Antibodies against yellow fever virus and methods for their production and use

Abstract

Antibodies and antigen-binding fragments thereof that are specific for the YFV E protein and have neutralizing potency against YFV are provided. These antibodies and antigen-binding fragments can be used to treat YFV.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 940,049, filed on November 25, 2019, which is hereby incorporated by reference in its entirety.

[0003] Reference to a "Sequence Listing", Table, or Computer Program Listing Appendix Submitted as an ASCII File

[0004] The sequence listing written in the file MAB-501001WO_SequenceListing_ST25.txt, created on November 24, 2020, having 493,241 bytes, in machine format IBM-PC, and using the MS Windows operating system, is incorporated herein by reference. Technical Field

[0005] The present disclosure relates to anti-Yellow Fever Virus (YFV) antibodies and antigen-binding fragments thereof, compositions containing such antibodies and antigen-binding fragments, and diagnostic uses of the antibodies, antigen-binding fragments, and compositions. Background Art

[0006] Yellow Fever Virus (YFV) is a mosquito-borne flavivirus found in the tropical and subtropical regions of Africa and South America. It is mainly transmitted to humans through the bites of infected Aedes or Haemagogus mosquitoes and has three different transmission cycles: 1) the jungle or forest cycle; 2) the African savannah (intermediate) cycle; and 3) the urban cycle. (www.cdc.gov / yellowfever / transmission / index.html). While many people infected with YFV are asymptomatic, others develop symptoms such as fever, chills, headache, backache, myalgia, loss of appetite, nausea, vomiting, and / or fatigue after a 3- to 6-day incubation period. (www.who.int / news-room / fact-sheets / detail / yellow-fever). Approximately 15% of infected individuals develop severe forms of YFV, including fever, hemorrhagic diathesis, abdominal pain, renal failure, cardiovascular instability, and liver failure; up to 50% of severe YFV patients die. (McGuinness et al., Neurohospitalist 2017, 7(4); 157-158).

[0007] YFV has an RNA genome of 10,862 nucleotides encoding three structural proteins and seven non-structural proteins. Starting from the 5' end, the order of the encoded proteins is: C; prM / M; E; NS1; NS2A; NS2B; NS3; NS4A; NS4B and NS5. The three structural proteins include the C (capsid) protein, the membrane protein M, and the envelope protein E. The envelope protein plays an important role in cell tropism, virulence, and immunity.

[0008] The 17D live attenuated vaccine is considered one of the safest and most effective vaccines developed to date. However, despite the availability of the vaccine, yellow fever remains a serious public health problem. There is some data indicating that immunity, although protective, may wane over time in certain populations. In addition, the outbreaks of YFV in non-endemic countries and the simultaneous depletion of the 17D stockpiles have highlighted the importance of developing treatments.

[0009] In fact, to date, there is no approved treatment for YFV (the only course of action is supportive therapy), and despite decades of research, it has been difficult to develop safe and effective therapeutic antibodies against YFV. The YFV E-specific serum antibody response has been shown to be mediated mainly by antibodies targeting domain I (DI) and / or domain II (DII) of the E protein, while antibodies targeting domain III (DIII) are present at very low titers or absent (DVratskikh et al., PLoS Pathogens 9, e1003458 (2013)). Accordingly, the six YFV E-specific human monoclonal antibodies described to date all target overlapping epitopes within DII of the E protein (Lu et al., Cell Reports 26, 438 - 446e435 (2019); Daffis et al., Virology 337, 262 - 272 (2005)). Recently, the crystal structure of one of these mAbs (5A) complexed with soluble YFV E dimer was determined, which showed that this mAb binds to a conserved neutralizing epitope within DII of one E monomer (Lu et al., Cell Reports 26, 438 - 446e435 (2019)). Thus, there remains a need for highly specific, high-affinity, and highly potent neutralizing anti-YFV antibodies and their antigen-binding fragments. SUMMARY OF THE INVENTION

[0010] The present disclosure relates to the discovery of antibodies and antigen-binding fragments thereof that bind to YFV proteins and exhibit neutralizing potency, specifically, antibodies that bind to domain III (DIII) of the E protein that exhibit high neutralizing potency. The antibodies of the present disclosure can also cross-react with other flaviviruses, e.g., show binding reactivity with DENV-2, DENV-4, WNV, and / or ZIKV E proteins. A broad panel of YFV-specific monoclonal antibodies is described. Binding studies indicate that the neutralizing antibody response to YFV-17D is primarily mediated by antibodies that recognize the FL-proximal epitope within DII of the YFV E protein. A small panel of DIII-targeting antibodies with potent neutralizing activity was also identified. In addition, binding assays indicate that YFV-17D vaccination appears to induce a subset of antibodies that display broad flavivirus binding activity, most of which target highly conserved FL and have little cross-neutralizing activity. Neutralization studies indicate that a proportion of the antibodies display high levels of neutralizing activity. In summary, the panel of antibodies described herein provides promising therapeutic candidates and a framework for the rational design of YFV vaccines.

[0011] Such antibodies can be used to mitigate the severity or duration of primary YFV infection or to ameliorate at least one symptom associated with the infection when administered prophylactically (before exposure to and infection with the virus). The antibodies can be used alone or in combination with a second agent that can be used to treat YFV infection. In certain embodiments, the antibodies can be administered therapeutically (after exposure to and infection with the virus), either alone or in combination with a second agent, to mitigate the severity or duration of primary infection or to ameliorate at least one symptom associated with the infection. In certain embodiments, the antibodies can be used prophylactically as a monotherapy to protect patients at risk of YFV infection, such as those described above. Any of these patient populations can benefit from treatment with the antibodies of the present disclosure when administered alone or in combination with a second agent that includes, for example, an antiviral therapy or other antiviral vaccine.

[0012] In certain embodiments, there is provided an isolated antibody or antigen-binding fragment thereof that binds specifically to YFV, wherein at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences of such antibody or antigen-binding fragment is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and / or all percentage identities therebetween to at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 amino acid sequences of the antibodies disclosed in Antibody Nos. 1 to Antibody No. 152 in Table 3.

[0013] The antibody or antigen-binding fragment thereof may also have one or more of the following characteristics: a) the antibody or antigen-binding fragment thereof exhibits a clean or low polyreactivity profile; b) the antibody or antigen-binding fragment thereof exhibits an in vitro neutralization potency (IC 50 ) between about 0.5 micrograms per milliliter (μg / ml) and about 5 μg / ml; between about 0.05 μg / ml and about 0.5 μg / ml; or less than about 0.05 mg / ml; c) the antibody or antigen-binding fragment thereof binds to YFV-17D particles; or d) the antibody or antigen-binding fragment thereof binds to the envelope protein of YFV. In certain embodiments, the isolated antibody or antigen-binding fragment thereof comprises at least two of the above characteristics a) to d); at least three characteristics; or 4 characteristics.

[0014] In certain embodiments, the isolated antibody or antigen-binding fragment thereof comprises: a) the CDRH1 amino acid sequence of any one of the antibodies designated as antibody numbers 1 to 152 disclosed in Table 3; b) the CDRH2 amino acid sequence of any one of the antibodies designated as antibody numbers 1 to 152 disclosed in Table 3; c) the CDRH3 amino acid sequence of any one of the antibodies designated as antibody numbers 1 to 152 disclosed in Table 3; d) the CDRL1 amino acid sequence of any one of the antibodies designated as antibody numbers 1 to 152 disclosed in Table 3; e) the CDRL2 amino acid sequence of any one of the antibodies designated as antibody numbers 1 to 152 disclosed in Table 3; f) the CDRL3 amino acid sequence of any one of the antibodies designated as antibody numbers 1 to 152 disclosed in Table 3; and / or g) any combination of two or more of a), b), c), d), e) and f).

[0015] In certain other embodiments, the isolated antibody or antigen-binding fragment thereof is selected from the group consisting of antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and / or all identity percentages therebetween to any one of the antibodies designated as antibody numbers 1 to 152 disclosed in Table 3.

[0016] In certain embodiments, the isolated antibody or antigen-binding fragment thereof comprises: a) the heavy chain (HC) amino acid sequence of any one of the antibodies designated as antibody numbers 1 to 152 disclosed in Table 3; and / or b) the light chain (LC) amino acid sequence of any one of the antibodies designated as antibody numbers 1 to 152 disclosed in Table 3.

[0017] The present disclosure also contemplates nucleic acids encoding the anti-YFV antibodies and expression vectors comprising such nucleic acids, as well as host cells expressing such antibodies via the nucleic acids and / or expression vectors.

[0018] In one embodiment, an isolated nucleic acid sequence encoding an antibody or an antigen-binding fragment thereof disclosed herein is provided.

[0019] In other embodiments, an expression vector comprising an isolated nucleic acid sequence encoding an antibody or an antigen-binding fragment thereof disclosed herein is provided.

[0020] In other embodiments, a host cell transfected, transformed or transduced with a nucleic acid sequence encoding an antibody or an antigen-binding fragment thereof disclosed herein or an expression vector comprising an isolated nucleic acid sequence encoding an antibody or an antigen-binding fragment thereof disclosed herein is provided.

[0021] In other embodiments, a pharmaceutical composition comprising one or more of the isolated antibodies or antigen-binding fragments thereof disclosed herein; and a pharmaceutically acceptable carrier and / or excipient is provided.

[0022] In other embodiments, a pharmaceutical composition is provided, which comprises one or more nucleic acid sequences encoding an antibody or an antigen-binding fragment thereof disclosed herein, or one or more expression vectors comprising a nucleic acid sequence encoding an antibody or an antigen-binding fragment thereof disclosed herein; and a pharmaceutically acceptable carrier and / or excipient.

[0023] In other embodiments, an expression vector comprising a nucleic acid sequence encoding an antibody or an antigen-binding fragment thereof disclosed herein; or a host cell comprising a nucleic acid sequence encoding an antibody or an antigen-binding fragment thereof disclosed herein is provided.

[0024] The present disclosure further contemplates prophylactic and / or therapeutic methods of using the anti-YFV antibodies (or the encoding nucleic acids or expression vectors comprising such nucleic acids).

[0025] In one embodiment, a method of treating or preventing yellow fever virus (YFV) infection or at least one symptom associated with YFV infection is provided, the method comprising administering to a patient in need or suspected of being in need: a) one or more antibodies or antigen-binding fragments thereof according to other embodiments disclosed herein; b) one or more nucleic acid sequences encoding an antibody or an antigen-binding fragment thereof disclosed herein; an expression vector comprising a nucleic acid sequence encoding an antibody or an antigen-binding fragment thereof disclosed herein; or a host cell comprising an expression vector comprising a nucleic acid sequence encoding an antibody or an antigen-binding fragment thereof disclosed herein; or c) a pharmaceutical composition according to other embodiments disclosed herein; such that the YFV infection is treated or prevented, or at least one symptom associated with YFV infection is treated, alleviated or reduced in severity.

[0026] In other embodiments, the method further comprises administering a second therapeutic agent to the patient.

[0027] In embodiments, the second therapeutic agent is selected from: antiviral agents; vaccines specific for YFV; vaccines specific for flaviviruses; siRNAs specific for YFV antigens; and second antibodies specific for YFV antigens.

[0028] In certain embodiments, there is provided a pharmaceutical composition for preventing YFV infection in a patient in need or suspected of being in need thereof, or for treating a patient suffering from YFV infection, or for ameliorating at least one symptom or complication associated with said infection, wherein as a result of such use, the infection is prevented, or at least one symptom or complication associated with said infection is prevented, ameliorated or reduced in severity and / or duration. In certain embodiments, there is provided a pharmaceutical composition for preventing YFV infection in a patient in need or suspected of being in need thereof. In certain embodiments, there is provided a pharmaceutical composition for treating a patient suffering from YFV infection. In certain embodiments, there is provided a pharmaceutical composition for ameliorating at least one symptom or complication associated with said infection. In certain embodiments, the infection is prevented. In certain embodiments, as a result of such use, at least one symptom or complication associated with said infection is prevented, ameliorated or reduced in severity and / or duration.

[0029] In certain embodiments, there is provided a pharmaceutical composition for treating or preventing YFV infection or at least one symptom associated with said YFV infection in a patient in need or suspected of being in need thereof, wherein as a result of such use, the infection is prevented, or at least one symptom or complication associated with said infection is prevented, ameliorated or reduced in severity and / or duration.

[0030] In certain other embodiments, there is provided the use of the pharmaceutical composition in the manufacture of a medicament for preventing YFV infection in a patient in need thereof, or for treating a patient suffering from YFV infection, or for ameliorating at least one symptom or complication associated with said infection, wherein the infection is prevented, or at least one symptom or complication associated with said infection is prevented, ameliorated or reduced in severity and / or duration.

[0031] In certain other embodiments, there is provided the use of the pharmaceutical composition in the manufacture of a medicament for preventing YFV infection or at least one symptom associated with said YFV infection in a patient in need or suspected of being in need thereof, wherein as a result of such use, the infection is prevented, or at least one symptom or complication associated with said infection is prevented, ameliorated or reduced in severity and / or duration.

[0032] In certain other embodiments, antibodies that bind to the YFV E-protein are provided. The antibody can bind to at least one of an epitope within the FL of Domain II of the YFV E protein, an epitope proximal to the FL of Domain II of the YFV E protein, and bind to a protein in Domain III of YFV. The antibody can also have one or more of the following characteristics: a) the antibody or its antigen-binding fragment exhibits a clean or low polyreactivity profile; b) the antibody or its antigen-binding fragment exhibits an in vitro neutralizing potency (IC 50 ) between about 0.5 micrograms per milliliter (μg / ml) and about 5 μg / ml; between about 0.05 μg / ml and about 0.5 μg / ml; or less than about 0.05 mg / ml; c) the antibody or its antigen-binding fragment binds to YFV-17D particles; and d) the antibody or its antigen-binding fragment binds to the envelope protein of YFV. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figures 1A and 1B illustrate the analysis of donor sera after YVF-14D vaccination. Figure 1A: Serum neutralizing activity against YFV-17D on days -5 (before vaccination), 10, 14, 28, 90, 180, 270, and 360 after vaccination. Shown are the means ± SD from two independent experiments (n = 6). Figure 1B: Neutralizing IC 50 of serum samples at each time point after vaccination, expressed as the reciprocal of the serum dilution.

[0034] Figures 2A to 2D show the characterization of the plasmablast response induced by YFV-17D vaccination on days 10 and 14. Figure 2A: Frequency of plasmablasts in CD19 + CD20 - / lo B cells in peripheral blood on days 0, 10, and 14 after vaccination. Plasmablasts are defined herein as CD19 + CD3 - CD8 - CD14 - CD16 - CD20 - / lo CD38 hi CD27 hi cells. Figure 2B: Percentage of PB-derived mAbs that exhibit ELISA binding reactivity to whole YFV-17D particles at 100 nM. Figure 2C: Neutralizing activity of PB-derived mAbs against YFV-17D at 100 nM and 10 nM concentrations. Green dots represent V H +V LThe number of nucleotide substitutions. Figure 2D: Proportion of YFV-17D-reactive PB-derived mAbs with a specified neutralizing potency (IC 50 ).

[0035] Figure 3 Illustrates the binding activity of germline-reverted plasmablast monoclonal antibodies. Binding traces and affinities of three somatically mutated PB-derived mAbs (ADI-46184, ADI-46185, and ADI-42168) and their corresponding UCA as determined by Biacore. UCA, unmutated common ancestor.

[0036] Figure 4 Shows the neutralization screening of PB-derived mAbs. Representative YFV-17D neutralization titration curves of PB mAbs screened by microtiter neutralization assay. Shown are the means ± SD from two independent experiments (n = 6).

[0037] Figures 5A and 5B show the presence of swIg + B cells reactive to YFV-17D. Figure 5A: YFV E reactivity of swIg + B cells at each sampling time point. The fluorescence-activated cell sorting (FACS) plots shown are gated on CD19 + CD20 + IgD—IgM—B cells. YFV E is labeled with two different colors to reduce background binding. Figure 5B: Percentage of swIg + B cells showing YFV E reactivity at each sampling time point.

[0038] Figures 6A to 6E illustrate that YFV E-specific antibodies show a preference for using the VH3-72 germline gene. Figure 6A: VH germline gene usage of YFV E-specific mAbs isolated from each sampling time point. Also included is the frequency of VH germline genes of an unselected human MBC library (“unselected”) for comparison. Sequencing data of unselected human MBCs were from multiple high-throughput sequencing studies. Figure 6B: VL germline gene usage of mAbs utilizing the VH3-72 germline gene. MAbs from all sampling time points were pooled for this analysis. The number in the center of the pie chart represents the total number of VH3-72 mAbs. Figure 6C: Length distribution of CDR H3 in YFV E-specific mAbs utilizing the VH3-72 germline gene, mAbs utilizing all other VH germline genes, or unselected Abs from MBCs. Figure 6D: SHM load (expressed as the number of nucleotide substitutions in VH) of YFV E-specific mAbs utilizing the VH3-72 germline gene or all other VH germline genes. Figure 6E: Apparent binding affinity of mAbs utilizing the VH3-72 germline gene or all other VH germline genes to the YFV E protein, determined by BLI. Black bars represent the median. Avid KD was plotted for mAbs isolated from MBCs on day 14 App , as only a small subset of these mAbs showed detectable binding to YFV E in a monovalent orientation. Statistical comparisons were made using the Mann-Whitney test (***P < 0.001, **P < 0.01, *P < 0.05).

[0039] Figures 7A to 7D illustrate the response of antibody-dominant memory B cells targeting epitopes within or proximal to FL to YFV-17D vaccination. Figure 7A: Proportion of mAbs in each major competition group at each sampling time point. Figure 7B: mAbs utilizing VH3-72 are shaded according to the competition group; the germline genes of the naturally paired light chains are shown. Figure 7C: Proportion of mAbs that compete with 4G2 and utilize the VH3-72 germline gene. Figure 7D: Apparent affinity of 4G2-competing mAbs utilizing the VH3-72 germline gene or all other germline genes. Statistical comparisons were made using the Mann-Whitney test (**P < 0.01).

[0040] Figures 8A to 8D illustrate that most highly potent neutralizing antibodies recognize FL-proximal epitopes. Figure 8A: Proportion of mAbs with neutralizing IC 50 (less than 1, 1–10, greater than 10–100, and greater than 100 nM) against YFV-17D in each epitope bin. n.n – non-binders. Figure 8B: Neutralizing IC 50 of individual mAbs across the specified epitope bins. Black bars represent the median. Figure 8C: Highly potent neutralizing antibodies (IC50 <1 nM). The number in the center of the pie chart represents the number of highly potent neutralizing antibodies. FIG. 8D: VH and VL germline gene usage of 5A or 5A / ADI-45107 competitor neutralizing antibodies only. MAbs from two donors were pooled for all analyses shown.

[0041] FIGS. 9A-9C show subsets of monoclonal antibodies that exhibit broad flavivirus cross-reactivity. FIG. 9A: Proportion of mAbs reactive with one or more of the tested flavivirus E proteins (YFV, DENV-1, DENV-2, ZIKV, and WNV). Recombinant E protein binding was measured by BLI in the affinity orientation. The number in the center of the pie chart represents the number of mAbs analyzed. FIG. 9B: Proportion of cross-reactive mAbs that recognize the designated antigenic sites. Cross-reactive mAbs from two donors were pooled for this analysis. FIG. 9C: Heat map showing the cross-reactivity curves of 50 mAbs that show binding to at least one flavivirus E protein other than YFV E. Apparent affinity (KD App ) was determined by BLI in the affinity orientation. Heat maps showing virus neutralization activity against YFV-17D and ZIKV are shown below the binding heat map. Competitive group assignments for individual mAbs are shown at the top of the heat map. N.B., non-binding; n.n., non-neutralizing; neut., neutralizing. DETAILED DESCRIPTION

[0042] In-depth understanding of the human antibody response to YFV infection will facilitate the development and evaluation of YFV vaccines and therapeutic and / or prophylactic antibodies for the treatment and / or prevention of YFV infection. The human memory B cell response to YFV was dissected in two vaccinated adult donors using a high-throughput antibody isolation platform, and highly potent and selective YFV neutralizing antibodies were isolated and characterized.

[0043] High-throughput epitope mapping studies have shown that epitopes within or proximal to FL on DII of the YFV E protein are immunodominant. Although many mAbs that bind to FL-specific epitopes are non-neutralizing, most mAbs targeting epitopes proximal to FL that overlap with the 5A epitope show neutralizing activity. In addition, the vast majority of potent nAbs recognize this antigenic site, indicating that the nAb response induced by YFV-17D vaccination is mainly mediated by such Abs. A subset of these mAbs shows unusually potent neutralizing activity, with an IC 50 that is approximately 10-fold lower than previously described YFV mAbs. Given the recent outbreaks of YFV in Brazil and the Democratic Republic of the Congo, combined with the shortage of YFV-17D vaccine supply and the lack of effective treatment for YFV disease, these mAbs represent promising candidates for prophylaxis and / or therapy

[0044] Accordingly, the present disclosure provides highly selective and effective anti-YFV antibodies for treating and / or preventing YFV infection, as well as potential vaccine candidates. In addition, the reagents disclosed herein provide a useful set of tools for evaluating clinical trials, which is crucial for selecting the best YFV vaccination or antibody-based treatment strategy from those currently under investigation.

[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification and the following claims, reference will be made to a number of terms that shall be defined to have the following meanings:

[0046] The terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting. As used herein, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise.

[0047] "Optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur.

[0048] When used prior to a numerical designation that includes a range of values, such as temperature, time, amount, concentration, and the like, the term "about" indicates an approximation that may vary by (+) or (-) 10%, 5%, 1%, or any subrange or subvalue therebetween. Preferably, when used with respect to an amount, the term "about" means that the amount may vary + / - 10%.

[0049] "Comprising" or "comprise" is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements. When used to define compositions and methods, "consisting essentially of" shall mean excluding other elements that have any substantial significance for the purpose of the combination. Thus, a composition consisting essentially of the elements as defined herein will not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed invention. "Consisting of" shall mean excluding other ingredients and substantial method steps in excess of trace amounts. Embodiments defined by each of these transitional terms are within the scope of this disclosure.

[0050] "Yellow fever virus", also referred to as "YFV", is an RNA virus that is typically transmitted by the bite of an infected Aedes or Haemagogus mosquito.

[0051] The term "YFV-17D" refers to an attenuated YFV vaccine strain developed by passage of the wild-type Asibi strain in chicken and mouse tissues. There are three currently produced 17D sublines: 17DD, produced in Brazil; 17D-213, produced in Russia; and 17D-204, produced in China, France, Senegal, and the United States. Although the attenuation mechanism is poorly understood, it is hypothesized that the limited genetic diversity of the 17D vaccine virus is attributed to vaccine attenuation and safety. There is evidence that 17D does not replicate as error-prone as wild-type RNA viruses. See Pugachev et al., Journal of Virology 78(2):1032-8 (2004).

[0052] The term "envelope protein" or "E protein" refers to the structural YFV protein that is the primary immunogen playing a central role in receptor binding and membrane fusion. The structure of the extracellular domain of the E protein (the soluble N-terminal portion consisting of 395 residues) contains three distinct structural domains, referred to as domains I, II, and III. (Volk et al., Virology 2009, 394(1):12-18). Domain II contains an S-S bridge-stabilized loop at its distal end, serving as a highly conserved fusion loop (FL). When the virus enters the target host cell, the FL of domain II is exposed and inserted into the host cell membrane. (Zhang et al., Viruses 2017, 9(11):338). In some embodiments, antibodies and their antigen-binding fragments bind to the FL of domain II of the YFV E protein. In other embodiments, antibodies and their antigen-binding fragments bind to domain III of the YFV E protein.

[0053] The development of effective YFV therapeutics presents many unique challenges. In-depth analysis of the human antibody response to the YFV vaccine provides insights for the development of such therapeutics. The antibody library analysis disclosed herein shows that most neutralizing YFV-specific antibodies target an FL-proximal epitope overlapping the 5A epitope, while a few effective neutralizing antibodies target a region of the DIII domain – an area of the E protein that, until now, has not been the epitope of any effective anti-YFV antibody.

[0054] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule called a paratope. A single antigen can have more than one epitope. Thus, different antibodies can bind to different regions on an antigen and can have different biological effects. The term "epitope" also refers to the site on an antigen to which B cells and / or T cells respond. It also refers to the region of an antigen that is bound by an antibody. Epitopes can be defined as structural or functional. Functional epitopes are generally a subset of structural epitopes and have those residues that directly contribute to the interaction affinity. Epitopes can also be conformational, i.e., composed of non-linear amino acids. In certain embodiments, an epitope can contain determinants that are chemical reactive surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and in certain embodiments, can have specific three-dimensional structural characteristics and / or specific charge characteristics. As used herein, the term "antibody" (or "Ab") is intended to refer to an immunoglobulin molecule that includes four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds (i.e., a "whole antibody molecule"), as well as its multimers (e.g., IgM) or its antigen-binding fragments.

