR LOU ASD Ser LYS Vai Guy AN AO “NE TIRER LE DE 222 iow PUR Lun CA à ES var à acte Cave Rovere 5 oem She. Aire 1 € men Noon 3 sta fone { s Acer Tiens Soy Turm oan Tares rer Yas Bho Arg 1 ve (55 GN sil WS Gly Asn Tyr Asn Tyr Leu Twi ANE LOU PRO APE LYS SEP ASH LEU LYS TEE TER rn

AGS RE AD N i “x © we = > x +2 eee AY RT om AY ELA vu Dyn Disay Te Ars Ans Tan Caps Thier DU pe Tie Tur Sin Alla Ass an The FPO FRS QLU Arg ASP Lie ner ihr Gilu lie TYP OIN Ala Gly der Thi tan “ae J. Sa a ea, à Naa len Lu is 220 = pu Ç oY saut oo EE Pv eee Aw ares Tr rae TY Ea oo Trees Som Te Car Se Sure Boer en SST Va Sr Tr De Ne ns Tarps Dha ren boos 2 X Sa “PO LYS ASD GLY Val Gli Loy FRE ASN LYS Ty Pig Pre LOU Gian Sei ne se se

AUS EG LD a - ci _ - a ~~ Eat JY _ N x RE pe A co RFA Tr Te Dha Sy Des Yin Aucun Dir Vind {ie Type Sin Pro Ts Avy Wad YP GLY PRE Gin FPO INT Asn Gly val Gly Tyr Gin Pre Tyr Arg Val er ng a LAS Fa Fa ; N 2 pe ; 2 yal a fs X x a ge ST 4 5 A Ned : : UE ny "ly sn X eau 3 sue NS AY Das AY Tiger AS Fare Yas Em Son à a eye 3e SEE AY on Lu = rte Na Ÿ Sas ss X Val Val Leu Ser Phe blu Leu Leu His Als Pro Ala Thr Val LYS Way Bar x ass AT Hage 33 eh SN SE AD ATT PC Pa a Tr Tv Sn an ar Jar 0 AN TEA ES - SE A SEA SCA = DENT ER UE > ;. y Rey à DINAN UT PTS LUS £3.08, AGE SSOQUENTES 2ISTINE(FOLIDE 443 225 FRA PER A AAD L234 ASS AS Bas Ye So Kar Val it ATS lan Tur fau Ale fas Sty Aon Aen Sia Fro LYS Gly Ser Val GLU ALS LOU yr LOU Gay DEP LLY ASD Ash wan san sus ane L803 aad 232 Ts Acr Deven AUT AT ov 3 men Tage Vey Far: SFr Aer GAN ASH FPO Var ALS LOU IVP Lin LOU QIU Ash PES 285 LAS 2023 HR Sn LSA» 55 STR Ts an bs > SZ 352;

TRS YALA

SELEY UNA SN TEN ARTE ST Cana A

LES APTITICIAL DEQUENCE ANTES

SETHE ASS = 5353 PSE

SIU DS Salad LENS ANS San Fryer <222> {EY 3957) ? X F N I Ana 33 FRI > 23 my rr me dhe ge af a ae A RL pm Am gm ee sey ms SN PEW SN an made a de ale on fes ang ger mn on an ARE eh i am en ge en SEN eh AR eh eh ye Fay Ato eta Foacsrareans Hrovarcente Theat or mes SAE Sy a ey APPRPON ét SUB CLECLEL LESEN BUERSLAALE KLEE ALLER SLGLL SLR dE SE greys acer A A hs PEN NN Te ae gee NN A en ag ee ey en ee ee ale FT EY PW ee ae +R gocouetrte sropocsocte copacortet tTtretootor toectecoïtot gototooass 138 ARLEBLLLLE SULAESRYESELLL WESFERL ALL LEAL ASA RSR S VERSER SSSR Ne REA an mw ew needa pwd ono Le en pen en en ay ES EE AY ay en a en ey ps py en oie gm an > a NV us ac au au a ae OR paoctTototTon SPPTOSNPTPRE ESTATE CTOs SERS HPoTARENPPTARR pro TTtTase à SLA GARE VE LSG ali LESE dagaaiilay LEER LOL db haie Cagctttactt ASF EY NS pe pres amy Re ma am a ee ge eng mc amy am mg Eee ee Ae vas gem mm ya gee ime gem am ane a) Arn gg eT a ew ea an, a STAN Sonoogeoobat ACT ACSC ranpovette SET AT SAIS Tahoe arty MASS ATA SEL dose 3 3 £ £ Fe SNS ES SEAT Des > se = ai Ÿ CPS SELEY LEARRLEVEL SA REV HOT OCTO NES MS LN SRR ASE LRLLaLAL LL SOUL RARE ALES ode grade au ge oman (AE cane de amin amr en mw ey an ee pee on fo pp ppd ov RUE en ame pan ey ee ple PES ep ep et a TEAS cheb eters crt ey cancot ones overt FORTS : SE oe y oTrroorpnpe ES LA CERCLE C LES CULLELLLIR SEGA LERLLLLALE LESEN Bulla SC AAT ARSE nEnpaTPeron Pansérrrots storspttTen aroacanoot atantttose DEAN ARTES KR aFage sa ca Croto Toce UTES RCTS STAC See sh GR LES SELLES Guna Ahan LEELLLLEAE SSSR SSL CSSS SSSR ES OEL AN ey NN ey nt PE NE EN a a oan mn an gman enn AR NN LAN AT OWES Ey Yay AN agracegaca soteocascat catcoaoaovoe tropatotteoeo rpcaccacact popacarcaap ALN NEE SERLLLGOLEL SG VS SR AESSLL LLL BYALA [LGN ER + a AN ES CSN NE CS ES Gus que ue be aman Jus en nan ON Rn an Qué ans ms ue ewan an aay arr nn en an ane ele ge ew le pis ee ep per dn ARI BOTT ASAT TOUT SOAT SO SANS SNS Ti BET AH SET VCH AARON DOTOCOHSETS SRY all.iagapil RL LS LLRS Keinen Sea SER LAGE SLSVHSS SLA So ua pabaste aides gas ger im wm an ay aR eee en nd ov Reap ew ep am apie N aed de en ay an Ee a aE STUY ET PNW aw ey ph DAM eo Sy asaaroostt cptecçorute Hneboat = DERN BR Ean gan ua Da CAgUidTECa algal COTERERCETC tadidiladla dydaldalaa HOBLLRBSLE A AR ASS SA AS save es LS GS SN ES SU GS am mm gm se ey ae le me gm ney on aude de ge gop ims ge ade = geen rade an an anon oe STINE aanagoonaot ESSEN KB At a Len of Terms a ON NUT NOS UNE Basic gaaagegact SootetTa Afcnococo aarasotorne ceottooagpta cote an de

EEE RE AA GSNSS VS LAN ES CTI ROCH ASE SSL LAS VE SES SSI VUS ps puise nee an an de oe ns Re pop my pn gdh pay Sh NEY AST RD AN SAN TY ON pates oy oy ghee on = STARS ON RST ET OE a ee ew SEN qu'a on panda gn ny she mp er my pn ame peg mn NEW EN SS ACTA INEY NS oben NES ne Torey ao cote SEE ï TT CCT C5 DA SES SOS HAN a sis eat cd AREA NOS {Far X ST S BY