[0055] As used herein, the terms "antigen-binding portion", "antigen-binding fragment", etc. encompass any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. In certain embodiments, as used herein, the term "antigen-binding portion" or "antibody fragment" refers to one or more fragments of an antibody that retain the ability to bind to YFV.

[0056] Antibody fragments can include Fab fragments, F(ab')2 fragments, Fv fragments, dAb fragments, fragments containing CDRs, or isolated CDRs. Antigen-binding fragments of an antibody can be derived, for example, from a whole antibody molecule using any suitable standard techniques, such as proteolytic digestion or recombinant genetic engineering techniques that involve manipulating and expressing DNA encoding the variable domains of the antibody and (optionally) the constant domains. Such DNA is known and / or readily obtainable from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated by chemical methods or by molecular biology techniques, for example, arranging one or more variable domains and / or constant domains into a suitable configuration, or introducing codons, generating cysteine residues, modifying, adding, or deleting amino acids, etc.

[0057] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units composed of amino acid residues that mimic the hypervariable regions of an antibody (e.g., isolated complementarity-determining regions (CDRs), such as CDR3 peptides) or constrained FR3-CDR3-FR4 peptides. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetra-bodies, micro-antibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen-binding fragment" as used herein.

[0058] Antigen-binding fragments of antibodies generally comprise at least one variable domain. The variable domain can have any size or amino acid composition and typically comprises at least one CDR adjacent to or within one or more framework sequences. In antigen-binding fragments having V L domains associated with V H domains, the V H domain and the V L domain can be positioned relative to each other in any suitable arrangement. For example, the variable region can be a dimer and contain V H -V H 、V H -V L or V L -V L dimers. Alternatively, the antigen-binding fragment of an antibody can contain a monomeric V H or V L domain.

[0059] In certain embodiments, the antigen-binding fragment of an antibody can contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that can be found within the antigen-binding fragments of the antibodies of the present disclosure include: (i) V H -C H 1; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (V) V H -C H 1-C H 2-C H3; (vi) V H -C H 2-C H 3; (vii) V H -C L ; (viii) V L -C H 1; (ix) V L -C H 2; (x) V L -C H 3; (xi) V L -C H 1-C H 2; (xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3; and (xiv) V L -C L . In any configuration of the variable and constant domains (including any of the exemplary configurations listed above), the variable and constant domains can be directly connected to each other or can be connected by a full or partial hinge or linker region. The hinge region can consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which result in a flexible or semi-flexible connection between adjacent variable and / or constant domains in a single polypeptide molecule. In addition, the antigen-binding fragments of the antibodies of the present disclosure can include homodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations listed above, which associate non-covalently with each other and / or with one or more monomeric V H or V L domains (e.g., via one or more disulfide bonds).

[0060] Like whole antibody molecules, the antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies generally include at least two different variable domains, where each variable domain is capable of specifically binding a separate antigen or different epitopes on the same antigen. Any multispecific antibody form that includes an exemplary bispecific antibody form disclosed herein can be adapted to the context of the antigen-binding fragments of the antibodies of the present disclosure using conventional techniques available in the art.

[0061] Each heavy chain includes a heavy chain variable region (“HCVR” or “V H ”) and a heavy chain constant region (including domains C H 1, C H 2 and CH 3). Each light chain includes a light chain variable region (“LCVR” or “V L ”) and a light chain constant region (C L ). The V H region and the V L region can be further subdivided into hypervariable regions called complementarity determining regions (CDRs), which are interspersed with more conserved regions called framework regions (FRs). Each V H and V L is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In certain embodiments of the present disclosure, the FR of the antibody (or its antigen-binding fragment) can be identical to the human germline sequence or can be naturally or artificially modified. Amino acid consensus sequences can be defined based on the alignment analysis of two or more CDRs. Thus, the CDRs in the heavy chain are named “CDRH1”, “CDRH2” and “CDRH3” respectively, and the CDRs in the light chain are named “CDRL1”, “CDRL2” and “CDRL3”.

[0062] In some embodiments, the antibody or its antigen-binding fragment contains a CDRL3 binding domain, which includes a consensus motif having the sequence QQX1X2X3X4X5X6T. X1 is Y, F or A, X2 is N, H or Y, X3 is R, S, T or D, X4 is D, F, Y, W or P, X5 is P or S, and X6 is Y, F, K or W. The following clones contain this consensus motif: ADI-50211; ADI-48899; ADI-45136; ADI-45078; ADI-49162; ADI-49141; ADI-42844; ADI-48910; ADI-45074; ADI-49041; ADI-50220; ADI-42172; ADI-42178; ADI-50218; and ADI-49194.

[0063] In some embodiments, the present disclosure provides an antibody comprising a YFV binding domain CDRL3, wherein the CDRL3 binding domain includes a consensus motif, which includes the sequence QX1X2X3X4TX5X6T, where X1 is Q or H, X2 is A or S, X3 is S or Y, X4 is T or S, X5 is R or P, and X6 is Y, L, W or R. The following clones contain this consensus motif: ADI-42201; ADI-45164; ADI-46729; ADI-42223; ADI-46718; ADI-45076; ADI-48968; ADI-45156; ADI-50536; and ADI-50537.

[0064] In some embodiments, the present disclosure provides an antibody comprising a YFV-binding domain CDRL3, wherein the CDRL3-binding domain comprises a consensus motif comprising the sequence GTWDX1SX2X3SAGX4V, where X1 is S or T, X2 is S or no amino acid, X3 is L or P, and X4 is K, G, or R. The following clones contain this consensus motif: ADI-45083; ADI-42225; ADI-42210; ADI-42198; ADI-42809; ADI-42830; ADI-42818; ADI-42151; and ADI-50533.

[0065] In some embodiments, the present disclosure provides an antibody comprising a YFV-binding domain CDRH3, wherein the CDRH3-binding domain comprises a consensus motif comprising the sequence AX1X2YDSX3X4YYX5X6X7X8, where X1 is K or R, X2 is Y, F, T, A, G, Y, or H, X3 is S, N, or R, X4 is A or G, X5 is W or Y, X6 is F, L, I, A, or E, X7 is D, E, or H, and X8 is Y, H, or S. The following clones contain this consensus motif: ADI-45085; ADI-50211; ADI-45078; ADI-49162; ADI-45136; ADI-42172; ADI-49194; ADI-50203; ADI-42178; ADI-48908; ADI-42844; ADI-48910; and ADI-49168.

[0066] In some embodiments, the present disclosure provides an antibody comprising a YFV-binding domain CDRL2, wherein the CDRL2 binding domain comprises a consensus motif that comprises the sequence X1X2X3X4RPS, where X1 is D or E, X2 is N, V or D, X3 is K, N, D or S, and X4 is K, E or R. The following clones contain this consensus motif: ADI-49039; ADI-42229; ADI-45097; ADI-45083; ADI-42225; ADI-49139; ADI-48969; ADI-48900; ADI-42786; ADI-42210; ADI-42198; ADI-49154; ADI-49188; ADI-42188; ADI-42809; ADI-46596; ADI-42830; ADI-46591; ADI-48955; ADI-42818; ADI-46586; ADI-42151; ADI-45140; ADI-46722; ADI-45128; ADI-45127; ADI-46739; ADI-46724; ADI-50539; ADI-42114; ADI-50533; and ADI-49205.

[0067] In some embodiments, the present disclosure provides an antibody comprising a YFV-binding domain CDRL2, wherein the CDRL2 binding domain comprises a consensus motif that comprises the sequence X1X2X3X4LX5X6, where X1 is A, G or R, X2 is A or T, X3 is S or T, X4 is T, G, S or I, X5 is Q or R, and X6 is S or R. The following clones contain this consensus motif: ADI-49133; ADI-49033; ADI-48895; ADI-42201; ADI-42230; ADI-48916; ADI-42211; ADI-5164; ADI-42191; ADI-49145; ADI-46729; ADI-42189; ADI-46718; ADI-45076; ADI-48968; ADI-50203; ADI-42227; ADI-48894; ADI-50218; ADI-45156; ADI-50536; ADI-50537; ADI-46737; ADI-45123; and ADI-50200.

[0068] In some embodiments, the present disclosure provides an antibody comprising a YFV-binding domain CDRL2, wherein the CDRL2-binding domain comprises a consensus motif, the consensus motif comprising the sequence X1X2SX3RAX4, wherein X1 is G, D, R or A, X2 is A or S, X3 is S, T or N, and X4 is T or A. The following clones contain this consensus motif: ADI-49147; ADI-50201; ADI-45113; ADI-50219; ADI-48897; ADI-42194; ADI-42847; ADI-48908; ADI-42231; ADI-42233; ADI-45148; ADI-42187; ADI-42787; ADI-49141; ADI-42213; ADI-42192; ADI-49590; ADI-48462; ADI-42200; ADI-42181; ADI-49037; ADI-49137; and ADI-42817.

[0069] In some embodiments, the present disclosure provides an antibody comprising a YFV-binding domain CDRL2, wherein the CDRL2-binding domain comprises a consensus motif, the consensus motif comprising the sequence X1VX2X3RPS, wherein X1 is D, E or R, X2 is S, T, N or A, and X3 is N, K or Q. The following clones contain this consensus motif: ADI-42228; ADI-42190; ADI-49183; ADI-49189; ADI-50205; ADI-50531; ADI-49138; ADI-45154; ADI-49161; ADI-49561; ADI-42219; ADI-48435; ADI-45161; ADI-42193; ADI-42149; ADI-42216; ADI-42810; ADI-48890; ADI-42206; ADI-48950; and ADI-42124.

[0070] In some embodiments, the present disclosure provides antibodies comprising a YFV-binding domain CDRL2, wherein the CDRL2-binding domain comprises a consensus motif comprising the sequence X1ASX2LEX3, where X1 is R, Q, or K, X2 is T, S, G, R, or I, and X3 is T or S. The following clones contain this consensus motif: ADI-42831; ADI-42821; ADI-45085; ADI-50211; ADI-48899; ADI-49168; ADI-45136; ADI-45078; ADI-42844; ADI-48910; ADI-49041; ADI-42172; ADI-42178; ADI-49032; and ADI-49194.

[0071] In some embodiments, the present disclosure provides antibodies comprising a YFV-binding domain CDRH2, wherein the CDRH2-binding domain comprises a consensus motif comprising the sequence X1X2X3HX4X5X6X7X8YX9PX 10 X 11 X 12 S, where X1 is D, E, or S, X2 is I or V, X3 is F or Y, X4 is X or T, X5 is G or E, X6 is S, G, or T, X7 is T or A, X8 is N, S, H, K, or T, X9 is N or S, X 10 is S or F, X 11 is L or V, and X 12 is K or E. The following clones contain this consensus motif: ADI-45083; ADI-42225; ADI-49139; ADI-48900; ADI-42232; ADI-42786; ADI-42210; ADI-42198; ADI-49154; ADI-42188; ADI-42809; ADI-42818; ADI-42151; ADI-46722; ADI-46742; ADI-49141; ADI-46739; ADI-46724; ADI-50539; ADI-48951; ADI-50538; and ADI-50533.

[0072] In some embodiments, the present disclosure provides antibodies comprising a YFV-binding domain CDRH2, wherein the CDRH2-binding domain comprises a consensus motif comprising the sequence X1X2X3X4DX5X6X7KX8X9ADSX 10 X 11G, where X1 is V or L, X2 is I or M, X3 is S, W or L, X4 is F or Y, X5 is E or G, X6 is S or T, X7 is K, N or Y, X8 is F, W or Y, X9 is Y or F, X 10 is V or L, and X 11 is K or R. The following clones contain this consensus motif: ADI-45097; ADI-42144; ADI-49138; ADI-45154; ADI-49561; ADI-42189; ADI-42844; ADI-45161; ADI-48462; ADI-42172; ADI-42178; ADI-42217; ADI-46737; ADI-49205; ADI-45151; and ADI-46728.

[0073] In some embodiments, the present disclosure provides an antibody comprising a YFV-binding domain CDRL1, wherein the CDRL1-binding domain comprises a consensus motif comprising the sequence RX1SX2X3X4X5X6X7X8X9, where X1 is A or T, X2 is Q or R, X3 is S or T, X4 is I or V, X5 is S or T, X6 is S, N, T, F, D or G, X7 is N, Y, W, F or K, X8 is L or V, and X9 is A or N. The following clones contain this consensus motif: ADI-49147; ADI-50201; ADI-45113; ADI-42201; ADI-42194; ADI-42847; ADI-45085; ADI-48908; ADI-50211; ADI-42231; ADI-45164; ADI-48899; ADI-46729; ADI-49168; ADI-49040; ADI-45136; ADI-45078; ADI-46718; ADI-49141; ADI-42844; ADI-42192; ADI-48910; ADI-42200; ADI-50203; ADI-42181; ADI-49041; ADI-50220; ADI-42172; ADI-42178; ADI-49032; ADI-49137; ADI-42817; ADI-45156; ADI-50536; ADI-50537; and ADI-49194.

[0074] In some embodiments, the present disclosure provides antibodies comprising a YFV-binding domain CDRL1, wherein the CDRL1-binding domain comprises a consensus motif comprising the sequence SGSX1SNX2GX3X4X5VX6, where X1 is N or S, X2 is I or F, X3 is S or N, X4 is N, Y, S or D, X5 is Y, F or D, and X6 is S or A. The following clones contain this consensus motif: ADI-49039; ADI-42229; ADI-45097; ADI-45083; ADI-42225; ADI-48900; ADI-42786; ADI-42210; ADI-42198; ADI-49154; ADI-42188; ADI-42809; ADI-46596; ADI-42830; ADI-46591; ADI-48955; ADI-42818; ADI-46586; ADI-42151; ADI-45140; ADI-46722; ADI-45128; ADI-46739; ADI-46724; ADI-50539; ADI-42114; and ADI-50533.

[0075] In some embodiments, the present disclosure provides antibodies comprising a YFV-binding domain CDRL1, wherein the CDRL1-binding domain comprises a consensus motif comprising the sequence X1GTX2X3DX4GX5X6X7X8VS, where X1 is A or T, X2 is S, G or R, X3 is S or T, X4 is V, F or I, X5 is G or A, X6 is Y, D or F, X7 is K or N, and X8 is Y or F. The following clones contain this consensus motif: ADI-48969; ADI-42228; ADI-42190; ADI-49183; ADI-49189; ADI-50205; ADI-50531; ADI-49138; ADI-45154; ADI-49161; ADI-49561; ADI-42219; ADI-48435; ADI-45161; ADI-45127; ADI-42149; ADI-42216; ADI-42810; ADI-48890; ADI-42206; ADI-48950; ADI-42124; and ADI-49205.

[0076] In some embodiments, the present disclosure provides antibodies comprising a YFV-binding domain CDRH1, wherein the CDRH1 binding domain comprises a consensus motif, the consensus motif comprising the sequence: X1X2FX3X4X5X6X7X8, where X1 is F, Y or L, X2 is T, A, S or N, X3 is S or T, X4 is S, T or R, X5 is Y or L, X6 is G, A, T, W, S or D, X7 is M, I or L, and X8 is H, S, N or T. The following clones contain this consensus motif: ADI-45090; ADI-49044; ADI-45113; ADI-42144; ADI-50026; ADI-45075; ADI-42230; ADI-42154; ADI-45085; ADI-42211; ADI-50211; ADI-42231; ADI-42233; ADI-49168; ADI-42187; ADI-49561; ADI-42219; ADI-50535; ADI-45136; ADI-42189; ADI-48435; ADI-46718; ADI-42844; ADI-45161; ADI-48910; ADI-48462; ADI-42200; ADI-50203; ADI-42149; ADI-42172; ADI-42178; ADI-50197; ADI-42810; ADI-50218; ADI-45156; ADI-50536; ADI-50537; ADI-46737; ADI-42114; ADI-49194; ADI-42124; and ADI-46728.

[0077] In some embodiments, the present disclosure provides antibodies comprising a YFV-binding domain CDRH1, wherein the CDRH1 binding domain comprises a consensus motif, the consensus motif comprising the sequence: X1SIX2X3X4X5X6WX7, where X1 is G or I, X2 is S or T, X3 is S, T, G or no amino acid, X4 is D, S, T or G, X5 is Y, N or D, X6 is W or Y, and X7 is S or T. The following clones contain this consensus motif: ADI-45083; ADI-42225; ADI-48900; ADI-42786; ADI-42210; ADI-49188; ADI-42188; ADI-42818; ADI-42151; ADI-48913; ADI-46722; ADI-49141; ADI-46741; ADI-46739; ADI-50539; ADI-50538; and ADI-50533.

[0078] In some embodiments, the present disclosure provides antibodies comprising a YFV-binding domain CDRH1, wherein the CDRH1-binding domain comprises a consensus motif comprising the sequence: FX1FSDX2YMX3, where X1 is I or T, X2 is H or Y, and X3 is A or D. The following clones contain this consensus motif: ADI-42191; ADI-49040; ADI-42223; ADI-42193; ADI-48968; ADI-42212; ADI-45126; ADI-42141; ADI-49140; ADI-48894; ADI-42226; ADI-49137; ADI-48890; ADI-42206; and ADI-49030.

[0079] Substitutions of one or more CDR residues or omission of one or more CDRs are also possible. Antibodies have been described in the scientific literature in which one or two CDRs can be omitted for binding. Padlan et al. (1995 FASEB J. 9:133-139) analyzed the contact regions between antibodies and their antigens based on published crystal structures and concluded that only about one-fifth to one-third of the CDR residues actually contact the antigen. Padlan also found many antibodies in which one or two CDRs have no amino acids contacting the antigen (see also Vajdos et al. 2002 J Mol Biol 320:415-428).

[0080] CDR residues that do not contact the antigen can be identified by molecular modeling and / or empirically from Kabat CDR regions outside of Chothia CDRs based on prior studies (e.g., residues H60-H65 in CDRH2 are generally not required). If a CDR or its residues are omitted, they are typically replaced with amino acids occupying the corresponding positions in another human antibody sequence or a consensus sequence of such sequences. Substitution positions within the CDR and the amino acids to be substituted can also be selected empirically.

[0081] Compared to the corresponding germline sequences, the fully human monoclonal antibodies disclosed herein can include one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains. Such mutations can be readily determined by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. The present disclosure encompasses antibodies and antigen-binding fragments derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more frameworks and / or CDRs are mutated to one or more corresponding residues of the germline sequence of the derived antibody, or to one or more corresponding residues of another human germline sequence, or to conservative amino acid substitutions of one or more corresponding germline residues (such sequence variations are collectively referred to herein as "germline mutations"). Starting from the heavy and light chain variable region sequences disclosed herein, one of ordinary skill in the art can readily generate many antibodies and antigen-binding fragments that include one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and / or CDR residues within the V H domain and / or the V L domain are mutated back to the residues found in the original germline sequence of the derived antibody. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2, or CDR3. In other embodiments, one or more of the framework and / or CDR residues are mutated to the corresponding residues of a different germline sequence (i.e., a germline sequence different from the germline sequence from which the antibody was originally derived). Additionally, the antibodies of the present disclosure can contain any combination of two or more germline mutations within the framework and / or CDR regions, e.g., where certain individual residues are mutated to the corresponding residues of a specific germline sequence while certain other residues different from the original germline sequence can be maintained or mutated to the corresponding residues of a different germline sequence. Once obtained, the one or more desired properties of antibodies and antigen-binding fragments containing one or more germline mutations, such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as appropriate), reduced immunogenicity, etc., can be readily tested. Antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present disclosure.

[0082] The present disclosure also encompasses fully monoclonal antibodies that include variants of any of the CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the present disclosure encompasses antibodies having CDR amino acid sequences that have, relative to any of the CDR amino acid sequences disclosed herein, for example, 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions. In some embodiments, the disclosed anti-YFV antibodies and antigen-binding fragments are human antibodies. As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the present disclosure may contain amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random or site-specific mutagenesis or by in vivo somatic mutation), such as in the CDRs, and specifically, in CDR3.

[0083] In some embodiments, the disclosed anti-YFV antibodies and antigen-binding fragments are recombinant antibodies. The term "recombinant" generally refers to any protein, polypeptide, or cell that is produced by genetic engineering methods to express a gene of interest. The term "recombinant" as used with respect to a protein or polypeptide refers to a polypeptide produced by the expression of a recombinant polynucleotide. The proteins used in the immunogenic compositions of the present disclosure may be isolated from natural sources or produced by genetic engineering methods.

[0084] In some embodiments, the antibodies of the present disclosure may be recombinant human antibodies. As used herein, the term "recombinant human antibody" is intended to include all antibodies prepared, expressed, produced, or isolated by recombinant means, including human antibodies or humanized antibodies, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal that is transgenic for human immunoglobulin genes (e.g., a mouse) (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, produced, or isolated by any other means that involve splicing human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when using a transgenic animal with human Ig sequences, in vivo somatic mutagenesis), and thus, the amino acid sequences of the V H and V L regions are sequences that, although derived from and related to human germline V H and V L sequences, may not naturally occur in the in vivo human antibody germline repertoire.

[0085] In some embodiments, the anti-YFV antibodies and antigen-binding fragments thereof are isolated antibodies. As used herein, an "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds YFV or a fragment thereof is substantially free of Abs that specifically bind antigens other than YFV). In some embodiments, the anti-YFV antibodies and antigen-binding fragments specifically bind to the YFV E protein, such as the FL of the DII domain or DIII. The terms "specifically binds" or "binds specifically to", etc. mean that an antibody or an antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiological conditions. Specific binding can be characterized by an equilibrium dissociation constant of at least about 1x10 -6 M or less (e.g., a smaller K D indicates tighter binding). Methods for determining whether two molecules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, etc. As described herein, antibodies have been identified by surface plasmon resonance (e.g., BIACORE TM , biolayer interferometry using, for example, a ForteBio Octet HTX instrument (Pall LifeSciences)), which specifically bind YFV. In addition, as used herein, a multispecific antibody that binds to a YFV protein and one or more additional antigens, or a bispecific antibody that binds to two different regions of YFV, is still considered an antibody that "specifically binds". In certain embodiments, the antibodies disclosed herein exhibit an equilibrium dissociation constant (and thus specificity) of about 1x10 -6 M; about 1x10 -7 M; about 1x10 -8 M; about 1x10 -9 M; about 1x10 -10 M; between about 1x10 -6 M and about 1x10 -7 M; between about 1x10 -7 M and about 1x10 -8 M; between about 1x10 -8 M and about 1x10 -9 M; between about 1x10 -9 M and about 1x10 -10 M; or between about 1x10 -9 M and about 1x10 -10 M.

[0086] In some embodiments, the anti-YFV antibodies and antigen-binding fragments are high-affinity binders. The term "high affinity" means having at least 10 -9 M for YFV; more preferably, 10-10 M, more preferably 10 -11 M, more preferably 10 -12 The binding affinity of M (expressed in K D ) of the mAb, as measured by surface plasmon resonance (e.g., BIACORE TM 、biolayer interferometry using, for example, a ForteBio Octet HTX instrument (Pall Life Sciences)) or solution affinity ELISA.

[0087] The terms "off-rate", "Koff", or "kd" refer to an antibody that dissociates from YFV with a rate constant of 1x10 -3 s -1 or less, preferably 1x10 -4 s -1 or less, as determined by surface plasmon resonance (e.g., BIACORE TM or a ForteBio Octet HTX instrument (Pall Life Sciences).

[0088] Specific embodiments, antibodies, or antibody fragments of the present disclosure can be conjugated to a therapeutic moiety ("immunoconjugate"), such as an antibiotic, a second anti-YFV antibody, a vaccine, or a toxoid, or any other therapeutic agent moiety useful for treating YFV infection.

[0089] Antibodies and antigen-binding fragments that are substantially the same as the antibodies provided herein are also contemplated. When referring to a nucleic acid or a fragment thereof, the terms "substantial identity" or "substantially the same" mean that, when optimally aligned with another nucleic acid (or its complementary strand) by appropriate nucleotide insertions or deletions, the nucleotide sequence identity is at least about 90% of the nucleotide bases, and more preferably at least about 95%, 96%, 97%, 98%, or 99%, as measured by any well-known sequence identity algorithm such as FASTA, BLAST, or GAP, as discussed below. Thus, nucleic acid sequences that show a certain percentage "identity" share that percentage identity and / or are "the same" as each other by that percentage. In some cases, a nucleic acid molecule that has substantial identity to a reference nucleic acid molecule can encode a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.