LL LESSIVE ARS RES RSS GS SR EEG EN GRASSE WS SUN RIAN Fda NN mn Peano onsta otto angates Tasaosasoe assoc stat ranseterste I LlLdadfaaisd Liigatgiilad crTidaagata LoCdgladZt aCaclttttat CaatCt£ZL8 Fa ~oagaatetos rtrassartt+ etotor Ses panséprseton Tepatetoss cnPtroprpate THREW CEEEATCUEC CLCOSSECLE CLELECICLE EaaUUlUtHE LEBALLLELL LOLLBRS SOLE fu aasatraccs seat ea artoctoosye ofFocacaonn orthcortons acctoocoat [AG GACHTLACLEO ESLULLARAt STETTEN CTECaldgad Era Oigadl aliiggligat SS a a N ya NEN NS EN ces Da HSSSNOSCROPIS DSSTDORNCHOS TOSTSDODD SOTTACTSTOD TosgoctTaocot SE ACER LAE

GELARLAERLE SEES SES ESS ES LES SAN N OR NS NE Baoan 3A

EEE

DOG - 35.88.2820 - sequence listina(P065527744) äccttectge tgaagtacas cgagaacgec accatraccg acgceogtega ttetgecett G68 gatceteotga gogagacaaa etgcacecte aagteotlea cogtgpassa gggeatotac 1828 cagaccagea acticogggt gcagcecace gaatecatee tTecogttece caatatrace 1888 astctgtgee cotiesgege ggteottcaat gccaccagat tegectetet gltacgeotgg 1149 8ACCggaagc ggatcageaa ttgcgtegeue gactactecg tgotgtacaa ctecgccage 1288 Tieagracet tcaagtgcta cygcetgtec cotaccaage tesacgacot gtgotteaca 1258 sacgigtacg cogacagott cotgatecgs gpagatgaag tgogpoagat tgceccotega T3 28 cagacaggea agateogeega ctacaactac aagotgooog acgactteac cggetgtgte 1388 atigootgge acagcaacaa cetggactee asagtoggeg graactacaa ttacctetac 14468 cysctgttece ggaaglcCHa totgaagoor ttesagcegs acateoteocac cgagatctat 1508 CAgEOCEECE gcacccottg taacgecets geaggottos actgctactt cecactgcag 1568 teotacgget Cicageccac asatggcgtg geclatoage cotacagagt gatggigety 1528 “aka ne Les ne À Lee NS = + ais TES a at agcttçegaac tgctgcatge ceoctgecaca gtgtgeggoe ctaagasaag caccaatete 1688 gtgaagaaca natgegtgaa cttcaactte aacggeclga CCHKTRCCHE ogtgotgaca 1748 Sagagcascta agaagtteot gecattecag cagttteece gegatatoge cyataccaca 1868 gacguegtta gagatcecca gacactggaa atcctggaca teacccotte cagottegec 1860 ggagtgtetg tgatraccec tggcaccasc accagcaate aggtegcagt getgtaccas 15238 Eacgtgaact glaccgaagt gccogtpece attcacgcez atragetgac acctacateg 1588 caggtgtact ccacoggeag caatetgttt cagaccagag cegactetet gateggagec 2049 gagcacgtga acaatagota cgagtgegae ateeccateg gcgotggcat otatgccage 2188 TACCANACAC ATACARNCHY cocramacey orcagatety Ttoovrragcen onappnteatt SH

KR REN SE LER ALELK VERLOR KORAN LO goctacacas Ygtototges cgocgagaac agegtggoaCt actecaacaa etetateogct 2228 atocccanca acttraccat cagcelgacc acagagatee tecotetete catgaccaag 2288 accagogigy actgcaccat gtacatetec gycgatteca ceogagtecte casceotacte 2348 Page 35

DEG - 25.98.2820 - sequence listing(P0985527744) ctecagtacg gcagettetg cacccagcte aatasagccc tgacagggat caccgtggaa 2400 cagçacaaga acacccaaga ggtettegec caagtgaage agatctacaa gacccctect 2469 äatcasggact teggeggett caatttcage cagattetge cegatectag caageccagc 2528 aagcagaget tcatcgagga cctgetgttc aacaaagtga cactggecga C@CCHZctte 2588 atcaagcagt atescgattg tctesgcgac atteccocca gegatotgat ttgcgcccag 2649 aagtttaacg gactgacagt gotgecacca ctgctgaccg atgagatgat cgcecagtac 2708 acatetgecc tgctggccgg cacaateaca ageggotgga catttiggagec tggcgecgct 2768 ctgcagatec cotttectat goagatggoe taccoggtica acggcatces agtgacccag 2828 aatgtectet acgagaacca gaagetgate gccaaccagt tcaacagcge catcggcaag 2888 atccaggaca gcoctpagcag cacagcaage geccigggaa agctgcagga cgtggteaac 2948 cagaatgeec aggcactgaa caccotgete aageagelgt cetecaactt cggegecate 3688 agctetetec tgaacgatat ceotgagcaga ctegacaagg tegaagcega gotgcagate 3868 gacagactga teaccggaag gotgeagice ctgcagacet acgttacces goagotgatc 3128 agagccgcez agattagage ctetgccaat ctggecgeooa ccaagatgte tgagtgtgtg 3188 ctggeccaga gcaagagagt ggactittge ggeaagggelt accacctgat gagettecet 3248 cagtetecee ctcacgacet ggtytttcotg cacgtgacat acgtececge tcaagagaag 3308 äatttcacca cegotccage catetgecac gacggcaaag cecacttteec tagagaagge 3368 gtgttcgtgt ccaacggcac ccattggtte gtgacccage egaactteta cgagceccag 3428 atcatcacca cegacaacac cttogtgtet ggcaactecg acgtecgtgat cggeattigig 3486 aacsataceg tgtacgacoe totgeageoo gagctggaca gcttcaaaga ggaactegat 3548 aagtacttta agaaccacac aagceccgac gtggacctgg gcgatatcag cggaatcaat 3668 gccagcgteg tgaacatocs gaaagagate gacceggetga acgaggtgge caagaatetg 3668 aacgagagee tgatcgacct goaagaactg gggaagtacg agcagtacat caagtegece 3728 tggtacatct ggetggactt tatcgcogga ctgatigoca tecgtgatggt cacaatcatg 3788 ctetottgca tgaccagetz ctetagctec ctgaaggget gitetagectg tggcagetge 3848 Page 36

- 38.280208 - listing(F685527744 Dog - 25.98.23 sequence listing{ 52774 u oe en ~~ po m a fe wa 9 fa PE 28 Ugcaagttce acgaggacga ttetgagcee gtgctgaage gcgtgnaact gcactacace 39 > 5 : . “ + - “ann - PROS - - gEttccgatg atgacggaat actcatacte atattgatte tiatacteat actttaa 3957 <3 DA <2185 34 3444 ARO SELL} A328 RS ser