[0090] In some embodiments, the antibody or its antigen-binding fragment comprises at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences of such antibody or its antigen-binding fragment, which is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and / or all percentage identities therebetween, to at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 amino acid sequences of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0091] In certain embodiments, the antibody and its antigen-binding fragment comprise the CDRH3 amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0092] In certain embodiments, the antibody and its antigen-binding fragment comprise the CDRH2 amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0093] In certain embodiments, the antibody and its antigen-binding fragment comprise the CDRH1 amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0094] In certain embodiments, the antibody and its antigen-binding fragment comprise the CDRL3 amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0095] In certain embodiments, the antibody and its antigen-binding fragment comprise the CDRL2 amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0096] In certain embodiments, the antibody and its antigen-binding fragment comprise the CDRL1 amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0097] In some embodiments, the anti-YFV antibody and its antigen-binding fragment are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and / or all percentage identities therebetween, to any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0098] In certain embodiments, the antibodies and antigen-binding fragments thereof comprise the heavy chain (HC) amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0099] In certain embodiments, the antibodies and antigen-binding fragments thereof of the present invention comprise the light chain (LC) amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3. In certain embodiments, the antibodies and antigen-binding fragments thereof of the present invention comprise the heavy chain (HC) amino acid sequence and the light chain (LC) amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0100] In certain embodiments, the antibodies and antigen-binding fragments thereof are each selected from the group consisting of: the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0101] Nucleic acids encoding the antibodies described herein are also provided. In certain embodiments, an isolated nucleic acid sequence encoding an antibody and antigen-binding fragment thereof that specifically binds YFV is provided, wherein at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 amino acid sequences of the antibody or its antigen-binding fragment is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and / or all percentage identities therebetween to at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 amino acid sequences of an antibody selected from antibody number 1 to antibody number 152 disclosed in Table 3.

[0102] In certain embodiments, an isolated nucleic acid sequence encoding an antibody and antigen-binding fragment thereof is provided, wherein such nucleic acid sequence comprises a sequence encoding the CDRH3 amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0103] In certain embodiments, an isolated nucleic acid sequence encoding an antibody and antigen-binding fragment thereof is provided, wherein such nucleic acid sequence comprises a sequence encoding the CDRH2 amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0104] In certain embodiments, an isolated nucleic acid sequence encoding an antibody and antigen-binding fragment thereof is provided, wherein such nucleic acid sequence comprises a sequence encoding the CDRH1 amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0105] In certain embodiments, there is provided an isolated nucleic acid sequence encoding an antibody and antigen-binding fragment thereof, wherein such nucleic acid sequence comprises a sequence encoding a CDRL3 amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0106] In certain embodiments, there is provided an isolated nucleic acid sequence encoding an antibody and antigen-binding fragment thereof, wherein such nucleic acid sequence comprises a sequence encoding a CDRL2 amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0107] In certain embodiments, there is provided an isolated nucleic acid sequence encoding an antibody and antigen-binding fragment thereof, wherein such nucleic acid sequence comprises a sequence encoding a CDRL1 amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3.

[0108] In certain embodiments, there is provided an isolated nucleic acid sequence encoding an antibody and antigen-binding fragment thereof, wherein such nucleic acid sequence comprises a sequence encoding a heavy chain (HC) amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3

[0109] In certain embodiments, there is provided an isolated nucleic acid sequence encoding an antibody and antigen-binding fragment thereof, wherein such nucleic acid sequence comprises a sequence encoding a light chain (LC) amino acid sequence of any one of the antibodies designated as antibody number 1 to antibody number 152 disclosed in Table 3. When applied to polypeptides, the terms "substantially identical" or "substantially the same" mean that two peptide sequences share at least 90% sequence identity when optimally aligned by a program such as GAP or BESTFIT using default gap weights, and even more preferably at least 95%, 98% or 99% sequence identity. Thus, amino acid sequences showing a certain percentage "identity" share that percentage identity and / or are that percentage "identical" to each other. Thus, amino acid sequences showing a certain percentage "identity" share that percentage identity and / or are that percentage "identical" to each other.

[0110] In certain embodiments, the disclosed antibody amino acid sequences are at least 70% identical to other sequences; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and / or all identity percentages therebetween and / or share such percentage identity with each other (or with certain subsets of the antibody sequences disclosed herein).

[0111] Preferably, the different residue positions differ due to conservative amino acid substitutions. A "conservative amino acid substitution" is an amino acid substitution in which one amino acid residue is replaced by another amino acid residue having a side chain (R-group) with similar chemical properties (e.g., charge or hydrophobicity). In general, conservative amino acid substitutions do not substantially alter the functional properties of the protein. In cases where two or more amino acid sequences differ from each other due to conservative substitutions, the percentage or degree of similarity can be adjusted upward to correct for the conservative nature of the substitution. Methods for making this adjustment are well known to those skilled in the art. (See, e.g., Pearson (1994) Methods Mol. Biol. 24:307-331). Examples of amino acid groups with side chains having similar chemical properties include: 1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) aliphatic-hydroxy side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartic acid and glutamic acid, and 7) sulfur-containing side chains: cysteine and methionine. Preferred conservative amino acid substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine. Alternatively, conservative substitutions are any changes having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256:1443-45. A "moderately conservative" substitution is any change having a non-negative value in the PAM250 log-likelihood matrix.

[0112] Sequence analysis software is typically used to measure the sequence similarity of polypeptides. Protein analysis software matches similar sequences using similarity measures assigned to various substitutions, deletions, and other modifications, including conservative amino acid substitutions. For example, the GCG software contains programs such as GAP and BESTFIT, which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different organism species, or between a wild-type protein and its mutant. See, for example, GCG version 6.1. The FASTA program (using default or recommended parameters) in GCG version 6.1 can also be used to compare polypeptide sequences. FASTA (e.g., FASTA2 and FASTA3) provides an alignment of the best overlapping regions between the query sequence and the search sequence and the percentage of sequence identity (Pearson (2000), supra). When comparing the sequences of the present disclosure with a database containing a large number of sequences from different organisms, another preferred algorithm is the computer program BLAST using default parameters, especially BLASTP or TBLASTN. (See, for example, Altschul et al. (1990) J. Mol. Biol. 215:403-410 and (1997) Nucleic Acids Res. 25:3389-402).

[0113] In certain embodiments, the antibodies or antibody fragments for use in the methods of the present disclosure can be monospecific, bispecific, or multispecific. Multispecific antibodies can be specific for different epitopes of one target polypeptide or can contain antigen-binding domains that are specific for epitopes of more than one target polypeptide.

[0114] As disclosed herein, anti-YFV antibodies can be obtained from human B cells using techniques available to those skilled in the art, for example, as described in the examples below. Methods for generating human antibodies in transgenic animals such as mice are also known in the art and can be used to derive antibodies according to the present disclosure. Any such known methods can be used in the context of the present disclosure to prepare human antibodies that specifically bind to YFV (see, for example, US 6,596,541).

[0115] In certain embodiments, when measured by binding to an antigen immobilized on a solid phase or in solution, the affinity (K D ) of the antibodies of the present disclosure ranges from about 1.0x10- 7 M to about 1.0x10 -12 M. In certain embodiments, when measured by binding to an antigen immobilized on a solid phase or in solution, the affinity (K D ) of the antibodies of the present disclosure ranges from about 1x10 -7 M to about 6x10 -10M. In certain embodiments, when measured by binding to an antigen immobilized on a solid phase or in solution, the affinity (K D ) of the antibodies of the present disclosure ranges from about 1 x 10 -7 M to about 9 x 10 -10 M.

[0116] In addition to the specific anti-YFV antibodies and antibody fragments disclosed herein, the present disclosure contemplates variants of those antibodies and antibody fragments that maintain bioequivalence. Such variant antibodies and antibody fragments include one or more additions, deletions, or substitutions of amino acids as compared to the parental sequence, but exhibit bioactivity that is substantially equivalent to the bioactivity of the described antibodies. Similarly, the DNA sequences encoding the antibodies of the present disclosure encompass sequences that include one or more additions, deletions, or substitutions of nucleotides as compared to the disclosed sequences, but encode antibodies or antibody fragments that are substantially bioequivalent to the antibodies or antibody fragments of the present disclosure.

[0117] If, for example, two antigen-binding proteins or antibodies are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose (single dose or multiple doses) under similar experimental conditions, they are considered to be bioequivalent. If some antibodies are equivalent in their extent of absorption but not in their rate of absorption, the antibodies are considered to be equivalents or pharmaceutical alternatives and can be considered to be bioequivalent because such differences in absorption rate that are intentional and reflected in the labeling are not necessary for achieving an effective body drug concentration, for example, upon long-term use, and are considered to be medically insignificant for the particular drug product under study.

[0118] In one embodiment, two antigen-binding proteins are bioequivalent if there are no clinically meaningful differences in their safety, purity, and potency.

[0119] In one embodiment, two antigen-binding proteins are bioequivalent if a patient can switch between a reference product and a biological product one or more times without an increased risk of expected side effects (including clinically significant changes in immunogenicity or decreased efficacy) as compared to continuous therapy without a switch between the reference product and the biological product.

[0120] In one embodiment, two antigen-binding proteins are bioequivalent if both act via one or more common mechanisms of action for one or more conditions of use (so long as those mechanisms are known).

[0121] Bioequivalence can be demonstrated by in vivo and / or in vitro methods. Bioequivalence measurements include, for example, (a) in vivo tests in humans or other mammals, where the concentration of the antibody or its metabolites is measured over time in blood, plasma, serum, or other biological fluids; (b) in vitro tests that are related to and reasonably predictive of in vivo bioavailability data in humans; (c) in vivo tests in humans or other mammals, where the appropriate acute pharmacological effects of the antibody (or its target) are measured over time; and (d) in well-controlled clinical trials that establish the safety, efficacy, or bioavailability or bioequivalence of the antibody.

[0122] Bioequivalent variants of the antibodies of the present disclosure can be constructed, for example, by making various substitutions to residues or sequences or deleting terminal or internal residues or sequences that are not required for biological activity. For example, cysteine residues that are not essential for biological activity can be deleted or replaced with other amino acids to prevent the formation of unnecessary or incorrect intramolecular disulfide bridges upon refolding. In other contexts, bioequivalent antibodies can include antibody variants that include amino acid changes that modify the glycosylation properties of the antibody, such as mutations that eliminate or remove glycosylation.

[0123] Biological and Biophysical Properties of Antibodies

[0124] In certain embodiments, the antibodies of the invention and their antigen-binding fragments specifically bind to YFV, wherein at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 amino acid sequences is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and / or all identity percentages in between to the corresponding CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 amino acid sequences of the antibodies disclosed in Antibody Nos. 1 to Antibody No. 152 in Table 3.

[0125] In some embodiments, the anti-YFV antibodies and antigen-binding fragments thereof are neutralizing antibodies, i.e., exhibit neutralizing potency. As used herein, a "neutralizing antibody" (or "antibody that neutralizes YFV activity" or "antibody with neutralizing activity") refers to an antibody whose binding to an antigen (e.g., the YFV E protein disclosed herein, as appropriate) results in the inhibition of at least one biological activity. For example, the antibodies of the present disclosure may contribute to blocking the fusion of YFV with host cells, or preventing syncytium formation, or preventing the primary disease caused by YFV. Alternatively, the antibodies of the present disclosure may demonstrate the ability to ameliorate at least one symptom of YFV infection. This inhibition of YFV biological activity can be evaluated by measuring one or more metrics of YFV biological activity using one or more standard in vitro assays (such as a neutralization assay, as described herein) or in vivo assays known in the art (e.g., an animal model observing the protection against YFV challenge after administration of one or more antibodies described herein).

[0126] In certain embodiments, the antibodies and antigen-binding fragments thereof exhibit an in vitro neutralizing potency (IC 50 ) between about 0.5 micrograms per milliliter (μg / ml) and about 5 μg / ml; between about 0.05 μg / ml and about 0.5 μg / ml; or less than about 0.05 mg / ml.

[0127] The term "IC 50 " refers to the "half maximal inhibitory concentration", a value that measures the effectiveness of a compound (e.g., an anti-YFV antibody) in inhibiting a biological or biochemical utility. This quantitative measure indicates the amount of a particular inhibitor required to inhibit a given biological process by half. In certain embodiments, the YFV neutralizing potency of the anti-YFV neutralizing antibodies disclosed herein is expressed as a neutralizing IC 50 value. Among the antibodies described herein, antibodies that typically bind to DIII of the YFV E protein have the highest neutralizing potency.

[0128] In some embodiments, the antibodies and antigen-binding fragments thereof cross-react with DENV-2, DENV-4, WNV or ZIKV E proteins, i.e., bind to the YFV E protein and E proteins from one or more other flaviviruses. In certain embodiments, such antibodies and antigen-binding fragments thereof have a high apparent affinity (K D AppBind to DENV-2, DENV-4, WNV, YFV, and ZIKV E proteins at <10 nM). In certain embodiments, the cross-reactive antibody or antigen-binding fragment thereof has neutralizing activity against YFV-17D and another flavivirus. In certain embodiments, the cross-reactive antibody and its antigen-binding fragment bind to the FL epitope. In certain embodiments, the cross-reactive antibody and its antigen-binding fragment bind to DIII. In one embodiment, the cross-reactive antibody is ADI-48905.

[0129] Epitope binning and related techniques

[0130] As described above and as demonstrated in the examples, the applicant has characterized the epitope binning of the antibodies and antigen-binding fragments of the present invention. In addition to the methods for performing such characterization, those skilled in the art can also use a variety of other techniques that can be used to perform such characterization or otherwise determine whether an antibody "interacts with one or more amino acids within a polypeptide or protein". Exemplary techniques include, for example, conventional cross-blocking assays, such as can be performed with the antibodies, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., NY). Other methods include alanine scanning mutagenesis analysis, peptide blotting analysis (Reineke (2004) Methods in Molecular Biology 248:443-63), peptide cleavage analysis, crystallographic studies, and NMR analysis. Additionally, methods such as epitope excision, epitope extraction, and chemical modification of the antigen can be employed (Tomer 2000, Protein Science 9:487-496). Another method that can be used to identify the amino acids within a polypeptide that interact with an antibody is hydrogen / deuterium exchange detected by mass spectrometry. Generally, the hydrogen / deuterium exchange method involves deuterium labeling of the protein of interest, followed by binding of the antibody to the deuterium-labeled protein. Next, the protein / antibody complex is transferred to water, and the exchangeable protons within the amino acids protected by the antibody complex undergo hydrogen-deuterium back-exchange at a slower rate than the exchangeable protons within the amino acids that are not part of the interface. Thus, the amino acids that form part of the protein / antibody interface can retain deuterium and thus exhibit a relatively higher mass compared to the amino acids that are not included in the interface. After dissociating the antibody, the target protein is subjected to protease cleavage and mass spectrometry, thereby revealing the deuterium-labeled residues corresponding to the specific amino acids that interact with the antibody. See, for example, Ehring (1999) Analytical Biochemistry 267(2):252-259; Engen and Smith (2001) Anal. Chem. 73:256A-265A.

[0131] As will be appreciated by those skilled in the art, epitopes can be formed by both contiguous amino acids or non-contiguous amino acids juxtaposed by the tertiary folding of a protein. Epitopes formed by contiguous amino acids generally remain upon exposure to denaturing solvents, while epitopes formed by tertiary folding are generally lost upon treatment with denaturing solvents. In a unique spatial conformation, an epitope generally contains at least 3 (and more commonly, at least 5 or 8 - 10) amino acids.

[0132] Modified Affinity Profiling (MAP), also known as Antibody Profiling Based on Antigen Structure (ASAP), is a method for classifying a large number of monoclonal antibodies (mAbs) against the same antigen according to the similarity of the binding characteristics of each antibody to the surface of a chemically or enzymatically modified antigen (US 2004 / 0101920). Each class can reflect a unique epitope that is distinct or partially overlapping with the epitope represented by another class. This technique allows for the rapid filtering of genetically identical antibodies, so that characterization can be focused on genetically distinct antibodies. When applied to hybridoma screening, MAP may help identify rare hybridoma clones that produce mAbs with the desired properties. MAP can be used to sort the antibodies of the present disclosure into groups of antibodies that bind different epitopes.

[0133] As will be understood by those skilled in the art, it can be readily determined whether an antibody binds the same epitope as a reference anti - YFV antibody or competes with the reference anti - YFV antibody for binding by using conventional methods available in the art. For example, to determine whether a test antibody binds the same epitope as the reference YFV antibody of the present disclosure, the reference antibody is bound to a YFV protein or peptide under saturating conditions. Next, the ability of the test antibody to bind to the YFV molecule is evaluated. If the test antibody is able to bind to the YFV after saturation binding with the reference anti - YFV antibody, it can be concluded that the test antibody binds a different epitope from the reference anti - YFV antibody. On the other hand, if the test antibody is unable to bind to the anti - YFV molecule after saturation binding with the reference anti - YFV antibody, the test antibody can bind the same epitope as the epitope bound by the reference anti - YFV antibody of the present disclosure.

[0134] To determine whether an antibody competes with a reference anti-YFV antibody for binding, the above binding method is performed in two orientations: in a first orientation, the reference antibody is allowed to bind to YFV molecules under saturated conditions, and then the binding of the test antibody to the YFV molecules is evaluated. In a second orientation, the test antibody is allowed to bind to YFV molecules under saturated conditions, and then the binding of the reference antibody to the YFV molecules is evaluated. If only the first (saturated) antibody is able to bind to the YFV molecules in both orientations, it is concluded that the test antibody and the reference antibody compete for binding to YFV. As will be understood by one of ordinary skill in the art, an antibody that competes with a reference antibody for binding may not necessarily bind to the same epitope as the reference antibody, but may sterically block the binding of the reference antibody by binding to overlapping or adjacent epitopes.

[0135] If each of two antibodies competitively inhibits (blocks) the binding of the other antibody to an antigen, the two antibodies bind to the same or overlapping epitopes. In other words, a 1-fold, 5-fold, 10-fold, 20-fold, or 100-fold excess of one antibody inhibits the binding of the other antibody by at least 50%, but preferably 75%, 90%, or even 99%, as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. (1990) 50:1495-1502). Alternatively, if substantially all amino acid mutations in an antigen that reduce or eliminate the binding of one antibody also reduce or eliminate the binding of the other antibody, the two antibodies have the same epitope. If some amino acid mutations that reduce or eliminate the binding of one antibody also reduce or eliminate the binding of the other antibody, the two antibodies have "overlapping epitopes".

[0136] Additional routine experiments (e.g., peptide mutagenesis and binding assays) can then be performed to confirm whether the observed lack of binding of the test antibody is actually due to binding to the same epitope as the reference antibody, or whether steric hindrance (or other phenomenon) is responsible for the observed lack of binding. Such sorting experiments can be performed using ELISA, RIA, surface plasmon resonance, flow cytometry, or any other quantitative or qualitative antibody binding assay available in the art.

[0137] Immunoconjugate

[0138] The present disclosure encompasses human YFV monoclonal antibodies conjugated to a therapeutic moiety (“immunoconjugates”), such as agents capable of reducing the severity of primary YFV infection or improving at least one symptom associated with YFV infection, including fever, muscle pain, headache, vomiting, diarrhea, bleeding, or the severity thereof. Such an agent can be a second, different antibody or a vaccine against YFV. The type of therapeutic moiety that can be conjugated to the anti-YFV antibody will take into account the condition to be treated and the desired therapeutic effect to be achieved. Alternatively, if the desired therapeutic effect is to treat sequelae or symptoms associated with YFV infection, or any other condition caused by such infection, such as but not limited to disseminated intravascular coagulation, acute renal failure, and acute respiratory distress syndrome, it may be advantageous to conjugate an agent suitable for treating the sequelae or symptoms of the condition or for mitigating any side effects of the antibodies of the present disclosure. Examples of suitable agents for forming immunoconjugates are known in the art, see, for example, WO 05 / 103081.

[0139] Multispecific antibodies

[0140] The antibodies of the present disclosure can be monospecific, bispecific, or multispecific. Multispecific antibodies can be specific for different epitopes of one target polypeptide or can contain antigen-binding domains that are specific for more than one target polypeptide. See, for example, Tutt et al., 1991, J. Immunol. 147:60-69; Kufer et al., 2004, Trends Biotechnol. 22:238-244. The antibodies of the present disclosure can be linked or co-expressed with another functional molecule, such as another peptide or protein. For example, the antibody or a fragment thereof can be functionally linked to one or more other molecular entities, such as another antibody or antibody fragment (e.g., by chemical conjugation, genetic fusion, non-covalent association, or otherwise), to produce a bispecific or multispecific antibody with a second binding specificity.

[0141] Therapeutic agent administration and formulations

[0142] The present disclosure provides therapeutic compositions comprising the anti-YFV antibodies or antigen-binding fragments thereof of the invention. Administration of the therapeutic agent compositions according to the present disclosure will be administered together with suitable carriers, excipients, and other reagents incorporated into the formulation to provide improved transfer, delivery, tolerance, etc. A large number of suitable formulations can be found in formularies known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, gels, waxes, oils, lipids, lipid-containing vesicles (cationic or anionic) (such as LIPOFECTIN TM ), DNA conjugates, anhydrous absorption pastes, water-in-oil and oil-in-water emulsions, polyethylene glycol emulsions of various molecular weights, semi-solid gels, and semi-solid mixtures containing polyethylene glycol. See, for example, Powell et al., "Compendium of excipients for parenteral formulations," PDA (1998) J Pharm Sci Technol 52:238-311.

[0143] The dosage of each antibody of the present disclosure can vary according to the age and body size of the subject to be administered, the target disease, the medical condition, the route of administration, etc. When the antibody of the present disclosure is used for treating YFV infection, or for treating one or more symptoms associated with YFV infection (such as fever, nausea or muscle pain associated with a patient's YFV infection) or for reducing the severity of the disease, it is advantageous to administer each antibody of the present disclosure intravenously or subcutaneously. Generally, each antibody will be administered as a single dose of about 0.01 to about 30 mg / kg body weight, more preferably, about 0.1 to about 20 mg / kg body weight, or about 0.1 to about 15 mg / kg body weight, or about 0.02 to about 7 mg / kg body weight, about 0.03 to about 5 mg / kg body weight, or about 0.05 to about 3 mg / kg body weight, or about 1 mg / kg body weight, or about 3.0 mg / kg body weight, or about 10 mg / kg body weight, or about 20 mg / kg body weight. Multiple doses can be administered if necessary. The frequency and duration of treatment can be adjusted according to the severity of the medical condition. In certain embodiments, the antibody or antigen-binding fragment thereof of the present disclosure can be administered at an initial dose of at least about 0.1 mg to about 800 mg, about 1 to about 600 mg, about 5 to about 300 mg or about 10 to about 150 mg, to about 100 mg or to about 50 mg. In certain embodiments, a second or multiple subsequent doses of the antibody or antigen-binding fragment thereof can be administered after the initial dose, and the amount can be substantially the same as or less than the initial dose, wherein the subsequent doses are separated by at least 1 day to 3 days; at least one week, at least 2 weeks; at least 3 weeks; at least 4 weeks; at least 5 weeks; at least 6 weeks; at least 7 weeks; at least 8 weeks; at least 9 weeks; at least 10 weeks; at least 12 weeks; or at least 14 weeks.

[0144] A variety of delivery systems are known and can be used to administer the pharmaceutical compositions of the present disclosure. For example, they can be encapsulated in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see, for example, Wu et al. (1987) J. Biol. Chem. 262:4429-4432). Methods of introduction include, but are not limited to, intradermal, transdermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition can be administered by any convenient route, such as by infusion or bolus injection, absorption through epithelial or skin mucosal linings (e.g., oral mucosa, nasal mucosa, rectal and intestinal mucosa, etc.), and can be administered in combination with other bioactive agents. Administration can be systemic or local. It can be delivered as an aerosolized formulation (see US2011 / 0311515 and US2012 / 0128669). The delivery of agents for the treatment of respiratory diseases by inhalation is becoming increasingly widely accepted (see A.J. Bitonti and J.A. Dumont, (2006), Adv. Drug Deliv. Rev, 58:1106-1118). In addition to effectively treating local lung diseases, this delivery mechanism can also be used for the systemic delivery of antibodies (see Maillet et al. (2008), Pharmaceutical Research, Vol. 25, No. 6, 2008).

[0145] The pharmaceutical compositions can also be delivered in vesicles, specifically, liposomes (see, for example, Langer (1990) Science 249:1527-1533).

[0146] In certain cases, the pharmaceutical compositions can be delivered in a controlled-release system. In one embodiment, a pump can be used. In another embodiment, polymeric materials can be used. In yet another embodiment, the controlled-release system can be placed near the target of the composition, so that only a fraction of the systemic dose is required.