CELLED BR ST EN Art dd Tal Cantianea SAL Artitricial dÏequence SEAS sé SÉQU> Dé Met Dia fan lan The The Lue Aro The Mat Dha Val Wie Uie Hide Me MET FRE LOU LOU INRP NP Lys Arg Ihr Mat Pho Val His His His His i N 10 nu: À > ARE 22 Mio Mig Hic Mie Oly Oly Ser Av Ale div Sor Siw Sly Cas Dla fan HIS HIS MALS HIS GAY GLY SP LLY GLY Gly Her Gly Gly Ser Phe Leu se _e we LB AD 3e Vie} E ends Ÿ macs Dawe Na Nia? Cormeen DT en Serer Tae UT Am bart They The Ser Val LOU LOU Hrd Lal val Ser her Gin (vs Val Asn Leu Thr Thre A: g 48 AD They EN Day Dees Dia AUS Turn Them Seer San Dike = They Ames Tar WaT Tae HP GAR LOU Fe Pro ALS tyr Thr Asn Ser Fhe Thr arg Gly Val Tw 5 SR as se >5 ow Taser Deny Acy ise Vim Piles Aer Darn Ceres NEA TR au de Zar Tle AY Am FFD MPO ASE LYS Val Fhe Arg ser Ser Val Leu His Ser Thr Gin Asp oe en pen ss

KT ER EN SE Hh 5 A Hd Pars Ohr Lan Ones Dhn She Team Ac Wal The Tem Dhs Mc ATs Tia idle LEW MRE LEU FPO FRE FRO SEP Ash Val Thr rp Png His Aia Tle His eu ne Ar 85 se U5 Wal Corn Sly The An Tv The Lue Ave Dha Aen Aen Dan Val tro Dr Val ser Lily Thr Asn Gly thr Lys Arg Fhe Asp Asn Pro Val Leu Pro FINN aT CIEE AVG 185 AL Divx Acer Aor MT WaT Tun Der ATs Tam Than AT Passe Cam Aer Tia TT; Phe Asn Asp Givy val Tyr Phe Als Ser Thr Glu LYS SEP ASN lig lie “ae an “se

LAD LEE ALD Ans Miss Terr Tio Da Ar The Thien Plant Acn San § are Thi Tw Cowen Este APE QALY irp Lie PRE GLY TP Ihr Leu Asp Ser Lys Thy Gin Ser Leu SRN “NE ten AS L232 AA E nas TY NEY Acn Som Alta The Acn Wal Wad TV are LRU Seger SUV a Tile es LEU Lie Val ASN ASH Alda Ihr Asn Val Val Ile Lys val Lys Glu Phe

TAN ER TER TAN Ld Loy 225 108 Sey Dea Mee ÂAcn Sea Dan Dla lan ST Val Tue Ten Wie lue Acn Soe LAT FRE LYS ASH ASD FPO FRS Leu DIV Val Syr 1d FV MLS LYS AST Asn qo are J 255 420 LED Den Can Tern Mot SF: Sar STi Dhae Arg Wad Tur Unn Sam AT Aen Acer LYS SEP PO Mat Glu Ser GLU Phe Arg Val Tyr Ser Ser Ala Asn Asn OA eu TON ASE 18D Ea

Pr TD A9 SA CEN ENT im MAS ES Va rele sven dS DISGAEA AN LEE ~ AD ON 4040 ~ SOQUENCE IISTINE(PUCIDES 461 2 DN # ace Thien Dlg Se Vanne AFT Una AT Deven Din Ponts Mat Nee Domus NT Aa EY + + pen AE EE Ta Fra RS Tu UF sat PSN bon So AR à AIN a 155 De D A5 LYS HP FRE QEU IP Val 580 DIR Frd PRE LOU Met ASS LOU GLU wldy DE San VIRE

AFD LX LW X N la ar A i a a vai tm Prin a Ÿ te A eu ve ln Tar Acer Dla [ve Acs fais Anse Alu Sha Val Dha lue Aen Tie LYS Gin GLY ASH FINE LYS ASN LOU arg GLU Fhe Val FRE LYS ASIN Lie SEA sue SON

LAKE SAD SEX As so Wr Nine Tare TH Tae © PRY oc Ade The Dae FU x New Frans MAT n tv x Dha Tus Tila Tus Cor fue Hig The Den x Acn lai Va ASD GLY TVD PRE LYS LAE TVD ST LYS HIS INT FPO LICE ash LEU Val eg aan ae sa Sd LI LBD SSD Agnes A une § sac TV ewe Sax TN cs PY Eee © ec AY 3 8 DT 24 Dhaene Bor Are} eux Saar Ans Agn [nu Des Sn Ser Da Tor Ala Days Sis Pra ni AT Ac Saas APE ASD Lal FPMO GUN LAY PRE SEP Add LOU Lil Fro LOU val asp LOU Re SA “ee 245 256 255 Dar TY NT TS N TU PH y Kane INa es AU ae Cage 1 eu Bouma: AUS 1 en 2e en as fiv Tip Aer Ta Tay Any Has SIM Sr | gay mi A 123 my Mae FPD ALES BLY LL© ASH 1.8 IND APE Fhe GAIN IT LOU LOU ALS LEU MAS JE A SEAS 273

SO GI AN Annee Use ms pus à ace Wl ae ne PU Le NE np Sn ve anus ST ay Free Tha AT « PT ae Ney me Yyrrs | are > Dane falar Sov an Tam Can VIRE Try Thien An AS x APE der Tyr Leu Far FPO Gly ASD SEP SEP ber QALY rp INT Ala Gly

DFE OR INE Ele a8 AWD Ala Aln Ala Tur Tur Val div Tur lan Sin Era Aro The Pho Pan | ou ALS ALR ALY TYP IVP Val Gay yr LEU ih Fro APE INT PRO LOU LOU CHA ON Tan LG Ln 352 ge Tin Acn SFr An AT Than Tia They den AT A Vs Ben Swe ATs arn LYS IVP ASH QIU ARM DIV Nr L318 INP ASD ALg Vol ASP LYS ALS LOU “ap 445 vue aes 385 338 315 328 AS Dan fan Sa Alu Then lue fre Than Tan lue Can Dikn The Wad ati ASD FPO LEU DEP QU INT LYS LYS INT LOU LYS SEP FO INT oval Gil SE SA “au 325 338 355 tue Ole Tila Tur On The dar Ask Bhe Arg Val alin Den The Slag San Lys Gly Lie Tyr Gin Thr ser Asn Pre arg Val Gin Pro Ihr GLLU Sei sas mar ar 348 345 358 Tia Val Aro She Den Aen Tle Thy Aen Tan Cuve Dra Phae Ally Qu Wal AIS VEL APE MRE FPO ASH Lie IT ASN LOU LYS PPO PRE dy GLU Val “ee sen sen 205 03 3h Bhn Acn Ata Thr Ars BPha Alan Sar Val Tur als Ten Asn Aro Luc Are FRE ASH Ald INT APE FRE ALS DEP val IVP ALS IPD ABM APE LYS APE Sa N SH 370 IF SES Tin Con Acn Sue Wad ATn An Tus Tops Wad fau Tur don Ta” Ala Can Île Ser Asn Lys Val Ada Asp Tyr der Val LOU Tyr Ash SeP ALS DOI se SR EX Su NERS 355 358 355 AGE he oo Cas YA Ie d'age au es TT Fal EVER VE] Lan Dar ie ger age Y mis Ac Ae Shao an Tres She À are Cr rues 5 Foy Sax: Tan se ze X mis er : an Fhe SEP INF Pe LYS LVS IV GLY Val Hor PPD OI LYS LOU Asn ASD ane ARR STE 485 418 415 Fonts Fares Das Thien Aes WaT San AT ay Agen Saver Dae Vim) TV Ay Tas Au Leu Lvs Phe Thr Asn Val Tyr Ala Asp ber Phe Val Lig APE biy Asp

ATH AE AIS S48 Hd AS MA PA UT Row WE OO AT N . Sas A Tha pe etais Ù TY AU + A owe Ties Dia Fer Are Sir te Des Siv Din is s iv a Ain An Vases Glu Val Arg Gin Lig Ala Pro GiLy Gin Ihr GLY LYS 118 Ala Asp iy ATE SAD Aa 43D 444 FD Page 38 man SE A9 SAUNA Crau VE RAR RÉ TEENA ENST à à 8 LS £2,808, dude sequence LIsting({FDG55277442 Asa Tum Fase fans Des Aecn Ser Dha The AT wre 30a Tan ANA Tan Ars ASHE IVP LYS LOU Pra ASD Asp Phe Tor Gly CyS Val fle Als Trp Asn ANA save ASS 458 455 AGO Car Aer Ace D omis Sen Ton Par fn oY er A on x EY « A + : ~~ Can dom Acer mis Âer Senin ose fe Nae oF cr [YI cu I - Tage SEP AS ASH LOU ASD SEP LVS Val IV QIV Asn Tyr ASN tyr Leu Tyre

ASK ATR ATS ARH S45 SiG 50 380 Nomen 1 A Dan Aero A N us es ; Se ar su A = en ADS Sa) HA Ary boss sn ATH Sam Sum Dey Dla Si Ars Ao Tin Can ÂPE Lal FRE APE LYS Ser Ash LEU LYS Pro Phe Glu Arg Asp Ile Ser ans San Coe

ARQ A A 48% 48% 495 ir Sa. TH > oo AN UE e + = pe vn EU o~ a They Amir Tip Tyr Ain Alm iv Can The Dan Sue Acn Shag Fad SD Tri DT ar PAS GLUE 220 YPO DIN ALS QLY SEP ihr Pro LYS Asn Gly Val Glu Gly Sad 585 512 Der Een Mure Trem The aves N ea Ye Cems x FSU be pan OT ia A mk 13 x oF = Yas neo du X es ANY Ka ery ES tas DhHa te Dep Myer Ao PRÉ ASH LYS INP PRO FRO LOU Gin Ser yr QIV Fig Gin Prog Thr Asn Dar San car

DAS DE SL Yar VAUT Sas aan Ye Trea M ce ROUEN fs à = € am et où ©" ; FE ; Taser - ¥ Ln 2e Avr Fu ï J à ait Unes Diem HU 4 a BAY Val Lay YU LIN FPO IYP APE Val Val val Lal ser Phe Glu LOU can pan an >30 235 Da Tarr Wie Ala Dra Ala The Wal Due OF Den Fare Fase dan Them Ace à LEU HIS ALS FO ALS INF Val LYS QALY Prog LYS Lys Ler Ihr Asn Leu vas Pre pre = TAR LEA CE Den 34D SHU S5S 56% Need Yosser Newry fase Saree Vu A err FYE A Dhs Ave pa ; N i oY “à LE {wg Aw se x; far As Oha | m Dhe ou Tag he Nr Thy WEL LYS ASN LYS LVS Val AST Ehe ASN FRE Asn GAvy Leu Thy biy ne po FA, fp Nr: Fa RC 585 579 57% Vas Vrai FH Thar Var Teves A ewe Par & vai * em ni a] ex nn sin sex ome Ÿ x a aa Aer su are ue pa Des Eos FET en Re SY ey pms GLY VAL LEU INRP Glu DEP Asn LYS LYS Phe Leu Pro Fhe Gin Gin PHE ron "ee cas 580 S585 558 star A nee A ee TI AY A.» Tu EAN He = N x uns A ~~ EN x. Bar Ney An Tin Ala Ao He They Acn AT tint Ares Aucun Deven SD a Thy ae LAY APR ASD LAR Ald ASD INT INF ASE AIS Val APE ASD MPO an Ine . > i ES Ï vor SEA SAR >75 ses DED Past PT TT er fus Rem TY er Thom Be ~ = ns nu a Len = a lai sit Tim tai Aer s 18 HE san Jus Soap Pho Su div Wal Leary Aad LEU id le LOU ASP 48 dP FPO LYS bS8P FRE Guy Gly val ser Val can au can EN a LA putes RIRES

SAC DL DES TT ey TE BY ae Soe Tier A = vi d'au \ ~~ Com TY CU Cre x Ce Tia Ties Dam FAS Thre Noe Yow Men Som ST ey Wim) AU» Lge Ÿ Soest Dases SY ae AAC THT FPO DIV INT AST INT DEP Ash Lun Val AIS Val LOU avr Gdn sam omen "an can G25 538 535 48 No dey Sa wen su Ll ae a à °° “x ™ ar 3 AU 7 Pe a N N 8 Ray Wal Agn ue Yes dar fai Dee Wal AT a Ter Me ATs Acn Un font ASP VAL AST LYS INT LAU Val FPO Val ALS 1168 HIS AIS ASD Gin LOU J era J. Odo SSH Dod Pis Pree Tio Tan Ras fed ow ed x = VEN ws J Tire Dany The Tere Ang Wald Vases ais Thee Tr ary Acn Wa Sha Sle The PRE FPO INT IPD ARE Val Tyr DEP INF DIV SEP Asn Val FRS Gin Tar

SHA SAT SP Loi Ses Gry A, : AT = Se 3 so TU au AN > a3 ja À x = pr SU âne Ain Sw Owe 1 pit Tin Als Adm d'a Mie Aal La. Rew Cares Tare Ta: APE ALG QiIY LYS LOU LAG Lay ALS Gil HIS Val ASH Asn der tyr Luu re son ue DO Dag DUD FN eam A en om De Ea] PU Le AT em Ses WY ps so ~~ — oy pd, x Fis à Fa} Voix Vpn TT is fixes Ads FOIRE Tin ve An apy Taser À Th IT LYS AED LAG PPO O Li® LAY ALS Gly 118 LYS Allg der yr Gin mmr DEN even ar AN SD ak SAA oR DED SO TE A eu Dave Dias AH Amer AT Aver aus Ades TU RD Can tas ne TY oe VU Pate I 3 RAP VHPA ARS ANVET # Nowy € pe > Noy ang sir a ln o INT ASIN SEP PPS APE APE Ala APE ser Val Ala ser Gin ser ile lie = os UN VASE 4 Mart 27

DOG - 25.08.2820 - sequence listing{PB@s527744) 785 718 715 728 Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser Val Ala Tyr Ser Asn 725 738 735 Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val Thr Thr Glu 748 745 758 Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys Thr Met Tyr 755 768 765 Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu Gin Tyr Gly 778 773 788 Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile Ala val Glu 785 798 795 898 Gin Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys Gin Ile Tyr ses 818 815 Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe Ser Gln Ile 828 825 838 Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Phe Ile Glu Asp Leu 835 848 845 Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile Lys Gin Tyr 858 855 859 Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile Cys Ala Gin 865 878 875 830 Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr Asp Glu Met 885 838 895 Ile Ala Gln Tyr Thr Ser Ala Leu Leu Als Gly Thr Ile Thr Ser Gly 288 ses sie Trp The Phe Gly Ala Gly Ala Alas Leu Gln Ile Pro Phe Ala Met Gln sis 928 925 Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gin Asn Val Leu Tyr 338 935 948 Glu Asn Gln Lys Leu Ile Ala Asn Gin Phe Asn Ser Ala Ile Gly Lys 345 358 955 268 Ile Gin Asp Ser Leu Ser Ser Thr Ala Ser Als Leu Gly Lys Leu Gln 965 G78 975 Page 40 a. a, a CE LES ee FEES EE A 24 TA pi AR SEIN LO ganuensa Tier Dann EST PAAN LI A008, AG L£U SEQUENCE LISTINE|FPOQIIÉS 441 Sen Wad Wad Arsen Un Aer Aa 20 An Fass Ann Fees Panne VAT D are PTS ASE Val Val Ash Gin ASH ALS DIT ALS LoU Ash Thr Leu Val Lys Gin