[0147] Injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injection, infusion, etc. These injectable preparations can be prepared by well-known methods. For example, an injectable preparation can be prepared by, for example, dissolving, suspending, or emulsifying the above-mentioned antibody or its salt in a sterile aqueous medium or an oily medium commonly used for injection. As the aqueous medium for injection, for example, there are physiological saline, isotonic solutions containing glucose, and other adjuvants, etc., which can be used in combination with appropriate solubilizers, such as alcohols (e.g., ethanol), polyols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, for example, sesame oil, soybean oil, etc. can be used, which can be used in combination with solubilizers such as benzyl benzoate, benzyl alcohol, etc. The injectable preparation thus prepared is preferably filled in appropriate ampoules.

[0148] The pharmaceutical compositions of the present disclosure can be delivered subcutaneously or intravenously using standard needles and syringes. Additionally, with respect to subcutaneous delivery, pen delivery devices are readily applicable for delivering the pharmaceutical compositions of the present disclosure. Such pen delivery devices can be reusable or disposable. Reusable pen delivery devices typically utilize replaceable cartridges containing the pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Instead, the disposable pen delivery device is pre-filled with the pharmaceutical composition held in a reservoir within the device. Once the pharmaceutical composition within the reservoir is emptied, the entire device is discarded.

[0149] Many reusable pen delivery devices and autoinjector delivery devices are applied to subcutaneous delivery of the pharmaceutical compositions of the present disclosure. Examples include but are of course not limited to AUTOPEN TM (Owen Mumford, Inc., Woodstock, UK), DISETRONIC TM Pen (Disetronic Medical Systems, Burghdorf, Switzerland), HUMALOG MIX 75 / 25 TM Pen, HUMALOG TM Pen, HUMALIN 70 / 30 TM Pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN TMI, II, and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR TM (Novo Nordisk, Copenhagen, Denmark), BD TM Pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN TM , OPTIPEN PRO TM , OPTIPEN STARLET TM and OPTICLIK TM (Sanofi - Aventis, Frankfurt, Germany), to name a few. Examples of disposable pen delivery devices for subcutaneous delivery of the pharmaceutical compositions of the present disclosure include but are of course not limited to SOLOSTAR TM Pen (Sanofi - Aventis), FLEXPEN TM (Novo Nordisk) and KWIKPEN TM (Eli Lilly and Company), SURECLICK TM Auto - injector (Amgen, Thousand Oaks, CA), PENLET TM (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, L.P.), and HUMIRA TM Pen (Abbott Labs, Abbott Park IL), to name a few.

[0150] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are formulated into unit dosage forms suitable for combination with a defined dose of the active ingredient. Such unit dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of the above - mentioned antibody contained is usually about 5 mg to about 500 mg per unit dosage form; particularly in the form of an injection, preferably the content of the above - mentioned antibody is about 5 mg to about 100 mg, and for other dosage forms, about 10 mg to about 250 mg.

[0151] Administration regimen

[0152] In some embodiments, a therapeutically effective amount of an anti-YFV antibody or an antigen-binding fragment thereof is provided to a subject, such as a subject infected with YFV or at risk of infection with YFV, in its formulation. The phrase "therapeutically effective amount" means an amount administered to produce a desired effect. The exact amount will depend on the purpose of the treatment and will be determinable by those skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0153] According to certain embodiments, multiple doses of an antibody against YFV can be administered to a subject over a defined time course. Methods according to this aspect of the disclosure include sequentially administering multiple doses of an antibody against YFV to a subject. As used herein, "sequentially administering" means that each dose of the antibody against YFV is administered to the subject at different time points, such as on different days separated by a predetermined interval (e.g., several hours, days, weeks, or months). The present disclosure encompasses methods that include sequentially administering a single initial dose of an antibody against YFV to a patient, followed by administering one or more second doses of an antibody against YFV, and optionally subsequently administering one or more third doses of an antibody against YFV.

[0154] The terms "initial dose," "second dose," and "third dose" refer to the chronological order of administration of the antibody against YFV. Thus, the "initial dose" is the dose administered at the start of a treatment regimen (also referred to as the "baseline dose"); the "second dose" is the dose administered after the initial dose; and the "third dose" is the dose administered after the second dose. The initial dose, second dose, and third dose may all contain the same amount of the antibody against YFV, but may generally differ from each other in terms of the frequency of administration. However, in certain embodiments, during the course of treatment, the amounts of the antibody against YFV contained in the initial dose, second dose, and / or third dose differ from each other (e.g., appropriately up or down adjusted). In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered as a "loading dose" at the start of a treatment regimen, followed by subsequent doses (e.g., "maintenance doses") on a less frequent basis.

[0155] In an exemplary embodiment of the present disclosure, from 1 to 26 (e.g., 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 / 2, 15, 15 1 / 2, 16, 16 1 / 2, 17, 17 1 / 2, 18, 18 1 / 2, 19, 19 1 / 2, 20, 20 1 / 2, 21, 21 1 / 2, 22, 22 1 / 2, 23, 23 1 / 2, 24, 24 1 / 2, 25, 25 1 / 2, 26, 26 1 Administer each second dose and / or third dose on a weekly basis for two (2) or more weeks. As used herein, the phrase "previous dose" refers to the dose of the antibody against YFV administered to a patient prior to the administration of the next dose in the sequence of multiple administrations, without an intervening dose.

[0156] The methods according to this aspect of the disclosure may include administering to a patient any number of second and / or third doses of an antibody against YFV. For example, in certain embodiments, only a single second dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) second doses are administered to the patient. Similarly, in certain embodiments, only a single third dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) third doses are administered to the patient.

[0157] In embodiments involving multiple second doses, each second dose may be administered at the same frequency as the other second doses. For example, each second dose may be administered to the patient 1 to 2 weeks after the previous dose. Similarly, in embodiments involving multiple third doses, each third dose may be administered at the same frequency as the other third doses. For example, each third dose may be administered to the patient 2 to 4 weeks after the previous dose. Alternatively, the frequency of administering the second dose and / or third dose to the patient may vary during the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by the physician based on the needs of the individual patient after a clinical examination.

[0158] Accordingly, in certain embodiments, there are provided pharmaceutical compositions comprising: one or more antibodies of the invention or antigen-binding fragments thereof disclosed herein and throughout the text, and a pharmaceutically acceptable carrier and / or one or more excipients. In certain other embodiments, there are provided pharmaceutical compositions comprising: one or more nucleic acid sequences encoding one or more antibodies of the invention or antigen-binding fragments thereof; or one or more expression vectors containing such nucleic acid sequences; and a pharmaceutically acceptable carrier and / or one or more excipients.

[0159] Therapeutic uses of the antibodies

[0160] The anti-YFV antibodies disclosed herein can be used to treat subjects suffering from YFV and / or prevent YFV infection.

[0161] As used herein, the terms "treat", "treatment" and "treating" refer to reducing or ameliorating the progression, severity and / or duration of YFV infection, or symptoms or conditions associated therewith (such as fever, chills, headache, low back pain, myalgia, anorexia, nausea, vomiting, fatigue or combinations thereof) caused by administration of one or more therapies, including but not limited to administration of one or more prophylactic or therapeutic agents. In certain embodiments, such terms refer to reducing or inhibiting the replication of YFV, inhibiting or reducing the transmission of YFV to other subjects, inhibiting or reducing the infection of cells by YFV, or ameliorating one or more symptoms associated with YFV infection.

[0162] As used herein, the terms "prevent", "preventing" and "prevention" refer to preventing or inhibiting the development or onset of YFV infection or conditions associated therewith in a subject, preventing or inhibiting the progression of YFV infection or conditions associated therewith caused by administration of a therapy (e.g., a prophylactic or therapeutic agent), preventing the symptoms of YFV infection or conditions associated therewith, or administering a combination of therapies (e.g., a combination of prophylactic or therapeutic agents). As used herein, the terms "ameliorate" and "alleviate" refer to reducing or lowering the severity of a condition or any of its symptoms.

[0163] Due to their binding to and interaction with YFV, it is believed that the antibodies of the present invention and their antigen-binding fragments – without wishing to be bound by any theory – can be used to prevent virus-host cell membrane fusion, to prevent intercellular virus spread, and to inhibit syncytium formation. Alternatively, the antibodies of the present disclosure can be used to ameliorate at least one symptom associated with the infection, such as fever, diarrhea, and bleeding, or to reduce the severity, duration, and / or frequency of the infection. The antibodies of the present disclosure also contemplate prophylactic use in patients at risk of developing or acquiring a YFV infection. It is contemplated that the antibodies of the present disclosure can be used alone, or in combination with a second or third agent to treat a YFV infection, or to reduce at least one symptom or complication associated with a YFV infection, such as fever, nausea, or muscle pain associated with or caused by such an infection. The second or third agent can be delivered concomitantly with the antibodies of the present disclosure, or they can be administered separately either before or after the antibodies of the present disclosure. The second or third agent can be an antiviral agent, an NSAID, or other agent that reduces fever or pain, a second but different antibody that specifically binds YFV, an agent (such as an antibody) that binds to another YFV antigen, a vaccine against YFV, and an siRNA that is specific for a YFV antigen.

[0164] In yet another embodiment of the present disclosure, the antibodies of the present invention are used to prepare a pharmaceutical composition for treating a patient suffering from a YFV infection. In another embodiment of the present disclosure, the antibodies of the present invention are used to prepare a pharmaceutical composition for reducing the severity of a primary YFV infection, or for shortening the duration of the infection, or for alleviating at least one symptom associated with a YFV infection. In additional embodiments of the present disclosure, the antibodies of the present invention are used as adjuvant therapy in combination with any other agent that can be used to treat a YFV infection, the other agent including an antiviral agent, a toxoid, a vaccine, a second YFV antibody, or any other antibody that is specific for a YFV antigen, or any other palliative therapy known to those skilled in the art.

[0165] Accordingly, in certain embodiments, there is provided a method of treating or preventing a YFV infection or at least one symptom associated with a YFV infection, the method comprising administering to a patient in need or suspected of being in need thereof one or more of the antibodies of the present invention or their antigen-binding fragments disclosed herein and throughout the text, such as one or more of the anti-YFV antibodies disclosed in Table 3, such that the YFV infection is treated or prevented, or at least one symptom associated with the YFV infection is treated, alleviated, or reduced in severity.

[0166] In certain other embodiments, provided is a method of treating or preventing YFV infection or at least one symptom associated with YFV infection, the method comprising administering to a patient in need or suspected of being in need a nucleic acid sequence encoding one or more antibodies of the invention or antigen-binding fragments thereof, the nucleic acid sequence encoding the amino acid sequences disclosed in Table 3 and their complementary sequences, such that the YFV infection is treated or prevented, or at least one symptom associated with YFV infection is treated, alleviated or reduced in severity.

[0167] In additional embodiments, provided is a method of treating or preventing YFV infection or at least one symptom associated with YFV infection, the method comprising administering to a patient in need or suspected of being in need a host cell that contains a nucleic acid sequence or an expression vector comprising such a nucleic acid sequence, wherein such nucleic acid sequence encodes an amino acid sequence selected from the sequences disclosed in Table 3 and their complementary sequences, such that the YFV infection is treated or prevented, or at least one symptom associated with YFV infection is treated, alleviated or reduced in severity.

[0168] In additional embodiments, provided is a method of treating or preventing YFV infection or at least one symptom associated with YFV infection, the method comprising administering to a patient in need or suspected of being in need a pharmaceutical composition comprising: one or more antibodies of the invention or antigen-binding fragments thereof as disclosed in Table 3; one or more nucleic acid sequences or an expression vector comprising such nucleic acid sequences, wherein such nucleic acid sequence encodes an amino acid sequence selected from the sequences disclosed in Table 3 and their complementary sequences; one or more host cells that contain one or more nucleic acid sequences or an expression vector comprising such one or more nucleic acid sequences, wherein such nucleic acid sequence encodes an amino acid sequence selected from the sequences disclosed in Table 3 and their complementary sequences; and a pharmaceutically acceptable carrier and / or one or more excipients, such that the YFV infection is treated or prevented, or at least one symptom associated with YFV infection is treated, alleviated or reduced in severity.

[0169] In certain embodiments, provided is a method of treating or preventing YFV infection or at least one symptom associated with the YFV infection, the method comprising administering to a patient in need or suspected of being in need one or more antibodies of the invention or antigen-binding fragments thereof disclosed herein and throughout the text, such as one or more anti-YFV antibodies disclosed in Table 3, such that the YFV infection is treated or prevented, or at least one symptom associated with YFV infection is treated, alleviated or reduced in severity.

[0170] In certain other embodiments, provided is a method of treating or preventing YFV infection or at least one symptom associated with said YFV infection, the method comprising administering to a patient in need or suspected of being in need a nucleic acid sequence encoding one or more antibodies of the present invention or antigen-binding fragments thereof, the nucleic acid sequence encoding the amino acid sequences disclosed in Table 3 and their complementary sequences, such that the YFV infection is treated or prevented, or at least one symptom associated with YFV infection is treated, alleviated or reduced in severity.

[0171] In additional embodiments, provided is a method of treating or preventing YFV infection or at least one symptom associated with said YFV infection, the method comprising administering to a patient in need or suspected of being in need a host cell containing a nucleic acid sequence or an expression vector comprising such a nucleic acid sequence, wherein such nucleic acid sequence encodes an amino acid sequence selected from the sequences disclosed in Table 3 and their complementary sequences, such that the YFV infection is treated or prevented, or at least one symptom associated with YFV infection is treated, alleviated or reduced in severity.

[0172] In additional embodiments, provided is a method of treating or preventing YFV infection or at least one symptom associated with said YFV infection, the method comprising administering to a patient in need or suspected of being in need a pharmaceutical composition comprising: one or more antibodies of the present invention or antigen-binding fragments thereof as disclosed in Table 3; one or more nucleic acid sequences or an expression vector comprising such nucleic acid sequences, wherein such nucleic acid sequence encodes an amino acid sequence selected from the sequences disclosed in Table 3 and their complementary sequences; one or more host cells containing one or more nucleic acid sequences or an expression vector comprising such one or more nucleic acid sequences, wherein such nucleic acid sequence encodes an amino acid sequence selected from the sequences disclosed in Table 3 and their complementary sequences; and a pharmaceutically acceptable carrier and / or one or more excipients, such that the YFV infection is treated or prevented, or at least one symptom associated with YFV infection is treated, alleviated or reduced in severity.

[0173] Combination therapy

[0174] As described above, according to certain embodiments, the disclosed method comprises administering to a subject one or more additional therapeutic agents and an antibody against YFV. As used herein, the phrase "in combination with" means that the additional therapeutic agent is administered before, after or simultaneously with the pharmaceutical composition comprising the anti-YFV antibody. The term "in combination with" also encompasses sequential or simultaneous administration of the anti-YFV antibody and the second therapeutic agent.

[0175] For example, when administered "before" a pharmaceutical composition comprising an anti-YFV antibody, an additional therapeutic agent can be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before the administration of the pharmaceutical composition comprising the anti-YFV antibody. When administered "after" a pharmaceutical composition comprising an anti-YFV antibody, the additional therapeutic agent can be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after the administration of the pharmaceutical composition comprising the anti-YFV antibody. Administering "simultaneously" with a pharmaceutical composition comprising an anti-YFV antibody means administering the additional therapeutic agent to a subject within less than 5 minutes (before, after, or simultaneously) of administering the pharmaceutical composition comprising the anti-YFV antibody, either in a separate dosage form or as a single combined dosage formulation comprising the additional therapeutic agent and the anti-YFV antibody.

[0176] The combination therapy can comprise the anti-YFV antibody of the present disclosure and any additional therapeutic agent that can advantageously be combined with the antibody of the present disclosure or with a biologically active fragment of the antibody of the present disclosure.

[0177] For example, a second or third therapeutic agent can be employed to help reduce the viral load in the liver, such as an antiviral agent. As described above, the antibody can also be used in combination with other therapies, which can include toxoids, vaccines specific for YFV, a second antibody specific for YFV, or an antibody specific for another YFV antigen.

[0178] Diagnostic uses of the antibody

[0179] The anti-YFV antibodies of the invention and antigen-binding fragments thereof can also be used to detect and / or measure YFV in a sample, for example, for diagnostic purposes. It is contemplated that an infection believed to be caused by YFV can be confirmed by measuring the presence of the virus using any one or more of the antibodies of the present disclosure. Exemplary diagnostic assays for YFV can include, for example, contacting a sample obtained from a patient with an anti-YFV antibody of the present disclosure, wherein the YFV antibody is labeled with a detectable label or a reporter gene molecule or used as a capture ligand to selectively isolate from the patient sample the virus containing the protein. Alternatively, an unlabeled YFV antibody can be combined with a secondary antibody that is itself detectably labeled for diagnostic applications. The detectable label or reporter gene molecule can be, for example, 3 H, 14 C, 32 P, 35 S, or 125Radioactive isotopes such as I; fluorescent or chemiluminescent moieties such as fluorescein isothiocyanate or rhodamine; or enzymes such as alkaline phosphatase, β-galactosidase, horseradish peroxidase, or luciferase. Specific exemplary assays that can be used to detect or measure YFV in a sample include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and fluorescence-activated cell sorting (FACS).

[0180] Samples that can be used in the YFV diagnostic assays according to the present disclosure include any tissue or fluid sample obtainable from a patient that contains a detectable amount of YFV protein or a fragment thereof under normal or pathological conditions. Typically, the level of YFV in a specific sample obtained from a healthy patient (e.g., a patient not suffering from a disease or condition associated with the presence of YFV) is measured to initially establish a baseline or standard level of the YFV protein. This baseline level of YFV can then be compared to the level of YFV measured in a sample obtained from an individual suspected of having a YFV infection or symptoms associated with such an infection.

[0181] Examples

[0182] After immunization with YFV-17D, the human antibody response to YFV was comprehensively analyzed by isolating and characterizing 152 YFV-specific monoclonal antibodies from memory B cells of two donors who had not been infected with flaviviruses. These antibodies were then used to map the antigenic topology of YFV. It was found that the obtained anti-YFV antibodies bind to several antigenic sites, most commonly targeting epitopes within or proximal to FL in domain II of the YFV E protein. Thus, it provides support for the development of YFV antibodies targeting domain II. However, it was found that a second, less common class of antibodies with high neutralizing activity targets the DIII of the virus. Such DIII-directed antibodies may be particularly valuable in the therapeutic application of monoclonal antibodies or mixtures because this epitope is secondary in the natural immune response. In summary, these results have important implications for the design and evaluation of YFV vaccines and antibody-based candidate therapeutics and provide new options for passive prophylaxis.

[0183] Study design: Two healthy adult donors who were not infected with flaviviruses ("Donor 8" and "Donor 9") were immunized with the YFV-17D vaccine (Stamaril; Sanofi), and blood samples were collected at 10 days, 14 days, 28 days, 90 days, 180 days, 270 days, and 360 days after vaccination. By 14 days after vaccination, serum neutralizing activity against YFV-17D had appeared in both donors and persisted throughout the study (Figure 1A). The pre-vaccination sera from both donors lacked reactivity with YFV-17D and did not show detectable neutralizing activity against YFV-17D (data not shown), and also lacked reactivity with the E and NS1 proteins of other common epidemic flaviviruses, namely dengue virus serotypes 1-4 (DENV1-4), JEV, TBEV, West Nile virus (WNV), and Zika virus (ZIKV), which confirmed that both donors were likely not infected with flaviviruses at the time of vaccination (data not shown).

[0184] Molecular and functional characterization of the plasmablast response induced by YFV-17D

[0185] The plasmablast response was monitored in the two donors at 10 days and 14 days after vaccination. In both donors, an expanded plasmablast population was observed at the 10-day and 14-day time points, which was approximately 10-fold higher than the pre-vaccination level (Figure 2A). Approximately 300 plasmablasts from each donor were sorted by single-cell PCR and the corresponding VH and VL regions were amplified. 161 and 210 naturally paired antibodies were cloned from Donor 8 and Donor 9, respectively, and expressed as full-length IgG in an engineered Saccharomyces cerevisiae strain. Sequence analysis showed that the plasmablast responses of the two donors were highly diverse, with only approximately 15% of the clones belonging to expanded clonal lineages (data not shown). Most of the plasmablast-derived antibodies from both donors contained high levels of somatic hypermutation (SHM), indicating effective recruitment of MBCs into the PB response (data not shown). The median level of SHM in PB-derived mAbs was significantly higher at day 10 than at day 14. Correspondingly, a greater proportion of mAbs cloned from PBs at day 14 lacked SHM, indicating an increase in cells recruited from the naive B cell compartment at this time point (data not shown).

[0186] To analyze whether somatic mutations in PB-derived mAbs contribute to binding activity, inferred un-resolved common ancestor (UCA) mAbs were generated from three somatically mutated PB clones and their binding affinities to recombinant YFV E protein were measured. In all three cases, the UCA mAbs showed substantially reduced binding affinities compared to the mature mAbs, indicating that somatic mutations in PB mAbs are important for the recognition of YFV E( Figure 3 ).

[0187] Then, the binding reactivity of PB-derived mAbs with YFV-17D particles was tested using a sandwich ELISA assay (Figure 2B). The frequencies of YFV-17D-binding mAbs isolated from PB on days 10 and 14 ranged from 8 - 41%. Forty-five and forty-six YFV-17D-binding mAbs were recovered from the expanded PB populations in donors 8 and 9, and then their neutralization activities were analyzed in a microtiter neutralization assay at 100 and 10 nM concentrations. The neutralization activities ranged from complete neutralization at 10 nM to no detectable neutralization at 100 nM (Figure 2C). A greater proportion of mAbs isolated from day 14 PB showed neutralization activity compared to day 10 PB, which was consistent with the increased serum neutralization activity on day 14 compared to day 10 in both donors (data not shown). Neutralization titration experiments on mAbs showing at least 50% inhibition of infection at 100 nM indicated that 9 - 12% of the YFV-17D-binding mAbs isolated from day 14 PB showed moderate to high neutralization activity (IC 50 ≤10 nM) (Figure 2D and Figure 4 ). Sequence analysis showed that 12.5–33% of PB-derived nAbs utilized VH4-4 / VL1-51 germline gene pairings, indicating recognition of common antigenic sites (data not shown).

[0188] Approximately 50% and 22% of the neutralizing antibodies isolated from donors 8 and 9, respectively, lacked somatic mutations, indicating that YFV-17D neutralizing antibodies are present in the naive B cell repertoire and suggesting that YFV-17D vaccination induces PB responses originating from naive and MBCs, and only a minority of these B cells encode Abs showing neutralization activity. See Figures 1A and 1B.

[0189] Molecular and functional characterization of the YFV-17D-induced MBC response

[0190] PBMC were collected at days 14, 28, 90, 180, 270, and 360 to monitor the MBC responses of two donors, and purified B cells were stained with a panel of previously described B cell surface markers (CD19, CD20, CD27, IgM, IgD, CD21, and CD71) and fluorescently labeled recombinant YFV E protein (Figure 5A). YFV E-specific swIg + MBCs emerged in both donors between days 14 - 28, peaked between days 90 and 180, and declined slowly between days 180 and 360 (Figure 5B).

[0191] At each sampling time point, 100 - 400 YFV E-reactive B cells were sorted from both donors. Non-binding mAbs derived from naive B cells were captured by the sorting strategy employed but were excluded from subsequent analysis. Analysis of B cell surface markers expressed on single-cell sorted YFV E-reactive B cells indicated that the MBC response to YFV E was highly heterogeneous at all time points (data not shown). At the earliest sampling time point (day 14), activated naive B cells and IgM+CD27+ MBCs dominated the responses in both donors, but these B cell populations waned rapidly over time. By day 90, less than 15% of the YFV E-specific responses included IgM+CD27+ MBCs, and by day 360, only ~5% of the YFV E-specific B cells belonged to this MBC population (Figure 8B). In contrast, the swIg+ MBC population (including both CD27+ and CD27- B cells) expanded between days 14 and 90 and then remained stable throughout the study. An MBC response similar to that observed after YFV-17D vaccination was also observed after natural infection with PUUV (data not shown).