QRS QAR GOH se VHS Se {aug ns Yan Acs Den Av Ala Tin Can Tam La Poor An Acun Tha ob man Leu ser Ser Asn Png Gay Alda Ils Ser Ser Val Leu Asn Asp Ile Leu

QO ENON EONAR Lae lag Ae AN EIGEN

WED LE LEED _ : x Son tb 0e N N foi 3 SY oY \ 8 ci San Asa Panty Ao, Tue Wal Sha Aa SY Wal fin Tia Nowy Arey 5 ati SEP APE LeU ASD LYS val Glu ALS GLU Val Gin 218 Asp APE Leu AAA “mue aan

TER TSAR TEAR

RRNA ARPA LS on Tle AUS Aen 1m ae ; Nn Whom UE «Ce Pi Fen nT an Tin rip Si Aro ati Sin ar {au Rhin The Tuam frs à Thee Tin Sir LAS im SAY APE Leu DIN DO? LOU LAN INT yn vai ET QUAN Gdn Wan 4 AVR Aone Ads ia Lush HE TN a Newey AY a AY TH TT A c ANY = A Nam ame Yams RAY a N° à 2ait a Ho Ain AI fit PS Ang Ain Lans Ain Aor > Ain 8 wy LEW OLIS APH ALS AIG LIN 2110 APE Ala Der AIS Asn Leu Ala Ala 1848 1845 1858 Thr lue Mot tar S87 Suc Wal Parr niv fin cars 1 ge Arg Wal Aon PAP LYS Met Ser Wily Lys Val LEH GLY DIN DEP LYS APE Val Asp qe PR PR TON SEA aa

AXED LAOS ADD Pha {vs Siv lve Sly Tye Hix leu Mot Ser Pha Pro Ain Ser Alan FRE LYS WAY LYS DAY IVP MAS LEU MEL SEP PRE Fre WAN 280 ALS

DENTE RENTE FAD ESS ASD Luan Dan Lise SUG WY wea Dies 8 ante WY ee Wal Tren Taos Wiad Dan ATs Tan FPS HIS RAY Val val Fig LEU NAS Val AP IV oval Prod ALS an

TSE TRAD TRG Free AIT A5 oY ; A ee Fax 3 3 AN SR Tu en ws fes ax Yous ÉD sa Pape Are Ain Tiens Thien AT. Dee ERE ? A are e = nas se LAW LYS ASH FRE INT RP ALS Pro Ala 128 LYS MIS ASP bay LYS 4 TNA TAT THON

AGE LEED ALLE Am Le Di Drop A «PEU SD qe fat DA a © Ro PA TE I Am ES € 3 Ene Dawes A ney Sov PI N Aan 3e Wal Sas Acn SNe Ye REA + Ald HIS PRO FPO APE GLU GAY Val FRE val Her ash Gly ihr Mis RARE 44 SA 442€

J AL LLL Trn Dhe Lai The QT An Ares Ae Die Teese Ts dress OV ey Tin TT Than TD PRO Val NP Gin APE Ash PRO Tyr LIU Fro Gin Ale lie (hf

PVR N N AN A OS ax SE AD 2239 LAS Thy Acer As The Dho Wal Can Axe Aen Sue Aou Wad iat Tia Sly TP ASD ASH TRY Mig Var Def GAY ASD LYS ASD val val 11g dy

PAS TTL THE

AA ST AL ALB TY en Vem Td Ace Acn The V4 Tas Aie Ya à ST ens Fehr 3 avr Avr Ra fn Aie 3 Fal is UNS Am See 3 nuit de Te aix >) Ar LAE VAL AST AST HP Var yi ASE FRO LEU GAIN FPO DIU LOU Asp TIEN TIAN 1178 Lab LAO: ALU Ta Dhe Bayer Tai Aa Tant Ac Pace Tarn ira face Ava te Thu Cee Ser FRE LYS DIU GLU LOU ASD Lys Tyr Phe Lys Asn His Thr Ses

THF TEND TAHOE 3 mi UNS 135% LISE LASS Dean Near Ay 3 Ace Dan Shar Ac TT Ta Das ATS Ye Sen A Seven AR SEO ASD Val ASD LOU GLY ASP dae der biy Lie Asn Ala ser Val

THON HO TER

ALTE JAWS ALO ial Acn Tl: d'in fee d'u Tia As Ang lai Aon Tr {ni ala tux VOL ASN 18 GIN LYS Gly LIE Asp Arg Lau Ash Glu Val Ala Lys an 4 TS EN ER

TAT STE STE LEWD LEA AE AT

DOG - 25.88.2028 - sequence listing(P805527744}

Asn Leu Asn Glu Ser Leu Ile Asp Leu Gin Glu Leu Sly Lys Tyr

1228 1225 1238 Glu Gin Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu Gly Phe Ile

1235 1248 1245 Ala Gly Leu Tle Ala Ile Val Met Val Thr Ile Met Leu Cys (ys

1258 1255 1268 Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys Ser Cys Gly

1285 1278 1275 Ser Cys (ys Lys Phe Asp Glu Asp Asp Ser Glu Pro Val Leu Lys

1288 1285 1298 Gly Val Lys Leu His Tyr Thr Gly Ser Asp Asp Asp Gly Ile Leu

1295 1388 1365 Tle Leu Ile Leu Tle Leu Ile Leu Ile Leu

1318 1315 <218> 35 <211> 888 <212> DNA <213> Artificial Sequence <2287 <221> CDS <2322> {1)..{888) <488> 35 atgaccatet acctgtgget gaagetgete geottogget tegcotttet ggacacagag 58 gtettcgtga ceggecacca ccaccaccac cCaccaccacg goggetotgy cggeggctec 1268 Egaggetetc coaacattac tTaatttetgt ccattcgggg aagtettcaa tgccactage 188 ttegcatcag totatgegte gaatagaaag cgcattteca actetetege tgactacagc 248 gtectetaca attecgecte Ettctetacg tttaaatgtt acggegttag tceccaccaag 388 ctcaatgact tetgcttcac gaacgtatac gcogacagot ttetaataag gggtgacgas 369 gtcegacaga tegetoogge tcagacagge asgategeecz attataatta caaacttect 428 gacgacttca caggttgegt aatcgoctgg aacagcaaca acctegatte caaggtggec 488