[0192] The SHM load, apparent binding affinity (K D App ) and neutralizing potency of YFV E-specific mAbs were tracked at each sampling time point. In both donors, the median level of SHM was low at day 14 (more than 50% of the Abs lacked somatic mutations) and increased gradually over the 6 - 9 month period, remaining stable in both donors 9 months after vaccination, with median nucleotide substitutions in VH of 9 and 7 for donors 8 and 9, respectively (data not shown). Binding studies with recombinant YFV E protein indicated that the K D App of MBC-derived mAbs was very weak at early time points and improved gradually within 6 - 9 months after vaccination (data not shown). At days 14 and 28 after vaccination, most YFV E-specific mAbs showed KD App > 50 nM, and by day 180, approximately 50% of the YFV E-specific mAbs showed a K D App < 5 nM. Concomitant with the increase in affinity, the emergence of highly potent neutralizing antibodies was observed starting from day 90 (IC 50 < 1 nM) (data not shown). These neutralizing antibodies were derived from multiple MBC subsets, including atypical IgM+ and / or IgD+ MBC (data not shown). Table 2 summarizes the affinity and neutralization data of the isolated and characterized neutralizing mAbs.

[0193] Sustained B cell activation was evaluated by analyzing the expression of CD71 and CD21 on YFV E-specific MBC. CD71 was expressed on 75–85% of YFV E-specific B cells on day 14 and remained elevated for approximately 6 months in both donors (data not shown). In both donors, YFV E-specific CD21 lo cells were present at high frequencies on days 14 and 28 post-vaccination, accounting for approximately 40–80% of the YFV E-specific response, and then rapidly declined by day 90. Although CD71 + and CD21 lo populations highly overlapped, with 50 - 80% of YFV E-specific activated B cells (defined as CD71 + and / or CD21 lo ) showing a CD71 + CD21 lo phenotype on day 14, by days 28 - 90, the CD71 + CD21 lo populations decreased to < 50% of the activated B cell response in both donors, and most YFV E-specific activated B cells showed a CD71 + CD21 + or CD71 ─ CD21 lo phenotype and were heterogeneous in isotype and CD27 expression (data not shown).

[0194] Isolation and Characterization of Anti-YFV Antibodies

[0195] Approximately 152 neutralizing monoclonal antibodies were isolated and characterized. Antibody variable heavy chain (VH) and variable light chain (VL) genes were rescued by single cell PCR. Tiller et al. (2008) Journal of Immunological Methods 329, 112 - 124. Subsequently, pairs of homologous heavy and light chains were cloned and expressed as full-length IgG in engineered Saccharomyces cerevisiae strains for further characterization. Bornholdt et al., (2016) Science 351, 1078 - 1083.

[0196] The germline gene usage of the isolated mAbs was analyzed. In two donors, mAbs utilizing the VH3 - 72 germline gene dominated the responses at all time points (Figure 6A). A large proportion of these mAbs also utilized one of five dominant light chain (LC) germline genes and showed shorter than average heavy chain (HC) complementarity determining region 3 (CDRH3) lengths, indicating a shared antigen recognition pattern (Figure 6B - C). The binding affinity of mAbs utilizing VH3 - 72 was significantly higher than that observed for mAbs utilizing other VH germlines, despite containing similar levels of SHM (Figure 6D - E). Table 1 summarizes the germline usage and number of nucleotide substitutions of the isolated mAbs.

[0197] To explore the epitope coverage of the isolated mAbs, pairwise competition experiments were performed using the newly isolated mAb and two well-characterized control mAbs (4G2 and 5A) that recognize proximal but non-overlapping epitopes within DII of the YFV E monomer. 4G2 is a flavivirus mAb targeting FL, while 5A is a YFV E-specific mAb that binds to an FL-proximal epitope overlapping with the proposed prM-associated region. The competition experiments were conducted using high-throughput surface plasmon resonance (SPR) on a Carterra LSA instrument. The reactivity of the mAbs with the recombinant YFV-17D DIII protein was also evaluated by BLI. Most mAbs recognized one of eight distinct antigenic sites defined based on reactivity with DIII and competition with 4G2, 5A, and three newly isolated mAbs (ADI-49147, ADI-44112, and ADI-45107) (Figure 7A). A subset of mAbs competed with both 5A and ADI-45107, indicating that these two antigenic sites are in close proximity. A small subset of mAbs (6 out of 772) recognized epitopes within DIII. Five of the DIII-directed mAbs cross-competed, while the sixth, ADI-48945, may recognize a unique epitope. More than half of the mAbs from two donors competed with 4G2 and / or 5A, indicating that most YFV E-specific responses are mediated by Abs targeting epitopes within or proximal to FL on DII (Figure 7A). Almost all mAbs utilizing the VH3-72 germline gene competed with 4G2 (Figure 7B). Thus, analysis of the sequence characteristics of mAbs clustered by competition groups revealed that more than half of the mAbs competing with 4G2 utilized the VH3-72 germline gene (Figure 7C). The 4G2 competitor mAbs utilizing VH3-72 showed significantly higher affinity compared to mAbs utilizing other VH germline genes (Figure 7D). Although the proportion of mAbs targeting each antigenic site did not change substantially over time, inhibition of 4G2 / 5A competitor mAbs was observed at later time points (day 270 and day 360) in donor 8. Additionally, in both donors, mAbs competing with both 5A and ADI-45107 did not appear until day 28 - 90. The results indicate that the vast majority of YFV E-specific responses are directed against epitopes within or proximal to FL on domain II, and there is only a small shift in the Ab immunodominance hierarchy during the maturation of the B cell response to YFV-17D.

[0198] Highly potent neutralizing antibodies recognize FL-proximal epitopes

[0199] The relationship between antigenic sites and neutralization potency was investigated. More than 90% of the mAbs that competed only with 5A or with both 5A and ADI-45107 exhibited neutralizing activity (Figure 8A). Most (78%) of the highly potent neutralizing antibodies (IC 50 <1 nM) in the group belonged to these two competing groups (Figures 8B - 8C). Table 2 provides the box data for these antibodies. Analysis of the sequence characteristics of these 5A-only or 5A / ADI-45107 competitor neutralizing antibodies revealed that nearly 40% utilized the VH4-4 / VL1-51 germline gene pairing and showed no evidence of convergent CDRH3 sequences, indicating a common pattern of germline-encoded antigen recognition (Figure 8D). Consistent with previous studies, most DIII-directed mAbs also showed highly potent neutralizing activity. In contrast to 5A competitor and DIII-directed mAbs, only a minority of mAbs belonging to other competing groups showed neutralizing activity. For example, only 12% and 20% of the mAbs that competed only with 4G2 or with both 4G2 and 5A showed neutralizing IC 50 <100 nM. The results suggest that the nAb response to YFV-17D is mainly mediated by Abs that recognize the FL-proximal epitope within DII of the YFV E protein.

[0200] A subset of mAbs showed cross-reactivity with the E proteins from other flaviviruses

[0201] The binding reactivity of the isolated mAbs with recombinant DENV-2, DENV-4, WNV, or ZIKV E proteins was evaluated. In two donors, approximately 6% of the YFV E-reactive mAbs showed cross-reactivity with at least one heterologous flavivirus E protein (Figure 9A). Most of these cross-reactive mAbs targeted the highly conserved FL epitope and bound to all five flavivirus E proteins with high apparent affinity (K D App <10 nM) (Figures 9B - 9C). Accordingly, a small subset of mAbs that bound to epitopes outside of FL generally showed more limited cross-reactivity profiles and lower K D App (Figure 9C). Among the 50 cross-reactive mAbs, only 6 showed neutralizing activity against YFV-17D, and only one mAb (the DIII binder ADI-48905) showed detectable neutralizing activity against ZIKV, although weak (IC 50 ~100 nM). The mAbs had no measurable neutralizing activity against West Nile virus or Japanese encephalitis virus reporter virus particles. Thus, YFV-17D vaccination appears to induce a subset of Abs that show broad flavivirus binding activity, most of which target the highly conserved FL, and little cross-neutralizing activity.

[0202] Table 1 below provides the germline usage and amino acid sequence information of the 152 anti-YFV antibodies described herein. The sequences provided in Table 1 include the CDRH3 sequences (SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 27, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300 and 302) and CDRL3 sequences (SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209211213 215 217 219 221 223 225 227 229 231 233 235 237 239 241 243 245 247 249 251 253 255 257 259 261 263 265 267 269 271 273 275 277 279 281 283 285 287 289 291 293 295 297 299 301 and 303).

[0203] Table 2 below provides the affinity and neutralization data for the 152 anti-YFV antibodies listed in Table 1.

[0204] Table 3 below provides the partial amino acid sequences of the CDRs of the heavy and light chains of each of the 152 anti-YFV antibodies listed in Table 1. The CDRs are shown in bold / underlined. Each CDR amino acid sequence is also listed separately in the Sequence Listing (CDRH1 and CDRH2 correspond to SEQ ID NO: 607-840; CDRL1 and CDRL2 correspond to SEQ ID NO: 841-1005).

[0205] Table 1: Germline Usage and Sequence Information for Anti-YFV Antibodies

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217] Table 2: Affinity and Neutralization Data for Anti-YFV Antibodies

[0218]

[0219]

[0220]

[0221]

[0222]

[0223] *NN - Non - neutralizing; n.d. – Not determined; Others – Did not block any of the listed competitive assay controls

[0224] Table 3: Informal Sequence Listing

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256] Materials and Methods

[0257] Study Design

[0258] Study subjects aged 30 and 31 years were vaccinated with the YFV-17D Stamaril vaccine. Heparinized blood (50–100 cc) was obtained from the subjects before vaccination and on days 10, 14, 28, 90, 180, 270, and 360 after vaccination. Samples were processed at the Immunomonitoring and Flow Cytometry Core Laboratory of the Geisel School of Medicine at Dartmouth to obtain plasma and isolate peripheral blood-derived B cells. The isolated cells and plasma were cryopreserved at -80 °C.

[0259] Cells: Huh 7.5.1 cells (obtained from Dr. Jan Carette; originally obtained from Dr. Frank Chisari) were passaged every 3 to 4 days using 0.05% trypsin / EDTA solution (Gibco) and maintained in Dulbecco's Modified Eagle's Medium (DMEM high glucose, Gibco) supplemented with 10% heat-inactivated fetal bovine serum (FBS, Atlanta Biologicals), 1% penicillin / streptomycin (P / S, Gibco), 1% Gluta-MAX (Gibco), and 25 mM HEPES (Gibco). Vero African green monkey kidney cells (obtained from ATCC) were passaged every 3 to 4 days using 0.05% trypsin / EDTA solution (Gibco) and maintained in Dulbecco's Modified Eagle's Medium (DMEM high glucose, Gibco) supplemented with 2% heat-inactivated fetal bovine serum (FBS, Atlanta Biologicals), 1% penicillin / streptomycin (P / S, Gibco), 1% Gluta-MAX (Gibco), and 25 mM HEPES (Gibco).

[0260] Production of yellow fever virus 17D: YFV-17D was obtained from BEI Resources (Catalog No. NR-115). A 15-cm plate of Huh 7.5.1 with 80% confluence was infected with 90 μL of the undiluted supernatant of the second passage of YFV-17D in 3 mL of infection medium (DMEM low glucose (Gibco), 7% FBS, 1% Pen-Strep, 1% Gluta-MAX (Gibco), 25 mM HEPES (Gibco)) at 37 °C and 5% CO2 for 1 hour. The supernatant was harvested 3 days later and centrifuged twice at 4,000 rpm for 15 minutes at 4 °C to remove cell debris. The pre-cleared supernatant was ultracentrifuged through a 2-mL 30% (v / v) D-sucrose / PBS cushion at 28,000 rpm for 4 hours using an SW28 rotor (Beckman Coulter) in a Beckman Coulter Optima LE-80K ultracentrifuge to produce the undiluted YFV-17D virus stock for neutralization assays. The pellet was resuspended in 300 μL of PBS on ice overnight, then aliquoted and frozen at -80 °C.

[0261] Production of Zika virus: Zika virus strain MR 766 was obtained from ATCC( VR-84 TM) For neutralization assays, at 37 °C and 5% CO2, a 15 cm plate of Vero cells with 80% confluence was infected with 90 μL of the undiluted passage 1 Zika supernatant in 3 mL of infection medium (DMEM low glucose (Gibco), 2% FBS, 1% Pen-Strep, 1% Gluta-MAX (Gibco), 25 mM HEPES (Gibco)) for 1 hour. The supernatant was harvested 3 days later and centrifuged twice at 4,000 rpm for 15 minutes at 4 °C to remove cell debris.

[0262] Antigen and antibody

[0263] Production of recombinant YFV antigen: The coding regions of the entire prM and soluble E (sE) regions of the YFV Asibi strain (Uniprot ID: Q6DV88, residues 122 - 678 of the genomic polyprotein) were cloned into pMT-puro, an insect expression vector encoding a C-terminal dual Strep tag. The expression construct was designed based on previously published flavivirus antigen structures 61,62,63. The YFV prM / E construct was used to generate an inducible, stable Drosophila S2 line. Protein expression was induced by the addition of copper sulfate and allowed to proceed for 5 - 7 days. The recombinant protein was affinity purified from the culture supernatant using a StrepTrap HP column (GE Healthcare). An additional purification step was performed using size exclusion chromatography steps with an S200 Increase column (GE Healthcare). The final protein preparation was stored in phosphate buffered saline pH 7.4 supplemented with an additional 150 mM NaCl. Small aliquots were stored at -70 °C until use. Additional flavivirus antigens used in this study – DENV-2E, DENV-4E, WNV E, and ZIKV E – were expressed and purified essentially as described for YFV sE.

[0264] Flavivirus NS1 protein antigens: NS1 proteins from Dengue virus (serotypes 1 - 4), JEV, TBEV, WNV, YFV were purchased from Native Antigen Company (catalog numbers FLAVX4 - NS1 - 100 and DENVX4 - NS1 - 100), and ZIKV NS1 was purchased from Meridian Life Science (catalog number R01636). Positive control antibodies reactive with the above NS1 proteins were obtained from Native Antigen Company: anti - DENV NS1 (catalog number AbDENVNS1 - DA034), anti - ZIKV NS1 antibody (catalog number AbZIKVNS1 - B4 - 100). Anti - YFV NS1 protein antibody was purchased from Meridian Life Science (catalog number C01906M). Anti - WNV NS1 antibody (catalog number HM484 - X0632) and anti - TBEV NS1 antibody (catalog number HM477 - X1462) were purchased from East Coast Bio. Flavivirus cross - reactive serum was used to detect JEV NS1 protein.

[0265] YFV - 17D DIII protein: The DIII region (aa293 - 397) of the YFV - 17D E protein (Uniprot ID: P03314) was produced in Drosophila S2 cells using the modified pT350 vector (Felix Rey, Institut Pasteur, France). CdCl2 was used to induce protein expression, and the supernatant was harvested 5 - 7 days after induction. The recombinant protein was purified using a Strep - Tactin column (IBA) and size - exclusion chromatography using an S200 Increase column (GE Healthcare) and 10 mM Tris pH8 / 150 mM NaCl buffer.

[0266] Single B - cell sorting

[0267] For plasmablast sorting, PBMCs were stained with anti-human CD38 (PE), CD27 (BV421), CD20 (PE-Cy7), CD3 (PerCP-Cy5.5), CD8 (PerCP-Cy5.5), CD14 (PerCP-Cy5.5), and CD16 (PerCP-Cy5.5). Plasmablasts were defined as CD19+CD3-CD20- / loCD27highCD38high cells. For MBC sorting, B cells were purified using the MACS B cell isolation kit (Miltenyi Biotec; catalog number 130-091-151), and subsequently stained with anti-human CD19 (PE-Cy7), CD20 (PE-Cy7), CD3 (PerCP-Cy5.5), CD8 (PerCP-Cy5.5), CD14 (PerCP-Cy5.5), CD16 (PerCP-Cy5.5), IgD (BV421), IgM (AF-488), CD27 (BV510), CD21 (BV605), CD71 (APC-Cy7 and a mixture of dual-labeled (APC and PE) YFV E tetramers (25 nM each). Tetramers were freshly prepared for each experiment, and B cells reactive to the YFV E tetramers were sorted as single cells. Single cells were sorted into 96-well PCR plates (BioRAD) containing 20 μL / well lysis buffer [5 μL of 5X first-strand cDNA buffer (Invitrogen), 0.625 μL NP-40 (New England Biolabs), 0.25 μL RNaseOUT (Invitrogen), 1.25 μL dithiothreitol (Invitrogen), and 12.6 μL dH2O] using a BD FACS Aria II (BD Biosciences). The plates were immediately stored at -80 °C. Flow cytometry data were analyzed using FlowJo software.

[0268] Amplification and cloning of antibody variable genes

[0269] As described above, the antibody variable genes (IgH, IgK, and IgL) were amplified by reverse transcription PCR and nested PCR using a mixture of IgG-specific and IgM-specific primers (Tiller et al., Journal of Immunology 2008). The primers used in the second round of PCR contained 40 base pairs and had 5' and 3' homology to the digested expression vector, which allowed cloning into Saccharomyces cerevisiae by homologous recombination. The PCR products were cloned into Saccharomyces cerevisiae using the lithium acetate method for chemical transformation (Gietz and Schiestl, Nat Protoc 2007). Each transformation reaction used 10 uL of unpurified heavy and light chain PCR products and 200 ng of digested expression vector. After transformation, single yeast colonies were picked for sequencing and characterization.

[0270] Expression and purification of IgG and Fab fragments

[0271] As described above, IgG was expressed in Saccharomyces cerevisiae cultures grown in 24-well plates (Bornholdt et al., Science 2016b). After 6 days, the cultures were harvested by centrifugation and IgG was purified by protein A affinity chromatography. The bound antibody was eluted with 200 mM acetic acid / 50 mM NaCl (pH 3.5) into 1 / 8 volume of 2M Hepes (pH 8.0), and the buffer was exchanged into PBS (pH 7.0).

[0272] Two YFV E-reactive control mAbs, 5A and 4G2, were generated in the human IgG1 constant region. The publicly available variable region sequences of the two control antibodies, 4G2 and 5A, were synthesized as gBlock fragments (IDT) with homologous overhangs for recombinant cloning into Saccharomyces cerevisiae. Subsequent production was carried out as described above.

[0273] Fab fragments were generated by digesting IgG with papain at 30 °C for 2 h. The digestion was terminated by adding iodoacetamide, and the Fab and Fc mixture was passed over protein A agarose to remove the Fc fragment and undigested IgG. The protein A resin was then flowed through CaptureSelect TM IgG-CH1 affinity resin (ThermoFischer Scientific), and eluted with 200 mM acetic acid / 50 mM NaCl pH 3.5 into 1 / 8 volume of 2M Hepes pH 8.0. The Fab fragments were then buffer exchanged into PBS pH 7.0.

[0274] Kinetics of binding measurements

[0275] IgG-binding surface plasmon resonance kinetic measurements (SPR): Biacore 8K system, interfaced with a CAP sensor chip, with the sample chamber set at 10 °C, the flow cell temperature set at 25 °C, and the data collection rate set at 10 Hz. HBS-EP+ (10 mM HEPES pH 7.3, 150 mM NaCl, 3 mM EDTA, 0.05% surfactant P20) was used as the running buffer. In each cycle, the biotinylated CAPture reagent (GE Healthcare) diluted 1:20 in the running buffer was injected into flow cells 1 and 2 at a flow rate of 5 μl / min for 600 s, and then biotinylated YFV E antigen (25 nM, in HBS-EP+) was captured (1 μl / min) in flow cell 2 for 900 s to reach a minimum capture level of 400 RU. Then the antibody (36–288 nM, in HBS-EP+) was injected into flow cells 1 and 2 for 300 s (30 μl / min), dissociation was monitored for 300 s (30 μl / min), and the surface was regenerated at the oligonucleotide level with 6 M guanidine-HCl in 0.25 M NaOH for 120 s (10 μl / min). At least two blank (HBS-EP+) injections were also run under the same conditions as above for assessment and subtraction of system artifacts. The data were aligned, double-referenced, and fit to a bivalent analyte binding model using Biacore 8K evaluation software version 1.0.

[0276] Fab - bound surface plasmon resonance kinetic measurements (SPR): Biacore 8K system, docked with a CAP sensor chip, sample chamber set at 10 °C, flow cell temperature set at 25 °C, and data collection rate set at 10 Hz. HBS - EP+ (10 mM HEPES pH 7.3, 150 mM NaCl, 3 mM EDTA, 0.05% surfactant P20) was used as the running buffer. In each cycle, biotinylated CAPture reagent (GE Healthcare) diluted 1:20 in the running buffer was injected into flow cells 1 and 2 at a flow rate of 1 μL / min for 600 s, then biotinylated YFV E protein (15 nM, in HBS - EP+) was captured (1 μL / min) in flow cell 2 for 900 s to reach a minimum capture level of 275 RU. Then Fab (A5:27–1 nM, in HBS - EP+; 4G2:4–0.125 nM, in HBS - EP+) was injected into flow cells 1 and 2 for 300 s (30 μL / min), dissociation was monitored for 1200 s (30 μL / min), and the surface was regenerated for 185 s (10 μL / min) with 6 M guanidine - HCl in 0.25 M NaOH at the oligonucleotide level. At least two blank (HBS - EP+) injections were also run under the same conditions as above for evaluating and subtracting system artifacts. The data were aligned, double - referenced, and fitted to a 1:1 binding model using Biacore 8K evaluation software version 1.0.

[0277] Biolayer interferometry kinetic measurements (BLI): For monovalent apparent KD determination, the binding of IgG to recombinant YFV E antigen was measured by biolayer interferometry (BLI) using a FortéBio Octet HTX instrument (Molecular Devices). IgG was captured (1.5 nm) onto an anti - human IgG capture (AHC) biosensor (Molecular Devices) and allowed to equilibrate in PBSF (PBS with 0.1% w / v BSA) for at least 30 min. After a short (60 s) baseline step in PBSF, the IgG - loaded biosensor tip was exposed (180 s, 1000 rpm orbital shaking) to YFV E antigen (100 nM, in PBSF), then immersed (180 s, 1000 rpm orbital shaking) in PBSF to measure any dissociation of the antigen from the biosensor tip surface. The data with binding responses > 0.1 nm were aligned, step - corrected (relative to the association step), and fitted to a 1:1 binding model using FortéBio data analysis software version 11.1.

[0278] For the divalent epigenetic KD determination, the binding of IgG to recombinant YFV E antigen was measured by Biolayer Interferometry (BLI) using a FortéBio Octet HTX instrument (Molecular Devices). Recombinant biotinylated YFV E was immobilized on a streptavidin biosensor (Molecular Devices) and allowed to equilibrate in PBSF (PBS with 0.1% w / v BSA) for at least 30 minutes. After a short (60 seconds) baseline step in PBSF, the antigen-loaded biosensor tip was exposed (180 seconds, 1000 rpm orbital shaking) to IgG (100 nM, in PBSF), then immersed (180 seconds, 1000 rpm orbital shaking) in PBSF to measure any dissociation of IgG from the biosensor tip surface. Data with a binding response > 0.1 nm were aligned, step-corrected (relative to the association step), and fit to a 1:1 binding model using FortéBio Data Analysis Software version 11.1.

[0279] High-throughput antibody epitope assignment

[0280] Biolayer Interferometry (BLI) epitope binning: For epitope binning, control antibodies A5 and 4G2 (produced as human IgG1 chimeras) were captured on an anti-human IgG capture biosensor (0.9 nm) (Molecular Devices), and then the biosensor was blocked by exposing it to adalimumab (0.5 mg / mL; 20 minutes, 350 rpm orbital shaking). After a short (60 seconds) baseline step in PBSF, cross-interaction checks (180 seconds, 1000 rpm orbital shaking) were performed between the sample IgG and the loaded biosensor. No cross-interaction was observed for this set of IgG. The loaded biosensor then underwent a second short (60 seconds) baseline step in PBSF, followed by an association step (180 seconds, 1000 rpm orbital shaking) in 100 nM recombinant YFV E monomer. Finally, a binning step (180 seconds, 1000 rpm orbital shaking) was performed in 100 nM sample IgG in PBS with 0.1% BSA (PBSF). The data were analyzed using FortéBio Data Analysis Software version 11.1. Sample IgG with a binning response < 0.1 nm was determined to compete with the control antibody. Sample IgG with a binning response > 0.1 nm was determined not to compete with the control antibody.

[0281] High-throughput epitope binning using Carterra LSA (SPR)

[0282] Combining kinetics and affinity. Using a Carterra high-throughput surface plasmon resonance (SPR) biosensor platform equipped with an HC-30M chip type, the kinetic rates and affinity constants of the binding of yellow fever antigen (provided by Adimab as a purified recombinant monomer, MW 45 kDa) to the 770+ADI mAb library (provided as a purified human IgG) were determined in the form of "capture kinetics" at a temperature of 25 °C. To prepare the surface for this experiment, the chip was coated as a "lawn" with a capture reagent, namely goat anti-human IgG Fc (Southern Biotech, catalog number 2014-01) that was polyclonally cross-absorbed to serum proteins from multiple other species, using standard amine coupling in a running buffer (HBSET) of 10 mM Hepes pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% Tween 20. Briefly, this involved priming a single flow cell (SFC) with the HBSET running buffer, injecting an activation solution of freshly prepared 1:1:1 v / v / v 0.1 M N-hydroxysulfosuccinimide (Sulfo-NHS, Pierce) + 0.4 M 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, Pierce) + 0.1 M MES pH 5.5 (Carterra) for 10 minutes, coupling 50 μg / ml goat anti-human IgG Fc diluted in 10 mM sodium acetate pH 4.3 for 15 minutes, and quenching the excess reactive esters with 1 M ethanolamine pH 8.5 for 7 minutes. This resulted in an average final coupling level of 6256 RU ± 4% variance (judged from 384 reaction spots). The 96-channel print head (96PH) was then primed in the running buffer and used to capture the ADI mAb as a ligand. The ADI mAb was diluted to 2 μg / ml in the running buffer and printed in batches of 96 print heads onto discrete spots at once. Four consecutive dockings of the 96PH were used to address all 4 print block positions, resulting in an array of 384 ligands. The 96PH was placed back in water for washing, the SFC was docked onto the printed array and primed with a measurement running buffer of HBSET + 0.5 g / l BSA. Analyte samples of the yellow fever monomer antigen were prepared as an 8-point 4-fold dilution series spanning a nominal concentration of 0.02 - 367 nM and injected into the SFC at increasing concentrations after several buffer (blank) injections. The binding and dissociation times were 5 minutes and 20 minutes, respectively. The data were analyzed in the Carterra kinetics software as follows. The binding data at the reaction points were double-referenced by subtracting the response from a local reference point (representing the bare capture reagent) and then subtracting the response from the buffer blank analyte 66.The dual-reference data is globally fitted to a simple Langmuir model, allowing each point to have its own associated association rate constant (ka), dissociation rate constant (kd), and Rmax value. The equilibrium dissociation (affinity) constant (KD) is calculated from the ratio of the kinetic rate constants, KD = kd / ka).

[0283] Epitope binning experiment: Carterra's LSA was used to perform epitope binning assays in a classical sandwich assay format 67 using 6 benchmark mAbs (ADI-49582, ADI-44112, ADI-45107, ADI-49147, 4G2, and 5A) as analytes to probe the epitope diversity of the 770+ADI library as a ligand. The HCX-30M (pre-activated) chip type was used and the experiment was carried out at 25 °C. SFC and 96PH were initiated in a running buffer of 25 mM Mes pH 5.5 + 0.01% Tween 20. The ADI mAbs were diluted to 2 μg / ml in 10 mM sodium acetate pH 4.5 (coupling buffer) and coupled by 96PH with a contact time of 7 minutes for each printed block position. After 4 consecutive dockings on 96PH to construct an array of 384 ligands, SFC was docked on the entire surface to quench the excess reactive esters by injecting ethanolamine pH 8.5 for 7 minutes. The final coupling level for each mAb ranged from 1000 - 4000 RU per point. 96PH was put back into water for washing and SFC was initiated in the assay running buffer of HBSET + 0.5 g / l BSA. Each binning cycle involved a co-injection sample delivery mode where antigen (50 nM yellow fever monomer) and antibody analyte (20 μg / ml mAb or buffer) samples were continuously injected with the shortest dissociation time between them on the array of 384 ligands. The typical binding time was 3 or 5 minutes and the surface was regenerated with 75 mM phosphoric acid after each binning cycle. The binding data was analyzed in Carterra's epitope software.

[0284] Microtiter neutralization assay

[0285] Monoclonal antibodies were serially diluted in DMEM high glucose medium (Gibco) containing 10% heat-inactivated FBS (Gibco), 1% Gluta-MAX (Gibco), 1% P / S (Gibco), and 25 mM HEPES (Gibco), and incubated with YFV-17D or ZIKV for 1 hour at room temperature. YFV-17D or ZIKV was diluted to achieve a 60% endpoint infection. The antibody-virus mixture was added in triplicate to 96-well plates (Costar 3595) containing a monolayer of 5x10^3 Huh 7.5.1 cells seeded the day before. The cells were cultured at 37 °C and 5% CO2 for 2 days. Then the cells were fixed with 4% paraformaldehyde (Sigma) for 10 minutes and then washed three times with Tris buffer (50 mM Tris, 150 mM NaCl (all from Thermo Fisher Scientific), pH 7.6). The fixed cells were incubated with 2 μg / ml flavivirus mouse mAb 4G2 (ATCC) in Tris buffer containing 3% skim milk powder (BioRad), 0.5% Triton X-100 (MP Biomedicals), and 0.05% Tween 20 (Thermo Fisher Scientific) for one hour at room temperature (RT). After that, the cells were washed three times and incubated with a secondary antibody conjugated to Alexa Fluor 488 goat anti-mouse (Invitrogen) at a 1:500 dilution for one hour at room temperature. The cells were washed again and the nuclei were stained with Hoechst-33342 (Invitrogen) diluted 1:2,000 in PBS. Virus infectivity was measured by automatically counting Alexa Fluor 488-positive cells from the captured images using a Cytation-5 automated fluorescence microscope (BioTek), and analyzed using Gen5 data analysis software (BioTek). The half-maximal inhibitory concentration (IC50) of the mAb was calculated using nonlinear regression analysis with GraphPad Prism software. Nonlinear regression analysis of the virus neutralization data was performed to extract the half-maximal inhibitory concentration (IC50) value (4-parameter, variable slope sigmoidal dose-response equation; GraphPad Prism).

[0286] Neutralization of donor plasma samples was performed exactly as described above for purified IgG. Serial dilutions of plasma were pre-incubated with the stock solution of YFV-17D infection for 1 hour before addition to the cell monolayer.

[0287] In the purified IgG neutralization assay against YFV-17D and ZIKV (Catalog No. AB_2337042, Jackson ImmunoResearch), purified total human IgG from non-immunized donors was used as a negative control.

[0288] FRNT assay

[0289] Virus-specific mAbs were screened as described previously. Briefly, all purified mAbs were serially diluted in 199 medium (Thermo Fisher Scientific) containing 5% heat-inactivated fetal bovine serum (FBS) (Gibco-Invitrogen) and incubated with YFV-17DD at 37 °C. After 1 hour of incubation, the Ab-virus mixture was added in duplicate to 96-well plates containing an 80% confluent monolayer of Vero E6 cells. The plates were incubated at 37 °C for 1.5 hours. Then the wells were overlaid with 1% methylcellulose in supplemented OptiMEM GlutaMAX medium (Invitrogen) containing 5% heat-inactivated FBS (Gibco-Invitrogen) and 1% amphotericin B, and the wells were incubated at 37 °C, 5% CO2 for 72 hours. The cells were then fixed and permeabilized with Perm / Wash buffer (BD Biosciences) for 30 minutes. After permeabilization, the cells were washed with phosphate-buffered saline (PBS) and incubated with anti-flavivirus antibody (MAB10216, EMD Millipore) diluted 1:2000 in Perm / Wash buffer for 2 hours. After incubation, the cells were washed with PBS and incubated with anti-mouse horseradish peroxidase (HRP)-conjugated secondary antibody (115035146, Jackson ImmunoResearch Laboratories) for 2 hours. The plates were washed and developed with peroxidase substrate (KPL). The half-maximal inhibitory concentration (IC50) of the mAbs was calculated using nonlinear regression analysis with GraphPad Prism software.

[0290] Serum and purified IgG ELISA

[0291] For the NS1 and E-binding ELISA, a 96-well plate (Corning; catalog number 3690) was coated with 5 μg / ml NS1 or E protein diluted in PBS and incubated overnight at 4 °C. The wells were washed and then blocked with 5% non-fat dry milk (NFDM) in PBS for 1 h at 37 °C. The wells were washed three times with PBS and serial dilutions of human plasma in 5% NFDM-PBS were added and incubated for 1 h at 37 °C. The plate was then washed three times with PBS and secondary cross-adsorbed anti-human IgG-HRP (Thermo Fisher Scientific; catalog number 31413) or anti-human IgM (Sigma Aldrich; catalog number AP114P) detection antibodies were added at a 1:8000 dilution in 5% NFDM-PBS at 37 °C for 1 h. After washing three times with PBS, the detection reagent was added according to the manufacturer's recommendations (Thermo Fisher Scientific; catalog number 34029) and absorbance was measured at 450 nM wavelength using a Spectramax microplate reader (Molecular Devices).

[0292] For the virus-binding ELISA, a 96-well ELISA plate was coated with 5 μg / ml 4G2 (Millipore MAB10216) diluted in PBS and incubated for 2 h at 37 °C. After washing three times with PBS, whole YFV-17D virus particles were diluted in PBS pH 7.4 and incubated overnight at 4 °C. The plate was then washed three times with PBS and blocked with 5% NFDM-PBS for 1 h at 37 °C. After removing the blocking solution, test antibodies diluted in 5% NFDM-PBS were allowed to bind for 1 h at 37 °C. The plate was then washed three times with PBS and secondary cross-adsorbed anti-human IgG-HRP (Thermo Fisher Scientific; catalog number 31413) or anti-human IgM (Sigma Aldrich; catalog number AP114P) detection antibodies were added at a 1:8000 dilution in 5% NFDM-PBS at 37 °C for 1 h. After washing three times with PBS, the detection reagent was added according to the manufacturer's recommendations (Thermo Fisher Scientific; catalog number 34029) and absorbance was measured at 450 nM wavelength using a Spectramax microplate reader (Molecular Devices).

[0293] Binding of purified IgG to virus particles was performed as described above. IgG was diluted in 5% NFDM-PBS and single-point reactivity testing was performed on plasmablasts and day 14 antibodies derived from MBCs at a concentration of 100 nM.