Page 42

© . NEN YY A AY SERIE TS od of DOG T FAA nas 25.08.3828 - sequence Listing: PAGSS277a41 Dos - 25.08.2838 - se QUENCES LEINE HERD) ; Pan $m nd fee RS A em TN ES BAD € Tee + PE EE EEE me ST FTFFRRTAON SAD ti t sitatottte Caseotttre cocannarcs attto aaa LLLLEdEaNS Le RECAATTATY attatlttta CoOsgctttte Flagdadgda atitgagacd TTYTEJdSA8 BRVGALLALS AULOLCLLLA CORECILLEC Cgagaag = BOE + Ù atte SARA ; avocagees trrarerett otanronpoot tonnopontte sas mon en AE Se eT en = "“YURARATSPRS se aooe amo trerareeett stagscpeepot tgaageattc Se SECHS CEEaaaty ci CHRLOAE . ALALGLLLL Raa gag = SH Haldiadgia (HEAL CLINRLORSS © 3 x SSRR Ë a tend tt SnSoën TTeendPPanN SransonpaoT eo at ta ccaa 8 a 9 aactgctact ttecsctteca sazctacesa ttercarcçcaa ccaacsea St cpottaccaa ets SOCLECLACT LYllACTità sagctacogga Ticcagccas E888 SS Jo om de rp on oy eyed TU Ct a a ett bb ong ct ottoraen STSSSSSaRS aote +sosot 720 ‘ataccece ttptoeettot etottthose ctettocace VÉRRLddS dNTLTECEST Sd Sratacrogo tro Ye N Ï STE ed GIE LLNLACE Lat igi aa X 5 A N 8 ES 8 HOES A 3 3 8 tgapecer ccrncacacoo acanmnpceot at sa avsta glggageete Ttrpotacatt cotsapecot € BEN GUSORSLAN LG SN CUO ana STSSRAOSOOT : LEESTaCaTy CCTEASESCED CCagaga "28 ac ECS LESSddRE LS HURSURSSAL (HERAT € BONS Rol sh ; San 3 In fd x en nr ey de QAR 2 we norneratttr Yogotteton rpottrrpat Seid FSPSARANO accotoaateo ootactette nos ae shed svettetes cesttoesat 248 SYCCOSARANS MNINOTOPANTO HSOTROT LLE AREAL REKEN ES 3 BSLLHadddE OCR VEAGLE SENSE SEHE © ERE Se SE # sono a La ; pdt Sune 3 $ de a be me my elle me ofr dn my ay glen ay de ey efoto ay SRK ee Rp Teh eatacrt sat attoaatd FETT AT A Cost ta Lei dos SATSAlSgan Yactca SO LLY Foil LL VLALGL Li et RN A AS LY HÉROS RERa LA LER Catatilgatl CLLAU NT EX ve

SITAR IR SLA» =D Fe ms

TUE TOR

SEA AS ABS © Ye Dn

SELEY PRI 47 As DS Es Caontanna SALE APLITICIal Séquence

SARS RE SATS 20 i © AN Plier Aa npka : i + 3 = lan lon Ala She Sly Dha Ata Pha det Thr Met Typ Leu Trp Leu Lvs Leu Leu Ala Phe Gly Phe Ala Phe Met Thr Met Tyr Leu Trp Leu Lys Leu Leu Ala Phe Gly Phe : 7 as oo ; = A ER 3 > 2e 5 — pt i 3 ae sa id 3 se Wie Mig LIS Hig do Aen Thr Su Val She Val They div Wiese Hic Wie OH LS PAS HAL RAS Leu Asp Thre Glu Val Phe Val Th GAY FILS TLLS nls HAS PI Hi LEU RST 1 3 28 25 38 EX pp ¥ 1 - nu © Durs Acn Tia Thin Aen o N PRE i. om ST lr ST ee ene FE Var Ves ary Bras Aon Piss cine ANN AL A oN x Kar N foobar Ta ENS fobs oy apn fu à 45 x AS ser 5 O ASH ig tir ASH HIS BAY WAY SEP Gly Quy GLY 580 GLY GLY SEP Fro | * ’ y AE 28 AR as SS AA > 4 € A > A Shea Als Car Val N - U ~~ mu, ‘ai Phe Asn Ala Thr Are Phe Alas Ser Val X 2 EY a a bey Tar Ty VENU Dia Ser ATa Thy A re Ph  ei Val ai LY PO FNS GLY À di FIRE ASH Aia 7 ANE M8 Ald SE LEU LYS #0 PRO GLY OU Val Pig Asn Aka IN = x ea oa Sy hy bu 232 IG ~ fal AVR Au Tarn Cam © x y x sam RE Ac use Va Alias Agen Vary Tow ea aT = Tn se Rex Rage fun Arno Tig Ser Ach Tus Val Ala Asn Si Se TWP ALE IPD ASN Arg LYS Arg lig ber ASN LYS Val Ala Asp ! X ; yon 0 sa on Fra Fe sa D SG #5 3 > Di Page Shree Tse Des Aad 5 + 2 Sor Ala Ser Phe Ser Thr Pha Lvs Cvs Tur Gly Val fad Tom Tur Aor Sar Ais Say Dha NEN Sr PIE LYS LVS SVT Lily Wal Wal LEU IYT OAS SET Aid SEP FRE Ler ine PE X X 3 X A J. or ren ne sy 5 SS N > + i A Asn Leu Cvs Fhe Thr Asn Val Tyr Ala Asn Cas Dreux Thin two ai: Ac Aon 1 mir Ars Hho Sit Asn Var HR ALS Asn DEP FPG INF LYS LOU Asn Asp Leu (ys Fhe In : 3 i * 2 + 5 TRIER TS Ce EX FUN FONE 118 ASC Lun LA ; | fo J sr ATa Des Su min si T N Giv Ash Glu Val Ars Gin Tie Ala Pro Gly 8h Ra es LES Tia Arno Al Acn à X Wal An ain 3 SO AL FU ALVY aan Sr he x a Ë a VW AD Wa à Ek «J ske Ann à AS FA ER A > SEP FRE Val LLE APE LAY ASD DIU val Arg bi € 3 rg wv SE à "32% es Ti LAR AS

AL À NS - : en ; ee Siam Tin ï Ss} + o w > ares Do a Ta Acn Agr Bho Thre ri ~~ Nr TY a Ale Ace Tiss Ace Turm Ève Leu Pro Asn Asn Phe The hp Gly 75 LL® ALS ASD IV ASN {LYS LOU FPC ASD ASD FHO HP GAY LYS LES Ala ASP IVD ASD IVP LYS LE { { , ; vu * A x

TOR TAS

TAG RE PAE A058 132 ASE

AR ax AD rear ELA LA EAE I SU AA N Dan 3 SE TAN LL carntnpnsae yong DRAKE DS TN VOS 45,08. JBL SEQUENCE AISTINE(FUCIDESFS4 3 , = ; = mn SSH 5 dus RU TA AU = Eee Non NREL TE At 1 ogy Sen Teen Pro Va Sir GLY Cys Val Lie Ala Trp Asn Ser Asn Asn Leu Asp Ser LYS Val Guy papa ees aoe Tad 145 158 435 150 DT Aen Turm Aen Tur Pan Tys Are fon Dho Ars Fug Tan Agen fan uw GLY ASH TYE ASH TYP LOU IVT APNE LEU Pha APE LYS SAP ASTM LOU LYS Tan 1TH TPE LO 179 EA] Dey Dla la Ares Ach Tia Cas The Ati Tia Tur d'in Ala Sly Cas The FRO FE GLU APE ASD 418 SEP INT QLU 148 SP wan Add dy ser oi

RH TRY OX 188 255 19a - ; a x © I. 2 ; ; mn en Dar Share Agn Ales Wal ATn Av Ohm Aen Sue Tur Oho Dea og Ain Raw Fro CVS Asn Gly Val Gil Gly PRE Asn LYS Tyr Fhe Pro LOU Gin DOI PU. sam “ar 155 Lug LY Re < wl a EET TE ~~ anon Fon A ever NPA ow SU Yin "DU TN pe Tiges Aer Tay Va BEN ane DE Dan Tags AA fm (rie Ÿ Dine cie Sy nf x ain fa TON YAS z > LA, \ ACT Sal PVE GAY PIE GAN Fra INT ASH LLY Val Qly PVP dn Fra pyr APE Val ; “ne san