[0294] All references, patents, and patent publications cited herein are hereby incorporated by reference in their entirety for all that is taught therein. Sequence Listing <110> Mablock LLC A·Wacker L·Walker <120> Anti-Yellow Fever Virus Antibodies and Methods for Their Production and Use <130> TMAB-501001WO <150> US 62 / 940,049 <151> 2019-11-25 <160> 1005 <170> PatentIn version 3.5 <210> 1 <211> 18 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 1 Ala Arg Asn Ala Pro Glu Asn Tyr Tyr Gly Ser Gly Arg Glu Ser Phe 1 5 10 15 Asp Ile <210> 2 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 2 Gly Thr Trp Asp Ser Ser Leu Ser Ala Trp Val 1 5 10 <210> 3 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 3 Ala Lys Asp His Gly Gly Lys Tyr Gly Trp Trp Tyr Phe Asp Leu 1 5 10 15 <210> 4 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 4 Gln Gln Tyr Asp Asn Trp Pro Leu Thr 1 5 <210> 5 <211> 18 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 5 Ala Arg Asn Ala Pro Glu Asn Tyr Tyr Gly Ser Gly Arg Glu Ser Phe 1 5 10 15 Asp Ile <210> 6 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 6 Gly Thr Trp Asp Ser Ser Leu Ser Ala Trp Val 1 5 10 <210> 7 <211> 19 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 7 Ala Arg Asp Leu Glu Val Gly Ala Glu Tyr Leu Tyr Tyr His Tyr Gly 1 5 10 15 Met Asp Val <210> 8 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 8 Ala Ala Trp Asp Asp Ser Leu Asn Gly Trp Val 1 5 10 <210> 9 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 9 Ala Lys Asp Ser Ser Thr Ser Trp Tyr Gln Val Val Tyr His Ile Asp 1 5 10 15 Tyr <210> 10 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 10 Glu Thr Trp Asp Ser Ser Leu Asn Ala Val Val 1 5 10 <210> 11 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 11 Ala Lys Asp Leu Ala Val Ser Thr Pro Arg Tyr Trp Phe Asp Ser 1 5 10 15 <210> 12 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 12 Gln Gln Ser Tyr Ser Ile Pro Arg Ile Thr 1 5 10 <210> 13 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 13 Ala Lys Asp Met Ala Val Ser Val His Arg Gly Trp Phe Asp Asp 1 5 10 15 <210> 14 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 14 Gln Gln Ser Tyr Ser Pro Pro Met Tyr Thr 1 5 10 <210> 15 <211> 19 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 15 Ala Arg Asp Leu Glu Val Gly Ala Glu Tyr Ile Tyr Tyr Tyr Tyr Gly 1 5 10 15 Met Asp Val <210> 16 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 16 Ala Ala Trp Asp Asp Ser Arg Asn Gly Trp Val 1 5 10 <210> 17 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 17 Ala Arg Ser His Trp Arg Ser Pro Gln Ser Val Thr Phe Asp Leu 1 5 10 15 <210> 18 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 18 Gly Thr Trp Asp Thr Ser Ser Leu Ser Ala Gly Arg Val 1 5 10 <210> 19 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 19 Ala Arg Ile Ala Ala Gly Tyr Ser Thr Ser Trp Tyr Tyr Phe Asp Tyr 1 5 10 15 <210> 20 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 20 Gly Thr Trp Asp Thr Ser Leu Ser Ala Gly Arg Val 1 5 10 <210> 21 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 21 Ala Lys Asp Met Trp Ala Gly Thr Thr Thr Asn Trp Phe Gly Pro 1 5 10 15 <210> 22 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 22 Gly Thr Trp Asp Thr Ser Leu Gly Val Val 1 5 10 <210> 23 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 23 Ala Arg Glu Phe Ser Ser Arg Pro Phe Asp Leu 1 5 10 <210> 24 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 24 Cys Ser Tyr Ala Gly Thr Tyr Thr Ser Asn Tyr Val 1 5 10 <210> 25 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 25 Ala Arg Val Asn Pro Pro Gln Tyr Ser Ser Gly Trp Tyr Ser Val Tyr 1 5 10 15 <210> 26 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 26 Gly Thr Trp Asp Asn Ser Leu Gly Ala Val Val 1 5 10 <210> 27 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 27 Ala Arg Val Ala Trp Thr Ser Ser Ser Ser Cys Tyr Tyr Asp Tyr 1 5 10 15 <210> 28 <211> 18 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 28 Ala Arg Asp Gly Glu Gly His Tyr Tyr Arg Ser Gly Asp Asn Trp Phe 1 5 10 15 Asp Arg <210> 29 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 29 Gly Thr Trp Asp Ser Ser Leu Ser Ala Val Val 1 5 10 <210> 30 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 30 Ala Arg Ala Glu Leu Ser Ala Trp Tyr Tyr Phe Asp His 1 5 10 <210> 31 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 31 Gly Thr Trp Asp Thr Ser Leu Ser Ala Gly Arg Val 1 5 10 <210> 32 <211> 19 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 32 Ala Arg Val Ser Pro Leu Asp Asp Gly Tyr Gly Tyr Thr Tyr Tyr Gly 1 5 10 15 Met Asp Val <210> 33 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 33 Gln Gln Tyr Asn Asn Trp Pro Pro Arg Thr 1 5 10 <210> 34 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 34 Ala Arg Asp Trp Ala Glu Leu Thr Thr Ile Thr Asn Tyr Phe Tyr Pro 1 5 10 15 <210> 35 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 35 Gln Gln Ala Lys Ser Phe Pro Pro Thr 1 5 <210> 36 <211> 22 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 36 Ala Lys Ala Glu Asn Arg Ile Gly Tyr Cys Ser Ala Gly Ser Cys Tyr 1 5 10 15 Leu Thr Tyr Phe Asp Tyr 20 <210> 37 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 37 Asn Ser Tyr Thr Ser Ser Ser Thr Leu Val 1 5 10 <210> 38 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 38 Ala Lys Asp Pro Lys Tyr Ser Ser Gly Trp Trp Ala Phe Asp Tyr 1 5 10 15 <210> 39 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 39 Gln Gln Tyr Asp Asp Trp Pro Leu 1 5 <210> 40 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 40 Ala Arg Val Glu Trp Ala Tyr Ser Ser Ser Trp Trp Leu Asp Tyr 1 5 10 15 <210> 41 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 41 Gly Thr Trp Asp Thr Ser Leu Ser Ala Gly Gly Val 1 5 10 <210> 42 <211> 20 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 42 Ala Lys His Thr Gly Asp Lys Pro Leu Val Trp Ala Pro Ser Val Tyr 1 5 10 15 Gly Leu Asp Val 20 <210> 43 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 43 Ser Ser Tyr Thr Arg Arg Ser Thr Leu Val 1 5 10 <210> 44 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 44 Ala Arg Val Ser Val Ser Thr Ser Ala Trp Tyr Ala Asp Tyr 1 5 10 <210> 45 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 45 Gly Thr Trp Asp Thr Ser Leu Ser Thr Val 1 5 10 <210> 46 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 46 Ala Arg Glu Leu Ser Ser Arg Ile Asp Tyr 1 5 10 <210> 47 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 47 Ser Ser Tyr Pro Gly Thr Ser Ala Leu Val Ile 1 5 10 <210> 48 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 48 Ala Arg Ala Gln Asp Gly Gln Gln Leu Val Asn Tyr Tyr Gly Met Asp 1 5 10 15 Val <210> 49 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 49 Gln Gln Ser Tyr Ser Thr Pro Tyr Thr 1 5 <210> 50 <211> 20 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 50 Ala Arg Gly Gly Asp Tyr Gly Asp Tyr Glu Ser Asn Asn Pro Ala Glu 1 5 10 15 Tyr Phe Gln His 20 <210> 51 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 51 Gln Ser Tyr Asp Ser Ser Leu Ser Gly His Val Val 1 5 10 <210> 52 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 52 Ala Gly His Arg Glu Asp Pro Tyr Gly Ala Tyr Gly Ala Ser 1 5 10 <210> 53 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 53 Gln Gln Arg Thr Asn Trp Pro Phe Thr 1 5 <210> 54 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 54 Ala Ser Arg Lys Glu Val Arg Gly Thr Glu Asp Tyr Phe Asp Tyr 1 5 10 15 <210> 55 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 55 His Gln Arg Thr Asn Trp Pro Trp Thr 1 5 <210> 56 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 56 Ala Lys Val Glu Glu Asp Gly Tyr Thr Asn Val Val Arg Asp Tyr 1 5 10 15 <210> 57 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 57 Leu Gln Arg Thr Asn Trp Pro Phe Thr 1 5 <210> 58 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 58 Ala Arg Glu Gly Thr Arg Gly Arg Met Asp 1 5 10 <210> 59 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 59 Ser Ser Tyr Thr Ser Gly Thr Thr Leu Gly Val 1 5 10 <210> 60 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 60 Ala Arg Asp Ser Trp Ser Gly Pro Thr Arg Asn Trp Phe Asp Pro 1 5 10 15 <210> 61 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 61 Gly Thr Trp Asp Ser Ser Leu Gly Gly Val Ile 1 5 10 <210> 62 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 62 Ala Arg Val Val Trp Glu Tyr Ser Asn Ala Trp Cys Val Asp Phe 1 5 10 15 <210> 63 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 63 Glu Thr Trp Asp Ser Ser Leu Gly Val Val Val 1 5 10 <210> 64 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 64 Ala Arg Asn Thr Tyr Tyr Asp Arg Ser Gly Leu Ile Ala Tyr 1 5 10 <210> 65 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 65 Gln Gln Tyr Asp Asn Leu Ser Arg Leu Thr 1 5 10 <210> 66 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 66 Ala Arg Gly Pro Leu Lys Ser Tyr Trp Tyr Phe Asp Leu 1 5 10 <210> 67 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 67 Gly Thr Trp Asp Thr Ser Leu Ser Ala Gly Arg Val 1 5 10 <210> 68 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 68 Ala Arg Tyr Cys Ser Gly Ala Thr Cys Tyr Gly Ser Asn Gly Met Asp 1 5 10 15 Val <210> 69 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 69 Gly Thr Trp Asp Phe Arg Leu Ser Ala Leu 1 5 10 <210> 70 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 70 Ala Lys Asp Gln Cys Gly Gly Asp Cys Thr Ala Asp Tyr 1 5 10 <210> 71 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 71 Ser Ser Tyr Thr Ser Ser Gly Thr Pro Val Val 1 5 10 <210> 72 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 72 Ala Ser Thr Leu Trp Gly Gly Pro Leu Ser Val Ala Ser Asp Tyr 1 5 10 15 <210> 73 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 73 Gly Thr Trp Asp Ser Ser Pro Ser Ala Gly Arg Val 1 5 10 <210> 74 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 74 Ala Arg Asp Tyr Tyr Ala Ser Gly Asp Gly Tyr Phe Asp Tyr 1 5 10 <210> 75 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 75 Gln Gln Tyr Tyr Ser Thr Pro Arg Thr 1 5 <210> 76 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 76 Val Arg Tyr Cys Ser Ser Thr Ser Cys Tyr Gly Leu Asn Gly Met Asp 1 5 10 15 Val <210> 77 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 77 Gly Thr Trp Asp Thr Arg Leu Ser Ala Leu 1 5 10 <210> 78 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 78 Ala Arg Asp Gly Ser Leu Val Asn Ala Ile Asp Tyr 1 5 10 <210> 79 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 79 Gly Thr Trp Asp Thr Ser Leu Ser Ala Ala Trp Val 1 5 10 <210> 80 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 80 Ala Arg Val Arg Trp Ser Gly Ser Thr Ser Trp Asp Leu Asp Tyr 1 5 10 15 <210> 81 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 81 Gly Thr Trp Asp Thr Ser Pro Ser Ala Gly Gly Val 1 5 10 <210> 82 <211> 23 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 82 Ala His Ser Pro Arg Arg Ile Thr Met Val Arg Gly Val Ile Ile Thr 1 5 10 15 Trp Gly Asp Gly Met Asp Val 20 <210> 83 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 83 Ser Ser Tyr Thr Ser Ser Ser Thr Leu Ala Val 1 5 10 <210> 84 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 84 Ala Arg Asp Gly Ser Met Val Asn Ala Ile Asp Tyr 1 5 10 <210> 85 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 85 Gly Thr Trp Asp Ser Ser Leu Ser Ala Ala Trp Val 1 5 10 <210> 86 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 86 Ala Arg Asp Ala Tyr Ala Ser Gly Asp Gly Gly Ile Asp Tyr 1 5 10 <210> 87 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 87 Ser Ser Tyr Arg Ser Ser Gly Thr Pro Tyr Val 1 5 10 <210> 88 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 88 Ala Lys Asp Leu Arg Gly Val Gly Gly Trp Tyr Tyr Phe Asp Tyr 1 5 10 15 <210> 89 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 89 Gln Gln Tyr Asp Asn Leu Pro Leu Thr 1 5 <210> 90 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 90 Ala Lys Asp Gln Gly Val Thr Thr Asp Trp Pro Ser Asp Tyr 1 5 10 <210> 91 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 91 Gln His Tyr Glu Thr Tyr Ser Val Arg 1 5 <210> 92 <211> 19 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 92 Pro Arg Asp Gly Leu Pro Gly Ala Asn Gln Tyr Phe Phe Tyr Tyr Gly 1 5 10 15 Met Asp Val <210> 93 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 93 Gln Lys Tyr Asn Ser Ala Pro Leu Thr 1 5 <210> 94 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 94 Val Arg Val Glu Glu Tyr Val Asn Asn Glu Glu Val Arg Asp Tyr 1 5 10 15 <210> 95 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 95 Leu Gln Arg Thr Asn Trp Pro Phe Thr 1 5 <210> 96 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 96 Ala Arg Asp Gln Gly Phe Thr Thr Asp Trp Pro Cys Asp Tyr 1 5 10 <210> 97 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 97 Gln His Tyr Asn Ser Phe Ser Val Lys 1 5 <210> 98 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 98 Ala Arg Asp Ser Asn Phe Asn Ser Asn Leu Asp Tyr 1 5 10 <210> 99 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 99 Gln Val Trp Asp Ser Ser Ser Asp His Pro Trp Val 1 5 10 <210> 100 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 100 Ala Arg Gly Pro Leu Lys Thr Tyr Trp Tyr Phe Asp Leu 1 5 10 <210> 101 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 101 Gly Thr Trp Asp Thr Ser Leu Ser Ala Gly Arg Val 1 5 10 <210> 102 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 102 Ala Arg Asp Ser Asn Tyr Phe Tyr Gly Leu Asp Val 1 5 10 <210> 103 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 103 Gln Val Trp Asp Thr Ser Ile Asp His His Trp Val 1 5 10 <210> 104 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 104 Ala Lys Asp Ile Cys Ser Gly Asp Cys Gly Gly Gly Asp Tyr 1 5 10 <210> 105 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 105 Ser Ser Tyr Ala Gly Ser Asn Asn Trp Val Val 1 5 10 <210> 106 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 106 Ala Arg Glu Asp Asp Asp Tyr Tyr Ser Met Asp Val 1 5 10 <210> 107 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 107 Ser Ser Tyr Thr Thr Thr Ser Leu Val Ile 1 5 10 <210> 108 <211> 22 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 108 Ala Arg Asp Ile Ser Cys Ile Ser Thr Ser Cys Tyr Gly Gly Tyr Tyr 1 5 10 15 Tyr Tyr Gly Met Asp Val 20 <210> 109 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 109 Met Gln Ala Leu Gln Thr Pro Pro Arg Thr 1 5 10 <210> 110 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 110 Ala Arg Asp Tyr Tyr Ala Ser Gly Asp Gly Ser Ile Asp Tyr 1 5 10 <210> 111 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 111 Leu Gln His Asn Ser Tyr Pro Leu Thr 1 5 <210> 112 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 112 Ala Lys Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Phe Asp Tyr 1 5 10 <210> 113 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 113 Lys Gln Tyr Asn Arg Asn Pro Tyr Thr 1 5 <210> 114 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 114 Ala Lys Gly Ser Val Ser Val Ala Gly Ala Glu Asp Tyr 1 5 10 <210> 115 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 115 Gln Lys Tyr Asn Ser Ala Pro Gln Thr 1 5 <210> 116 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 116 Ala Lys Gly Tyr Asp Ser Ser Gly Tyr Tyr Trp Ala Asp Tyr 1 5 10 <210> 117 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 117 Gln Gln Tyr Asn Asn Trp Pro Pro Leu Thr 1 5 10 <210> 118 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 118 Ala Arg Glu Arg Gly Gly Tyr Phe Thr Glu Pro Phe Asp Ile 1 5 10 <210> 119 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 119 Gln Gln Tyr Tyr Arg Thr Pro Trp Thr 1 5 <210> 120 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 120 Ala Ala Thr Ile Phe Gly Val Val Ser Phe Asp Tyr 1 5 10 <210> 121 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 121 Gly Thr Trp Asp Ser Ala Leu Gly Ala Ala Val 1 5 10 <210> 122 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 122 Ala Lys Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Leu Asp Tyr 1 5 10 <210> 123 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 123 Gln Gln Tyr Asn Arg Asp Pro Tyr Thr 1 5 <210> 124 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 124 Cys Arg Glu Ser Gly Glu Gly Phe Asp Pro 1 5 10 <210> 125 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 125 Gln Ser Ala Asp Arg Ser Gly Ser Val Ile 1 5 10 <210> 126 <211> 26 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 126 Ala Arg Asp Gln Ser His Gly Thr Phe Gly Gly Val Ile Asp Ser Thr 1 5 10 15 Thr Leu Phe Tyr Tyr Tyr Gly Met Asp Val 20 25 <210> 127 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 127 Gln Gln Arg Ser Asn Trp Pro Ser 1 5 <210> 128 <211> 19 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 128 Ala Arg Gly Tyr Cys Ser Ser Thr Ser Cys Phe Tyr Tyr Tyr Tyr Gly 1 5 10 15 Met Asp Val <210> 129 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 129 Gln Gln Ser Tyr Ser Thr Pro Leu Thr 1 5 <210> 130 <211> 22 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 130 Ala Arg Asp His Tyr Phe Asp Ser Ser Gly Asp Tyr Leu Ser Tyr Tyr 1 5 10 15 Tyr Asn Gly Met Asp Val 20 <210> 131 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 131 Gln Gln Tyr Gly Ser Ser Pro Arg Ala 1 5 <210> 132 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 132 Ala Arg Val Tyr Gly Gly Pro Asp Asp Tyr 1 5 10 <210> 133 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 133 Gln Gln Ser Ser Ile Thr Pro Pro Thr 1 5 <210> 134 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 134 Ala Lys Asp Gly Val Thr Thr Ile Asn Gly Trp Phe His Phe Glu Tyr 1 5 10 15 <210> 135 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 135 Gln Gln Tyr Asn Ser Phe Pro Phe Thr 1 5 <210> 136 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 136 Thr Arg Ile Thr Gly Asp Arg Tyr Trp Tyr Leu Asp Leu 1 5 10 <210> 137 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 137 Gln Gln Thr Tyr Ser Ala Ser Gly Ser 1 5 <210> 138 <211> 20 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 138 Ala Arg Gly Trp Phe Gly Tyr Ser Asn Tyr Gly Leu Tyr Tyr Tyr Tyr 1 5 10 15 Gly Met Asp Val 20 <210> 139 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 139 Gln Gln Ser Tyr Ser Thr Pro Trp Thr 1 5 <210> 140 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 140 Ala Arg Asp Phe Trp Ser Gly Ser Asn Trp Phe Asp Pro 1 5 10 <210> 141 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 141 Gly Thr Trp Asp Asn Ser Leu Gly Val Val 1 5 10 <210> 142 <211> 25 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 142 Ala Lys Asp Ile Gly Asp Ser Tyr Gly Ser Gly Ser Tyr Tyr Leu Pro 1 5 10 15 Tyr Gly Ala Tyr Tyr Gly Met Asp Val 20 25 <210> 143 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 143 Gln Gln Tyr Gly Ser Ser Pro Gly 1 5 <210> 144 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 144 Ala Lys His Tyr Asp Ser Ser Gly Tyr Tyr Tyr Glu Asp Tyr 1 5 10 <210> 145 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 145 His Gln Tyr Lys Asp Phe Pro Trp Thr 1 5 <210> 146 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 146 Ala Arg Val Arg Asp Gly Glu Tyr Asp Tyr 1 5 10 <210> 147 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 147 Gln Gln Tyr Asn Ser Tyr Ser Pro 1 5 <210> 148 <211> 23 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 148 Ala Arg Asp Asn Ser Glu Val Glu Asp Tyr Gly Asp Tyr Val Leu Tyr 1 5 10 15 His Tyr Tyr Gly Met Asp Val 20 <210> 149 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 149 Gln Gln Tyr Gly Ser Ser Pro Phe 1 5 <210> 150 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 150 Ala Lys Asp Gln Cys Gly Gly Asp Cys Thr Ala Asp Tyr 1 5 10 <210> 151 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 151 Ser Ser Tyr Thr Ser Ser Ser Thr Pro Val Val 1 5 10 <210> 152 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 152 Ala Arg Gly Tyr Thr Gly Tyr Asp Gly Phe Asp Tyr 1 5 10 <210> 153 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 153 Cys Ser Tyr Ala Thr Asn Tyr Gly Val Val 1 5 10 <210> 154 <211> 18 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 154 Ala Arg Arg Pro Tyr Tyr Tyr Gly Ser Arg Arg Pro Ala Gly His Met 1 5 10 15 Asp Val <210> 155 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 155 Gln Ser Tyr Asp Ser Ser Asn Val Val 1 5 <210> 156 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 156 Gly Arg Asp Ser Asp Lys Asn Tyr Phe Asp Tyr 1 5 10 <210> 157 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 157 Gly Ala Trp Asp Ser Ser Leu Ser Ala His Val Val 1 5 10 <210> 158 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 158 Ala Lys Thr Tyr Asp Ser Asn Ala Tyr Tyr Tyr Leu Asp Tyr 1 5 10 <210> 159 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 159 Gln Gln Tyr Asn Arg Tyr Pro Tyr Thr 1 5 <210> 160 <211> 18 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 160 Ala Ser Leu Trp Phe Ile Val Met Thr Met Ser Lys Asn Pro Glu Thr 1 5 10 15 Asp Tyr <210> 161 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 161 Leu Gln His His Ser Tyr Pro Trp Thr 1 5 <210> 162 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 162 Ala Lys Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Phe Asp His 1 5 10 <210> 163 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 163 Gln Gln Tyr Asn Arg Asp Pro Tyr Thr 1 5 <210> 164 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 164 Ala Lys Phe Tyr Asp Ser Ser Gly Tyr Tyr Tyr Phe Asp Tyr 1 5 10 <210> 165 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 165 Gln Gln Tyr Asn Thr Tyr Pro Tyr Thr 1 5 <210> 166 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 166 Val Arg Leu Tyr Gly Asp Tyr Val Ala Tyr Phe Asp Tyr 1 5 10 <210> 167 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 167 Gln Gln Ser Tyr Ser Thr Pro Trp Thr 1 5 <210> 168 <211> 21 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 168 Ala Arg Arg Gly Thr Thr Val Thr Arg Phe Gly Val Ile Gln Tyr Tyr 1 5 10 15 Tyr Gly Met Asp Val 20 <210> 169 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 169 Ser Ser Tyr Thr Ser Ser Ser Thr Leu Val 1 5 10 <210> 170 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 170 Ala Arg Glu Thr Ala Asn Asn Trp Phe Asp Pro 1 5 10 <210> 171 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 171 Gln Val Trp Asp Asn Ser Ser Asp Arg Arg Val 1 5 10 <210> 172 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 172 Ala Arg Ala Ser Met Met Pro Arg Pro Pro Val His Asp Tyr 1 5 10 <210> 173 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 173 Gln Gln Tyr Asn Thr Trp Trp Thr 1 5 <210> 174 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 174 Ala Lys Asp Arg Ser Gln Gly Asp Tyr Gly Asp Tyr Val Ala Asp Tyr 1 5 10 15 <210> 175 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 175 Gln Gln Ser Tyr Ser Thr Pro Leu Thr 1 5 <210> 176 <211> 18 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 176 Ala Arg Val Gln Thr Ser His Ser Glu Leu Trp Phe Gly Glu Phe Gly 1 5 10 15 Ala Asp <210> 177 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 177 Gln Gln Tyr Asn Thr Trp Pro Lys Thr 1 5 <210> 178 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 178 Ala Lys Asp Gly Gly Tyr Ser Thr Asp Trp Tyr Phe Asp Leu 1 5 10 <210> 179 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 179 Gln Gln Tyr Gly Ser Ser Arg Arg Thr 1 5 <210> 180 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 180 Ala Lys Gly Tyr Asp Ser Asn Gly Tyr Tyr Tyr Ile Asp Tyr 1 5 10 <210> 181 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 181 Gln Gln Tyr Asn Arg Tyr Pro Tyr Thr 1 5 <210> 182 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 182 Ala Arg Asp Val Gly Tyr Gln Leu Leu Gln Val Tyr Gly Met Asp Val 1 5 10 15 <210> 183 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 183 Ser Ser Tyr Thr Ser Ser Ser Thr Leu Asp Val Val 1 5 10 <210> 184 <211> 21 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 184 Ala Arg Ala Glu Tyr Asp Thr Ser Gly Tyr Tyr Gln Gln Arg Leu Pro 1 5 10 15 Glu Tyr Phe Gln His 20 <210> 185 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 185 Gln Gln Tyr Asn Ser Trp Pro Pro Ile Thr 1 5 10 <210> 186 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 186 Ala Lys Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Phe His Ser 1 5 10 <210> 187 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 187 Gln Gln Tyr Asn Arg Tyr Pro Tyr Thr 1 5 <210> 188 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 188 Ala Arg Glu His Gly Asp Tyr Gly Leu Asp Tyr 1 5 10 <210> 189 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 189 Ala Thr Trp Asp Val Ser Leu Ser Asn Asp Val Leu 1 5 10 <210> 190 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 190 Tyr Val Asp Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Ser Pro Phe Asp 1 5 10 15 Tyr <210> 191 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 191 Gln Gln Tyr Gly Ser Ser Pro Pro Ile Thr 1 5 10 <210> 192 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 192 Ala Arg Val Asp Gly Glu Glu Val Ala Leu Ile Tyr 1 5 10 <210> 193 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 193 Gln Gln Ser Ser Thr Thr Arg Trp Thr 1 5 <210> 194 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 194 Val Arg Val Trp Gly Gly Glu Ala Ala Arg Tyr Asp Tyr 1 5 10 <210> 195 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 195 Gln His Ala Ser Thr Thr Pro Trp Thr 1 5 <210> 196 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 196 Ser Arg His Met Gly Phe Gly Leu Asp Leu 1 5 10 <210> 197 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 197 Gln Ala Trp Asp Thr Thr Thr Ala Gly Gly Val 1 5 10 <210> 198 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 198 Ala Arg Asp Tyr Tyr Gly Ser Gly Asp Gly Tyr Phe Asp Tyr 1 5 10 <210> 199 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 199 Gln Gln Tyr Gly Ser Ser Pro Arg Ala 1 5 <210> 200 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 200 Ala Arg Ile Pro Val Glu Tyr Gly Thr Pro Arg Gly Ser Phe Asp Thr 1 5 10 15 <210> 201 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 201 Ser Ser Tyr Gly Gly Asn Asn Asp Leu Val 1 5 10 <210> 202 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 202 Ala Gly Gly Ser Pro Asp Tyr 1 5 <210> 203 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 203 Gln Gln Arg Ser Asn Trp Pro Tyr Thr 1 5 <210> 204 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 204 Ala Arg Ala Tyr Asp Ser Arg Gly Tyr Tyr Tyr Ile Glu His 1 5 10 <210> 205 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 205 Gln Gln Tyr Lys Thr Tyr Trp Thr 1 5 <210> 206 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 206 Ala Arg Glu Ile Asp Ser Asn Tyr Val Phe Asp Tyr 1 5 10 <210> 207 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 207 Ser Ser Tyr Thr Ser Ser Gly Thr Asn Ile 1 5 10 <210> 208 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 208 Ala Arg Lys Leu Ser Tyr Ser Ser Gly Trp Tyr Tyr Phe Asp Tyr 1 5 10 15 <210> 209 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 209 Gln Gln Tyr Asn Asn Trp Pro Pro Leu Thr 1 5 10 <210> 210 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 210 Val Thr Thr Thr Val Ile Leu Phe Asp Tyr 1 5 10 <210> 211 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 211 Tyr Ser Thr Asp Ser Ser Gly Leu Leu Gly Val 1 5 10 <210> 212 <211> 20 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 212 Ala Arg Gly Arg Leu Ala Trp Gly Leu Arg Gly Gln Lys Ser Pro Asn 1 5 10 15 Phe Phe Ala Tyr 20 <210> 213 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 213 Gln Gln Phe His Ser Pro Pro Trp Thr 1 5 <210> 214 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 214 Ala Thr Ala Gly Ile Phe Gly Val Val Ile Met Lys Gly Phe Asp His 1 5 10 15 <210> 215 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 215 Gln Gln Tyr Asn Asp Tyr Pro Trp Thr 1 5 <210> 216 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 216 Ala Arg Glu Thr Tyr Tyr Tyr Gly Ser Gly Ser Val Pro Val His Asp 1 5 10 15 <210> 217 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 217 Leu Gln His Asn Thr Tyr Pro Trp Thr 1 5 <210> 218 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 218 Ala Arg Gly Tyr Asp Ser Ser Gly Tyr Trp Gly Phe Gly Asp Asn 1 5 10 15 <210> 219 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 219 Gln Gln Tyr Tyr Ser Tyr Pro Tyr Thr 1 5 <210> 220 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 220 Ala Arg Val Glu Gly Gly Ala Trp Gly Ala Phe Asp Ile 1 5 10 <210> 221 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 221 Gln Ser Ala Asp Arg Ser Gly Thr Val Val 1 5 10 <210> 222 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 222 Ala Arg Leu Trp Phe Thr Glu Tyr Pro Gly Ala Phe Asp Ile 1 5 10 <210> 223 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 223 Ser Ser Tyr Ala Gly Ser Asn Ala Leu Val 1 5 10 <210> 224 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 224 Ala Arg His Ser Ser Gly Ser Tyr Tyr Leu Ala Gly Tyr Tyr Phe Asp 1 5 10 15 Tyr <210> 225 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 225 Gln Ser Tyr Asp Ser Ser Asn Trp Val 1 5 <210> 226 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 226 Ala Arg Leu Thr Asp Ser Gly Tyr Asp Asp 1 5 10 <210> 227 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 227 His Ser Pro Asp Ser His Val Val 1 5 <210> 228 <211> 20 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 228 Ala Arg Glu Thr Cys Ser Gly Gly Ser Cys Tyr Tyr Arg Val Gly Ser 1 5 10 15 Ala Phe Asp Ile 20 <210> 229 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 229 Gln Val Trp Asp Ser Ser Ser Asp His Glu Val 1 5 10 <210> 230 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 230 Val Lys Asp Tyr Cys Ser Gly Gly Arg Cys Tyr Ser Phe Asp Tyr 1 5 10 15 <210> 231 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 231 Gln Gln Trp Gly Thr 1 5 <210> 232 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 232 Ala Lys Ala Tyr Asp Ser Ser Ala Tyr Tyr Tyr Leu Asp Tyr 1 5 10 <210> 233 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 233 Gln Gln Tyr Asn Arg Tyr Pro Tyr Thr 1 5 <210> 234 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 234 Ala Lys Ala Tyr Asp Ser Arg Gly Tyr Tyr Tyr Leu Asp Tyr 1 5 10 <210> 235 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 235 Gln Gln Tyr Asn Arg Tyr Ser Tyr Thr 1 5 <210> 236 <211> 22 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 236 Ala Lys Asp Leu Thr His Arg Leu Gly Ser Ile Phe Gly Lys Leu Thr 1 5 10 15 Phe Asp Ala Phe Asp Ile 20 <210> 237 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 237 Gln Gln Tyr Asn Asn Phe Trp Thr 1 5 <210> 238 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 238 Ala Lys Asp Leu Thr Pro Tyr Phe Tyr Asp Ser Gly Ala Phe Asp His 1 5 10 15 <210> 239 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 239 His Ser Tyr Asp Ser Asn Met Ser Gly Ser Val 1 5 10 <210> 240 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 240 Ala Arg Val Phe Gly Gly Pro Thr Asp Tyr 1 5 10 <210> 241 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 241 Gln Lys Tyr Tyr Ser Ala Pro Leu Ile Thr 1 5 10 <210> 242 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 242 Ala Arg Val Val Asn Gly Leu Asp Val 1 5 <210> 243 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 243 Gln Ser Ala Asp Ser Ser Val Ala Asp Ser Ser Val Val 1 5 10 <210> 244 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 244 Ala Arg Gly Gln Pro Asp Tyr 1 5 <210> 245 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 245 Gln Gln Arg Ser Asn Trp Pro Tyr Thr 1 5 <210> 246 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 246 Ala Gly Lys Lys Trp Glu Leu Leu Gly Phe Arg Phe Asp Pro 1 5 10 <210> 247 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 247 Gly Thr Trp Asp Asn Ser Leu Gly Met Val Val 1 5 10 <210> 248 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 248 Ala Arg Gln Trp Leu Gly His Phe Asp Tyr 1 5 10 <210> 249 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 249 Ser Ser Tyr Thr Ser Ser Ser Thr Tyr Val 1 5 10 <210> 250 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 250 Ala Arg Val Phe Ser Tyr Tyr Leu Asp Tyr 1 5 10 <210> 251 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 251 Gln Gln Pro Gly Asn Trp Pro Pro Ala Phe Thr 1 5 10 <210> 252 <211> 18 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 252 Ala His Arg His Ile Ala Ala Arg Leu Tyr Arg Asp Asp Asp Val Phe 1 5 10 15 Asp Val <210> 253 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 253 Gln Gln Tyr Asn Asn Trp Ile Thr 1 5 <210> 254 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 254 Ala Arg Gly Leu Asn Thr Val Thr Asn Ser Asp Tyr 1 5 10 <210> 255 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 255 Gln Gln Ala Asn Ser Phe Pro Trp Thr 1 5 <210> 256 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 256 Ala Ser Gly Leu Ser Pro Asp Phe Ser Val Leu Asp Val 1 5 10 <210> 257 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 257 Met Gln Ala Leu Gln Thr Pro Tyr Thr 1 5 <210> 258 <211> 23 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 258 Ala Arg Glu Gly Ala Gly Tyr Tyr Asp Ser Ser Gly Tyr Tyr Pro Leu 1 5 10 15 Ser Tyr Asp Ala Phe Asp Ile 20 <210> 259 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 259 Ala Ala Trp Asp Asp Asn Leu Ile Gly Val Val 1 5 10 <210> 260 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 260 Ala Arg Val Arg Gly Ser Tyr Trp Asp Tyr 1 5 10 <210> 261 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 261 Ser Ser Phe Ala Gly Ser Asn Asn Leu Tyr Val 1 5 10 <210> 262 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 262 Gly Arg Asp Arg Gly Trp Leu Asp Ile 1 5 <210> 263 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 263 Ser Ser Tyr Thr Arg Ser Ser Thr Arg Val 1 5 10 <210> 264 <211> 23 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 264 Ala Arg Val Ile Arg Asp Leu Arg Asp Tyr Tyr Asp Gly Ser Gly Tyr 1 5 10 15 Gly Pro Asp Ala Phe Asp Ile 20 <210> 265 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 265 Glu Thr Trp Asp Ser Arg Leu Ser Val Val 1 5 10 <210> 266 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 266 Ala Arg Ala Arg Trp Glu Asp Gly Asn Tyr Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 267 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 267 Gly Thr Trp Asp Ser Ser Leu Ser Ala Val Val 1 5 10 <210> 268 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 268 Ala Lys Asp Gln Ser Ser Gly Trp Pro Asn Tyr Tyr Tyr Gly Met Asp 1 5 10 15 Val <210> 269 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 269 Gln Gln Ser Tyr Ser Thr Pro Trp Thr 1 5 <210> 270 <211> 19 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 270 Val Arg Gly Tyr Cys Ser Ser Thr Ser Cys Tyr Gly Gly Leu Tyr Trp 1 5 10 15 Phe Asp Pro <210> 271 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 271 Gln Gln Ser Tyr Ser Thr Pro Arg Thr 1 5 <210> 272 <211> 19 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 272 Ala Arg His Ser Gly Gly Tyr Ser Ser Lys Asp Lys Pro Thr Glu Tyr 1 5 10 15 Phe Gln His <210> 273 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 273 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Val Val 1 5 10 <210> 274 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 274 Ala Arg Asp Val Gly Val Ala Ala Val Ile Thr Gly Ser Val Arg 1 5 10 15 <210> 275 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 275 Gln Gln Phe Tyr Thr Thr Pro Ser Thr 1 5 <210> 276 <211> 19 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 276 Ala Arg Gly Tyr Cys Ser Ser Thr Ser Cys Tyr Gly Gly Leu Tyr Trp 1 5 10 15 Phe Asp Pro <210> 277 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 277 Gln Gln Ser Tyr Ser Thr Pro Arg Thr 1 5 <210> 278 <211> 26 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 278 Ala Arg Asp Gly Ala Gly Asp Tyr Ile Trp Gly Ser Tyr Arg His Lys 1 5 10 15 Gly Leu His Tyr Tyr Tyr Gly Met Asp Val 20 25 <210> 279 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 279 Leu Gln His Asn Ser Tyr Pro Leu Thr 1 5 <210> 280 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 280 Ala Lys Asp Pro Arg Thr Phe Tyr Gly Val Val Met Leu Leu Asp Asp 1 5 10 15 Pro <210> 281 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 281 Gln Ser Tyr Asp Ser Thr Thr Val Val 1 5 <210> 282 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 282 Ala Arg Gly Phe Gly Glu Leu Pro Gly Phe Asp Ile 1 5 10 <210> 283 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 283 Ser Ser Tyr Ala Gly Ser Asn Asn Phe Val Val 1 5 10 <210> 284 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 284 Ala Arg Asp Ser Trp Gly Pro Phe Asp Tyr 1 5 10 <210> 285 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 285 Gly Thr Trp Asp Ser Ser Leu Ser Ala Lys Val 1 5 10 <210> 286 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 286 Ala Lys Thr Tyr Asp Ser Arg Ala Tyr Tyr Tyr Leu Asp Tyr 1 5 10 <210> 287 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 287 Gln Gln Tyr Asn Arg Tyr Pro Tyr Thr 1 5 <210> 288 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 288 Ala Lys Asp Leu Phe Tyr Asp Phe Trp Thr Gly Ile Thr Ile Asp Tyr 1 5 10 15 <210> 289 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 289 Cys Ser Tyr Ala Gly Ser Tyr Thr Phe Val Leu 1 5 10 <210> 290 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 290 Ala Arg Asp Gly Gly Thr Val Ser Asp Gly Leu Asp Val 1 5 10 <210> 291 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 291 Gln Gln Thr Phe Ser Ile Trp Thr 1 5 <210> 292 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 292 Ala Arg Val Val Trp Tyr Ser Ser Ser Ser His Leu Phe Asp Tyr 1 5 10 15 <210> 293 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 293 Gly Thr Trp Asp Ser Ser Leu Ser Ala Gly Lys Val 1 5 10 <210> 294 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 294 Ala Arg Ile Lys Ser Asp Ala Phe Asp Leu 1 5 10 <210> 295 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 295 Phe Ser Tyr Ala Gly Ser Asn Asn Tyr Val 1 5 10 <210> 296 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 296 Ala Lys Phe Pro Leu Arg Asp Gly Gly Ser Gly Glu Gly Phe Asp Tyr 1 5 10 15 <210> 297 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 297 Met Gln Ala Ser Gln Phe Pro Leu Thr 1 5 <210> 298 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 298 Ala Arg Asn Thr Tyr Tyr Asp Arg Arg Arg Thr Phe Asp Tyr 1 5 10 <210> 299 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 299 Gln Gln Tyr Asp Asn Leu Pro Pro Val Thr 1 5 10 <210> 300 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 300 Ala Gly Val Gly Ile Thr Gly Thr Thr Gly Ile Asp Tyr 1 5 10 <210> 301 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 301 Gln Ala Trp Asp Ser Ser Thr Asp Val Val 1 5 10 <210> 302 <211> 18 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 302 Ala Lys Gly Ala Ala Ala Gly Pro Phe Pro Tyr Phe Tyr Tyr Ala Met 1 5 10 15 Asp Val <210> 303 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 303 Gln Lys Tyr Gln Ser Ala Pro Pro Thr 1 5 <210> 304 <211> 125 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 304 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser Ser Gly 20 25 30 Phe Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Ser Met Tyr Gln Ser Gly Ile Thr