IIH TR TRH É AN SAD Sa Fant N eo DE et] ï 3 AT = £3 ay am A+ Sn APS T Tres EN Ta > Wat Wal Tan Sor Dho Ti au [lat Hig Ala Pris Ain The Val ve fiv Vai val Leu Har PRE QIU LOU LOU HIS ALS FPO ALS HP val LYS Lay aa sa RS An 225 238 235 248 2 or oo ot © = a 2) ann AU as AY = Dons An A eu Deen Powe Shy Can Sw Div Cas Sy Ten Tia Pres Qu Ain Drs Arg San FPD LYS GLY S580 Lay GLY DSP GLY IVP 148 Fro Lal ada vit APE ASD FAT SEQ 355 Sa ALOK Ki .. - . oe x ao x a px UE N ~~ VEN Yo i su ne Dis Ar Ain Tur Wal Ars we fom Sly Alu Ten Val ton lan San The GAY DIN Aa TVD Vai APE LYS ASP QIV Luu rd val Lad Lad SEP im ; sex Ne SEX 36e TE

LOW ES EN . — N + ~ ~ a . ~y x Co A N wT a Oho fan Sly Ror Sly Sly Lan Agn Aan Aor Sv Tie Lau Tia lou Tia FRE LOU Gay SEP GUY GLY SEP ASD ASD ASP LLY LLC LEU Lig LOU ALLG “0m Sen ser 255 S88 ASS ; i. ea ; Ta: THe Tair Tha aus Ya fais LE LS LOU LISE LEU 218 LOU Eves ao

LW LHD AN AN a «BES Nf SELL Dd

AAN RID Ral LS SAY

SR BA <232> DNA A Te Arti Elem al Censnpnra CLAS, APTITICIGL SÉQUENTE

RER $F AS ÉASV>

SYN SENG : >55 Le

SALA LUS

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DOG - 25.88.2028 - sequence listing(PRAS527744) Ala Val The arg Gln Leu Val Gly Ser 165 <218> 35 <211> 584 <212> DNA <213> Artificial Sequence <228> <221> CDS <222> (1)..(504) <4ge> 39 atgaccatgt acctgtggct gaagctgetz goottegget tcaceotttet ggacacagag 58 gtgttogtga coggegtegt gatcggcatt etgaacanta ceoptgtacga coctolgeag 128 cocgagctez acagcttcaa agaggaacte gataagtact ttaagaacca cacaageece 180 gacgtggacc tgggegatat cagcggaatc aatgccagcg tcgtgaacal ccagaaagag 248 atcgaccgge tgaacgaget ggocaagaat ctgaacgaga goctgatega cotgcaagaa 388 ctggggaagt acgagcagta catcggtagt gçagggtete ggtacattee Tgaggcgcec 368 agagacggac aagegtatgl ccgaasagac ggtgaatggg Tactottgag cacatttets 420 gettctggea taaatcacgt gegeggaacg ggcegtecaa taatggeace agltigotgtyg 488 accegacage tggtaggaag ttaa 504 <210> 48 <211> 167 <212> PRT <213> Artificial Sequence <4B8> 48 Met Thr Met Tyr Leu Trp Leu Lys Leu Leu Ala Phe Gly Phe Ala Phe i 5 18 15 Leu Asp Thr Glu Val Phe Val Thr Gly Val Val Ile Gly Ile Val Asn 28 25 38 Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu 48 45 Page 45

Man ROAD NASA coanstianca Tied inod DATOS TTAMLN VEE AD OEL 2520 - sequence LISTINE(POOSS27744; 4 ; ; > > ; A : ot = =. peus Vas As Eons Sl Leu An ves Tur Dhe Tyg Agen Mig The Sor Den dan Wad Aon feu GU Lael ASP LYS Tyr FRE LYS Asn His Thr ser Pro AOD Vai ASD LOU a J sa 58 55 Hid Gly Ash Tle Ser Sly Tie Aen Ala Ter Val Val Aen Tle ain us On WAY ASD L118 SET GAY O LISE ASH AIS DEP Val Val Asn Lie in LYS Laud EX za 75 sa O5 A #3 Se + ; 5 ; ; au = ; 24 Tip Acn Aro lou An STi Wal Als Tue Acn Pan Aen Alu Cas Pons Tla Lie Asp Arg Leu Asn Glu Val Ala Lvs Asn Leu Asn Gly Ser Lou Ile es an Qu TB > >» . ; + _ a nu > > — ~ pL een Aon lou Sin Gl Lan Sly Tue Tur Sr allen Tue Tia Sly Sar dv Ov ASD LOU Win QIU LOU QIY LYS Tyr Glu Gin Tyr Iie Gay Ser Gly Gly

THR ERIN TAO A0 LEED LAW RE Te ee ea Shr AUS Deen Ans Aen Ale fn An Vie Aal Ames pas ES PAN + i Ty Dee Es sut Ai SN AA ES : mf SO EM AA IE HRY Jovy MAUR SEP BLY IyP 2120 Fro QIX ALS Prod Arg Asp oiy Gin Als Tyr Val Ar 8 se TA TIR A5 RES LL + x : ; à ~ wi > ; Ye. en x ws ture Awe tes 27 ue Ad Tad: lan Rar Ther Dha fais fiv Can Sw Tia Lys Asp Qiv Glu Trp Val Leu Leu Ser Thr Phe Leu QA ST GLV LA nS TRE AD AS 13D Lay A an ge SA A BO FA OP ge Dhs Yay AU > Tin Mat AT Diem 7 Al Aad x AN in a iX5 i $ Het fs ; T° ACTA SE MENT = + Va au Se ASH HAS Val GLY Gly TP Gly biy Ala Lie Met Ala Pro Val Ala Val

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Dee - 25.88.2828 - sequence listing(PBB5527744) Gly Ser Asp Asp Asp Gly Leu Leu Leu fle Ile Ile Val Val val Ala 1 5 18 15 Ala Ala <218> 43 <211> 18 <212> PRY <213> artificial sequence <238> <223> Mic2 <488> 43 Gly Ser Asp Asp Asp Gly Ile Leu Ile Leu Ile Leu Tle Leu Ile Leu 1 5 18 15 Ile Leu x<218> 44 <211> 18 <212> PRY <213> artificial sequence <228> <223> Mic3 <400> 44 Gly Ser Asp Asp Asp Gly Gin Gin Asn Asn Leu Leu Leu Leu Leu Leu 1 5 18 15 Leu Leu <21@> 45 <2313> 18 <242> PRT <213> artificial sequence Page 48

~ - sa 8 . DEE - 25.88.2828 - sequence listing(P6085527744) <225> KEN AY oA

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RRR JL SX >

Claims (18)

1. A polypeptide comprising a polypeptide antigen domain genetically fused via a flexible polypeptide linker to a self-assembling polypeptide scaffold, wherein the self- assembling polypeptide scaffold is configured to form a self-assembled nanoparticle comprising the polypeptide antigen in an oligomerized state, wherein the number of polypeptide antigen domains in the self-assembled nanoparticle is equal or more than six, and wherein the self-assembling polypeptide scaffold comprises the following domains: a core oligomerizing domain based on packing based on hydrophobic amino acids, beta sheet forming peptide segments, or clusters of aromatic residues comprising at least two phenylalanine residues; charged solubility and repulsion enhancing residues preferably comprising 1-6 residues of the same charge, and optionally at least one oligomerizing domain configured to present protein antigens defined oligomers comprising, for example, two, three or four copies.

2. The polypeptide according to claim 1, wherein the self-assembling polypeptide scaffold is selected from a foldon peptide, preferably according to any of SEQ ID NOs: 6 (AA 228-256), 14 (AA 112-140), 36 (AA 246-274), and 40 (AA 112-140), a beta- annulus peptide, preferably according to any of SEQ ID NOs: 2 (AA 26-49), 16 (AA 26-49), 38 (AA 146-169), and 40 (AA 144-167) or the corresponding homologous segments, and/or a scaffold for soluble protein antigen oligomers, such as a scaffold according to any of SEQ ID NOs: 22 (AA 25-42), 24 (AA 244-260), 26 (AA 244-260), 28 (AA 244-260), 30 (AA 244-252), 32 (AA 244-267), 34 (AA 1302-1318) and 36 (AA 280-295) or the corresponding homologous segments and/or wherein the linker comprises 0 to 10 amino acid residues preferentially selected from glycine and serine.

3. A DNA or RNA nucleotide sequence comprising a coding sequence for the LU102016 polypeptide according to claim 1 or claim 2, optionally wherein the DNA or RNA nucleotide sequence is incorporated in a plasmid, a linear or circular nucleic acid or within another delivery vector such as a virus.

4. A protein comprising the polypeptide according to claim 1 or claim 2.

5. A vaccine comprising the nucleotide sequence according to claim 3, or the protein according to claim 4.

6. The polypeptide according to claim 1 or claim 2, wherein the polypeptide antigen domain comprises a domain from the Spike protein of SARS-CoV-2 fused to the N- terminus of the self-assembling polypeptide scaffold and/or a domain from the Spike protein of SARS-CoV-2 fused to C-terminus of the self-assembling polypeptide scaffold, optionally wherein the self-assembling polypeptide scaffold is a foldon peptide and/or is configured to form a self-assembled nanoparticle comprising six copies of the Spike protein domain, preferably wherein the self-assembling polypeptide scaffold is a foldon peptide and is configured to form a self-assembled nanoparticle comprising six copies of the Spike protein domain.

7. The polypeptide according to claim 1 or claim 2, wherein the polypeptide antigen domain comprises a RBD domain from the Spike protein of SARS-CoV-2 fused to the N-terminus of the self-assembling polypeptide scaffold and/or a RBD domain from the Spike protein of SARS-CoV-2 fused to the C-terminus of the self-assembling polypeptide scaffold, preferably wherein the RBD domain is independently selected from any of SEQ ID NOs: 2 (AA 65-263), 4 (AA 227-399), 6 (AA 26-224; 259-458), 8 (AA 225-377), 18 (AA 26-224), 22 (AA 43-241), 24 (AA 44-242), 26 (AA 44-242), 28 (AA 44-242), 30 (AA 44-242), 32 (AA 44-242) and 36 (AA 43-242) or the corresponding homologous segments, optionally wherein the self-assembling polypeptide scaffold is a trimerizing peptide and/or is configured to form a self- assembled nanoparticle comprising six copies of the RBD Spike protein domain,

preferably wherein the self-assembling polypeptide scaffold is a trimerizing peptide LV102016 and is configured to form a self-assembled nanoparticle comprising six copies of the RBD Spike protein domain.

8. The polypeptide according to claim 1 or claim 2, wherein the polypeptide antigen domain comprises an HRC domain from the Spike protein of SARS-CoV-2 fused to the N-terminus of the self-assembling polypeptide scaffold and/or an HRC domain from the Spike protein of SARS-CoV-2 fused to the C-terminus of the self-assembling polypeptide scaffold, preferably wherein the HRC domain is independently selected from any of SEQ ID NOs: 10 (AA 26-108), 12 (AA 26-108), 14 (AA 26-108; 144-226), 16 (AA 65-147), 20 (AA 177-159), 38 (AA 26-108) and 40 (AA 26-108) or the corresponding homologous segments, optionally wherein the self-assembling polypeptide scaffold is a trimerizing peptide and/or is configured to form a self- assembled nanoparticle comprising six copies of the HRC Spike protein domain, preferably wherein the self-assembling polypeptide scaffold is a trimerizing peptide and is configured to form a self-assembled nanoparticle comprising six copies of the HRC Spike protein domain.

9. The polypeptide according to claim 1 or claim 2, wherein the polypeptide antigen domain comprises a domain from the Spike protein of SARS-CoV-2 fused to the self- assembling polypeptide scaffold, wherein the self-assembling polypeptide scaffold is a beta-annulus peptide according to any of SEQ ID NOs: 2 (AA 26-49), 16 (AA 26- 49), 38 (AA 146-169), and 40 (AA 144-167) or the corresponding homologous segments and optionally is configured to form a self-assembled nanoparticle comprising more than six copies of the Spike protein domain.

10. The polypeptide according to claim 1 or claim 2, wherein the polypeptide antigen domain comprises a RBD domain from the Spike protein of SARS-CoV-2 according to SEQ ID NO: 2 (AA 26-49) or the corresponding homologous segment, fused to the self-assembling polypeptide scaffold, wherein the self-assembling polypeptide scaffold is a beta-annulus peptide according to SEQ ID NO: 2 (AA 65- 263) or the corresponding homologous segment and optionally is configured to form a self- LU102016 assembled nanoparticle comprising six copies of the RBD Spike protein domain.

11. The polypeptide according to claim 1 or claim 2, wherein the polypeptide antigen domain comprises an HRC domain from the Spike protein of SARS-CoV-2 according to any of SEQ ID NOs: 16 (AA 65-147), 38 (AA 26-108) and 40 (AA 26-108) or the corresponding homologous segments, fused to the self-assembling polypeptide scaffold, wherein the self-assembling polypeptide scaffold is a beta-annulus peptide according to any of SEQ ID NOs: 16 (AA 26-49), 38 (AA 146-169), and 40 (AA 144- 167) or the corresponding homologous segments and optionally is configured to form a self-assembled nanoparticle comprising more than six copies of the HRC Spike protein domain.

12. A vaccine comprising a protein comprising a polypeptide according to any of claims 6-11.

13. A nucleic acid coding for the polypeptide according to any of claims 6-11.

14. A vaccine comprising a nucleic acid according to claim 13 in form of DNA or RNA, optionally included into a vector for the delivery to cells or organism.

15. A vaccine according to claim 12 or claim 14 for use in therapy, particularly in the treatment and/or prevention of a viral infection.

16.A polypeptide comprising the RBD or HRC domains of the Spike protein of SARS- CoV-2 fused to a self-assembling polypeptide scaffold, wherein the self-assembling polypeptide scaffold is an Aequifex aeolicus lumazine synthase preferably according to any of SEQ ID NOs: 8 (AA 224-377) and 20 (AA 15-168) or the corresponding homologous segments.

17. A nucleic acid coding for the polypeptide according to claim 16.

18.A vaccine comprising a nucleic acid according to claim 17 in form of DNA or RNA, optionally included into a vector for the delivery to cells organism.