Tyr Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Ser Gln Phe Ser 65 70 75 80 Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Asn Ala Pro Glu Asn Tyr Tyr Gly Ser Gly Arg Glu Ser Phe 100 105 110 Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 125 <210> 305 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 305 Gln Val Gln Leu Gln Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Asn Arg Gly Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp His Gly Gly Lys Tyr Gly Trp Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 306 <211> 125 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 306 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser Ser Gly 20 25 30 Phe Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Ser Met Tyr His Ser Gly Ile Thr Tyr Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Asn Ala Pro Glu Asn Tyr Tyr Gly Ser Gly Arg Glu Ser Phe 100 105 110 Asp Ile Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 307 <211> 126 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 307 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Pro Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Leu Ile Arg Phe Asp Gly Thr Ile Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Glu Val Gly Ala Glu Tyr Leu Tyr Tyr His Tyr Gly 100 105 110 Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 308 <211> 124 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 308 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ser His 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Thr Lys Lys Tyr Phe Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Ser Ser Thr Ser Trp Tyr Gln Val Val Tyr His Ile Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 309 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 309 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Gly Gly Gly Asp Ser Thr Asn Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Asn Thr Leu Tyr 65 70 75 80 Leu Gln Leu Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Leu Ala Val Ser Thr Pro Arg Tyr Trp Phe Asp Ser Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 310 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 310 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Asn Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Phe Ser Gly Ser Gly Gly Ser Ala Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Arg Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Met Ala Val Ser Val His Arg Gly Trp Phe Asp Asp Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 311 <211> 126 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 311 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Met Arg Phe Asp Gly Thr Lys Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Asp Leu Glu Val Gly Ala Glu Tyr Ile Tyr Tyr Tyr Tyr Gly 100 105 110 Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 312 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 312 Gln Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Asp 20 25 30 Tyr Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Tyr 35 40 45 Ile Gly Glu Ile Tyr His Thr Gly Ser Thr Asn Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Val Ser Leu Asp Arg Ser Lys Asn Val Phe Ser 65 70 75 80 Leu Thr Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser His Trp Arg Ser Pro Gln Ser Val Thr Phe Asp Leu Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 313 <211> 123 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 313 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Thr Ser Ser 20 25 30 Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Asp Ile Tyr His Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn His Phe Ser 65 70 75 80 Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Ala Ala Gly Tyr Ser Thr Ser Trp Tyr Tyr Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 314 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 314 Glu Val Gln Leu Val Glu Thr Gly Ser Gly Leu Val Arg Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Asp Ser Ile Ser Ser Asn 20 25 30 Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Ile Asp Lys Ser Asn Asn His Phe Ser 65 70 75 80 Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Met Trp Ala Gly Thr Thr Thr Asn Trp Phe Gly Pro Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 315 <211> 118 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 315 Gln Val Thr Leu Lys Glu Ser Gly Gly Ala Leu Val Lys Pro Ala Gly 1 5 10 15 Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Ser Ser Ile Tyr Tyr Thr Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Phe Ser Ser Arg Pro Phe Asp Leu Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 316 <211> 123 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 316 Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser 20 25 30 Asp Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Ser Tyr Asn Pro Ser Val 50 55 60 Lys Ser Arg Val Ser Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Gln Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Val Asn Pro Pro Gln Tyr Ser Ser Gly Trp Tyr Ser Val Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 317 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 317 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Asp Ser Ile Ser Ser Ser 20 25 30 His Trp Trp Cys Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Val Ala Trp Thr Ser Ser Ser Ser Cys Tyr Tyr Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 318 <211> 125 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 318 Glu Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser 20 25 30 Tyr Trp Trp Ser Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Glu Val Tyr His Ser Gly Ser Thr His Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Glu Gly His Tyr Tyr Arg Ser Gly Asp Asn Trp Phe 100 105 110 Asp Arg Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 319 <211> 120 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 319 Glu Val Gln Leu Leu Glu Ser Gly Pro Gly Leu Val Gln Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Gly Ser Ile Ser Ser Ser 20 25 30 Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Asp Ile Tyr His Thr Gly Ser Thr Ser Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Glu Leu Ser Ala Trp Tyr Tyr Phe Asp His Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 320 <211> 126 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 320 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Ser Asp Tyr 20 25 30 Tyr Met Asn Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Val 35 40 45 Ser Thr Ile Ser Gly Ser Gly Lys Ser Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Ser Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ser Pro Leu Asp Asp Gly Tyr Gly Tyr Thr Tyr Tyr Gly 100 105 110 Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 321 <211> 123 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 321 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Thr Ser Ser Gly Asn Thr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Ile Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Trp Ala Glu Leu Thr Thr Ile Thr Asn Tyr Phe Tyr Pro 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 322 <211> 129 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 322 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Gly Gly Gly Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Ala Glu Asn Arg Ile Gly Tyr Cys Ser Ala Gly Ser Cys Tyr 100 105 110 Leu Thr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 115 120 125 Ser <210> 323 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 323 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu His 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Pro Lys Tyr Ser Ser Gly Trp Trp Ala Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 324 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 324 Glu Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Asn 20 25 30 Lys Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Ser Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Glu Trp Ala Tyr Ser Ser Ser Trp Trp Leu Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 325 <211> 127 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 325 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Asp 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Gly Ser Gly Arg Ala Met Tyr Tyr Ala Asp Ser Val 50 55 60 Gln Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe 65 70 75 80 Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys His Thr Gly Asp Lys Pro Leu Val Trp Ala Pro Ser Val Tyr 100 105 110 Gly Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 326 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 326 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Ser Ser Ile Thr Ser Ser 20 25 30 His Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Ala Trp 35 40 45 Ile Gly Asp Ile Tyr His Ser Gly Gly Thr Thr Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ser Val Ser Thr Ser Ala Trp Tyr Ala Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 327 <211> 117 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 327 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Asn Asn Tyr 20 25 30 Tyr Met Arg Trp Met Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gln Ile Ser Ser Ser Gly Ser Ile Lys Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Leu Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Glu Leu Ser Ser Arg Ile Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 328 <211> 124 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 328 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Leu Arg Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ser Trp Tyr Asp Gly Ser Asn Lys His Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gln Asp Gly Gln Gln Leu Val Asn Tyr Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 329 <211> 127 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 329 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Asp Tyr Gly Asp Tyr Glu Ser Asn Asn Pro Ala Glu 100 105 110 Tyr Phe Gln His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 330 <211> 120 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 330 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Ser Val Ser 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Phe Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Asn Ser Gly Asn Ala Asn Tyr Asn Pro Ser Leu Glu 50 55 60 Ser Arg Val Thr Ile Ser Ile Asp Thr Ser Lys Asn Arg Phe Ser Leu 65 70 75 80 Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Gly His Arg Glu Asp Pro Tyr Gly Ala Tyr Gly Ala Ser Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 331 <211> 123 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 331 Glu Val Gln Leu Leu Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Leu Ser Ser Asp 20 25 30 Ser His Phe Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Asn Ala Asn Tyr Asn Pro Ser 50 55 60 Leu Gln Ser Arg Val Thr Ile Ser Leu Asp Lys Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Arg Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Ser Arg Lys Glu Val Arg Gly Thr Glu Asp Tyr Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 332 <211> 123 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 332 Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Asp Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Arg Gln Phe 65 70 75 80 Ser Leu Arg Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Lys Val Glu Glu Asp Gly Tyr Thr Asn Val Val Arg Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 333 <211> 117 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 333 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Cys Ile 35 40 45 Ala Cys Ile Ser Ser Ser Gly Ser Met Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Leu Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Thr Arg Gly Arg Met Asp Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 334 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 334 Glu Val Gln Leu Leu Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Thr Thr 20 25 30 Asp Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Glu Ile Asn Gln Ser Gly Ser Thr Ser Tyr Ser Pro Ser Phe 50 55 60 Lys Ser Arg Val Ser Ile Ser Val Asp Lys Ser Lys Arg Gln Phe Ser 65 70 75 80 Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Trp Ser Gly Pro Thr Arg Asn Trp Phe Asp Pro Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 335 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 335 Glu Val Gln Leu Leu Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Glu Ile Tyr His Ser Gly Ser Ala Asn Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Val Trp Glu Tyr Ser Asn Ala Trp Cys Val Asp Phe Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 336 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 336 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Thr Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ala Val Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Asn Thr Tyr Tyr Asp Arg Ser Gly Leu Ile Ala Tyr Trp Gly 100 105 110 Gln Gly Ala Leu Val Thr Val Ser Ser 115 120 <210> 337 <211> 120 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 337 Gln Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Asp Ser Ile Ser Ser Thr 20 25 30 Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Tyr 35 40 45 Ile Gly Glu Ile Phe His Ser Gly Ser Thr Asn Tyr Asn Pro Phe Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn His Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Pro Leu Lys Ser Tyr Trp Tyr Phe Asp Leu Trp Gly Arg 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 338 <211> 124 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 338 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Asn 20 25 30 Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Asp Thr Tyr His Ser Gly Ser Pro Ser Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Glu Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Tyr Cys Ser Gly Ala Thr Cys Tyr Gly Ser Asn Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 339 <211> 120 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 339 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Tyr Asp Arg Ser Asn Lys Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Gln Cys Gly Gly Asp Cys Thr Ala Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 340 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 340 Glu Val Gln Leu Leu Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Ala Ser Ile Ser Ser Asn 20 25 30 His Trp Trp Thr Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Glu Ile Tyr His Ser Gly Ser Pro Thr Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Thr Leu Trp Gly Gly Pro Leu Ser Val Ala Ser Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 341 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 341 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ser 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val 35 40 45 Ala Leu Ile Ser Tyr Thr Gly Glu Thr Lys Tyr Tyr Ser Asp Ser Leu 50 55 60 Lys Ala Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Ser Asn Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Tyr Tyr Ala Ser Gly Asp Gly Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 342 <211> 124 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 342 Gln Val Gln Leu Gln Gln Trp Gly Pro Glu Leu Val Lys Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ile 20 25 30 Ser Trp Trp Ser Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Glu Ile Asn His Ser Gly Ser Thr Val Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Lys Gln Phe Ser 65 70 75 80 Leu Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Tyr Cys Ser Ser Thr Ser Cys Tyr Gly Leu Asn Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 343 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 343 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Asn Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Asn Thr Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Ser 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Ser Leu Val Asn Ala Ile Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 344 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 344 Glu Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Thr Gly Ser 20 25 30 Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Glu Ile Tyr His Thr Gly Ser Thr Ser Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Asn Ser Lys Asn His Phe Ser 65 70 75 80 Leu Arg Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Arg Trp Ser Gly Ser Thr Ser Trp Asp Leu Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 345 <211> 131 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 345 Glu Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Leu Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala His Ser Pro Arg Arg Ile Thr Met Val Arg Gly Val Ile Ile 100 105 110 Thr Trp Gly Asp Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr 115 120 125 Val Ser Ser 130 <210> 346 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 346 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Thr Ser Ser Gly Asn Thr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Asp Gly Ser Met Val Asn Ala Ile Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 347 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 347 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ser 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Trp Tyr Asp Glu Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ala Tyr Ala Ser Gly Asp Gly Gly Ile Asp Tyr Trp Gly 100 105 110 Gln Gly Ala Leu Val Thr Val Ser Ser 115 120 <210> 348 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 348 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Ser Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Leu Arg Gly Val Gly Gly Trp Tyr Tyr Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 349 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 349 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ile Asn Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Asn Gly Asp Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Leu Ser Arg Asp Asn Ala Lys Asn Thr Ile Tyr 65 70 75 80 Leu His Met Ser Ala Leu Arg Asp Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Gln Gly Val Thr Thr Asp Trp Pro Ser Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 350 <211> 126 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 350 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser His Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Ile Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Pro Arg Asp Gly Leu Pro Gly Ala Asn Gln Tyr Phe Phe Tyr Tyr Gly 100 105 110 Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 351 <211> 123 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 351 Glu Val Gln Leu Leu Glu Ser Gly Pro Arg Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Arg Gly Gly 20 25 30 Ser His Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Val Tyr Asp Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Ser Ile Ser Val Asp Met Ser Lys Lys Gln Phe 65 70 75 80 Ser Leu Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr His 85 90 95 Cys Val Arg Val Glu Glu Tyr Val Asn Asn Glu Glu Val Arg Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 352 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 352 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Pro Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Leu Ser Arg Asp Thr Ser Lys Lys Met Val Tyr 65 70 75 80 Leu His Met Ser Asn Leu Arg Asp Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gln Gly Phe Thr Thr Asp Trp Pro Cys Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 353 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 353 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Thr Ser Ser Gly Asn Thr Met Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Asn Phe Asn Ser Asn Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 354 <211> 120 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 354 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser 20 25 30 Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Thr Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Pro Leu Lys Thr Tyr Trp Tyr Phe Asp Leu Trp Gly Arg 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 355 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 355 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Asn Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Leu Asn Ser Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Asn Tyr Phe Tyr Gly Leu Asp Val Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <210> 356 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 356 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Val Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Cys Ser Gly Asp Cys Gly Gly Gly Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 357 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 357 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Asn Thr Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Thr Tyr Asn Gly Asn Thr Val Phe Gly Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Leu Ser Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Asp Asp Asp Tyr Tyr Ser Met Asp Val Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <210> 358 <211> 129 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 358 Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ile Ser Cys Ile Ser Thr Ser Cys Tyr Gly Gly Tyr Tyr 100 105 110 Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser 115 120 125 Ser <210> 359 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 359 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ser 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Ser Arg Asn Gln Asn Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Tyr Tyr Ala Ser Gly Asp Gly Ser Ile Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 360 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 360 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Phe Ser Gly Arg Gly Gly Ser Thr Tyr Tyr Ala Asp Phe Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 361 <211> 120 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 361 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Gly Gly Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Lys Lys Tyr Ser Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Ser Val Ser Val Ala Gly Ala Glu Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 362 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 362 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Ala Glu Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Trp Asn Ser Gly Arg Ile Gly Tyr Val Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Phe Tyr Tyr Cys 85 90 95 Ala Lys Gly Tyr Asp Ser Ser Gly Tyr Tyr Trp Ala Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 363 <211> 120 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 363 Glu Val Gln Leu Leu Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Leu Ile 35 40 45 Gly Arg Ile Tyr Thr Ser Gly Ser Gly Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Arg Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Ile Ser Leu 65 70 75 80 Arg Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Arg Gly Gly Tyr Phe Thr Glu Pro Phe Asp Ile Trp Gly Gln 100 105 110 Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 364 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 364 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val His Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser His Ile Ser Ser Ser Gly Asn Ile Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asp Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Thr Ile Phe Gly Val Val Ser Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 365 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 365 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ala Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Asp Arg Arg Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 366 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 366 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp His 20 25 30 Tyr Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Asn Lys Pro Asn Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg His Asp Ser Glu Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Cys Arg Glu Ser Gly Glu Gly Phe Asp Pro Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 367 <211> 133 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 367 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Gly Tyr Ser Gly Asp Thr Asn Tyr Ala Gln Lys Val 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gln Ser His Gly Thr Phe Gly Gly Val Ile Asp Ser Thr 100 105 110 Thr Leu Phe Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr 115 120 125 Val Thr Val Ser Ser 130 <210> 368 <211> 127 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 368 Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser 20 25 30 Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Gly Tyr Cys Ser Ser Thr Ser Cys Phe Tyr Tyr Tyr Tyr 100 105 110 Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 369 <211> 129 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 369 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser His Ser Gly Arg Tyr Ile Tyr Tyr Ala Asp Ser Glu 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp His Tyr Phe Asp Ser Ser Gly Asp Tyr Leu Ser Tyr Tyr 100 105 110 Tyr Asn Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser 115 120 125 Ser <210> 370 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 370 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp His 20 25 30 Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Thr Arg Asn Lys Pro Asn Ser His Thr Thr Glu Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Gln Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Val Tyr Gly Gly Pro Asp Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 371 <211> 123 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 371 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Tyr Thr Asn Tyr 20 25 30 Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Lys Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Gly Val Thr Thr Ile Asn Gly Trp Phe His Phe Glu Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 372 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 372 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Ser Asp Tyr 20 25 30 Tyr Met Asp Trp Val Arg Gln Thr Pro Gly Lys Gly Pro Glu Trp Val 35 40 45 Gly Arg Ile Thr Asn Arg Pro Asn Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Thr Asn Ser 65 70 75 80 Leu Phe Leu His Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Thr Arg Ile Thr Gly Asp Arg Tyr Trp Tyr Leu Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 373 <211> 128 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 373 Glu Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Arg Ile Tyr Thr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Gly Trp Phe Gly Tyr Ser Asn Tyr Gly Leu Tyr Tyr Tyr 100 105 110 Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 374 <211> 120 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 374 Glu Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser 20 25 30 Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Glu Ile Tyr His Ser Glu Ser Thr Asn Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Phe Trp Ser Gly Ser Asn Trp Phe Asp Pro Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 375 <211> 132 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 375 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Gly Asp Ser Tyr Gly Ser Gly Ser Tyr Tyr Leu Pro 100 105 110 Tyr Gly Ala Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val 115 120 125 Thr Val Ser Ser 130 <210> 376 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 376 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Thr Gly Arg Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Arg Ser Ser Gly Gly Arg Thr Glu Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys His Tyr Asp Ser Ser Gly Tyr Tyr Tyr Glu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 377 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 377 Glu Val Gln Leu Val Glu Ser Gly Gly Ala Leu Val His Pro Gly Gly 1 5 10 15 Ser Leu Gly Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp His 20 25 30 Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Asn Lys Pro Asn Ser Tyr Ala Thr Gln Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Lys Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Asn Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Val Arg Asp Gly Glu Tyr Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 378 <211> 130 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 378 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Ser Arg Ser Ser Phe Met Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Asn Ser Glu Val Glu Asp Tyr Gly Asp Tyr Val Leu Tyr 100 105 110 His Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val 115 120 125 Ser Ser 130 <210> 379 <211> 120 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 379 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Leu Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Gln Cys Gly Gly Asp Cys Thr Ala Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 380 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 380 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Leu 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Tyr Asp Val Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Tyr Thr Gly Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 381 <211> 125 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 381 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Pro Tyr Tyr Tyr Gly Ser Arg Arg Pro Ala Gly His Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 382 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 382 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ala Ile Ser Ser Gly 20 25 30 Asp Tyr Tyr Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile His Tyr Ser Gly Thr Thr Tyr Asn Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ala Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe 85 90 95 Cys Gly Arg Asp Ser Asp Lys Asn Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 383 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 383 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Arg Phe Asp Gly Ser Asn Thr Val Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Thr Tyr Asp Ser Asn Ala Tyr Tyr Tyr Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 384 <211> 125 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 384 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Trp 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Tyr Lys Trp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Leu Trp Phe Ile Val Met Thr Met Ser Lys Asn Pro Glu Thr 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 385 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 385 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser His 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Gln Trp Val 35 40 45 Ser Ser Ile Arg Gly Ser Asp Arg Thr Thr Asn Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Lys Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Phe Asp His Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 386 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 386 Glu Val Gln Leu Val Glu Ser Gly Gly Thr Phe Leu Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Gly Thr His 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Phe Ser Gly Ser Gly Gly Arg Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Thr Leu Tyr 65 70 75 80 Leu Glu Met Ser Ala Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Phe Tyr Asp Ser Ser Gly Tyr Tyr Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 387 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 387 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Gly Ile Arg Asn Lys Pro Asn Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser 65 70 75 80 Leu Phe Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg Leu Tyr Gly Asp Tyr Val Ala Tyr Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 388 <211> 128 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 388 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Gly Thr Thr Val Thr Arg Phe Gly Val Ile Gln Tyr Tyr 100 105 110 Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 389 <211> 117 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 389 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Ala Ser Ile Arg Ser Tyr 20 25 30 Leu Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Glu Leu Glu Trp Leu 35 40 45 Gly Ser Ile Tyr His Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Ala Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Phe Tyr Cys Ala 85 90 95 Arg Glu Thr Ala Asn Asn Trp Phe Asp Pro Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 390 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 390 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ser Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Asn 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Leu Tyr Asp Gly Ser Asn Gln Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Ser Met Met Pro Arg Pro Pro Val His Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 391 <211> 123 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 391 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Arg Ser Gln Gly Asp Tyr Gly Asp Tyr Val Ala Asp Tyr 100 105 110 Trp Ser Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 392 <211> 125 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 392 Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser 20 25 30 Asn Trp Trp Thr Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu 50 55 60 Glu Ser Arg Val Thr Met Ser Val Asp Lys Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gln Thr Ser His Ser Glu Leu Trp Phe Gly Glu Phe Gly 100 105 110 Ala Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 393 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 393 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Tyr Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Gly Ser Gly Asp Ser Thr Tyr Asn Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Gly Gly Tyr Ser Thr Asp Trp Tyr Phe Asp Leu Trp Gly 100 105 110 Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 394 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 394 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Lys Lys Tyr Phe Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Ser Cys 85 90 95 Ala Lys Gly Tyr Asp Ser Asn Gly Tyr Tyr Tyr Ile Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Pro Val Thr Val Ser Ser 115 120 <210> 395 <211> 123 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 395 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Val Gly Tyr Gln Leu Leu Gln Val Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 396 <211> 129 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 396 Glu Val Gln Leu Leu Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Thr Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe 85 90 95 Cys Ala Arg Ala Glu Tyr Asp Thr Ser Gly Tyr Tyr Gln Gln Arg Leu 100 105 110 Pro Glu Tyr Phe Gln His Trp Gly Gln Gly Thr Leu Val Thr Val Ser 115 120 125 Ser <210> 397 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 397 Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Arg Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Met Asn His Ser Gly Asp Arg Thr Asn Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Phe His Ser Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 398 <211> 120 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 398 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Ser Asp His 20 25 30 Tyr Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ser Arg Asn Arg Pro Asn Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55 60 Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Thr Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Glu His Gly Asp Tyr Gly Leu Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 399 <211> 124 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 399 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Tyr Val Asp Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Ser Pro Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 400 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 400 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Phe Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Ser Asp Tyr 20 25 30 Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Asn Lys Pro Asn Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Leu Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Glu Tyr 85 90 95 Tyr Cys Ala Arg Val Asp Gly Glu Glu Val Ala Leu Ile Tyr Trp Gly 100 105 110 Gln Gly Ala Leu Val Thr Val Ser Ser 115 120 <210> 401 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 401 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Gly Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Lys Phe Thr Phe Ser Asp His 20 25 30 Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Asn Lys Pro Asn Gly Tyr Thr Thr Glu Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Asp Ser Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Lys Ser Leu Lys Ile Glu Asp Thr Ala Ile Tyr 85 90 95 Tyr Cys Val Arg Val Trp Gly Gly Glu Ala Ala Arg Tyr Asp Tyr Trp 100 105 110 Gly Gln Gly Ala Leu Val Thr Val Ser Ser 115 120 <210> 402 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 402 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp His 20 25 30 Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ser Arg Asn Lys Pro Asn Ser Tyr Ile Thr Glu Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ser Arg His Met Gly Phe Gly Leu Asp Leu Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 403 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 403 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Tyr Tyr Gly Ser Gly Asp Gly Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 404 <211> 124 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 404 Glu Val Gln Leu Val Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Arg Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Thr 20 25 30 Lys Leu Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala His Ile Phe Ser Asn Ala Glu Lys Ser Ser Ser Lys Ser 50 55 60 Leu Lys Ser Arg Leu Ser Ile Ser Gln Asp Thr Ser Lys Ser Leu Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Phe 85 90 95 Cys Ala Arg Ile Pro Val Glu Tyr Gly Thr Pro Arg Gly Ser Phe Asp 100 105 110 Thr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 405 <211> 114 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 405 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Ser Thr Tyr 20 25 30 Thr Leu His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Ser Asp Gly Gly Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Gly Gly Ser Pro Asp Tyr Trp Gly Gln Gly Ala Leu Val Thr Val 100 105 110 Ser Ser <210> 406 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 406 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg ...

Claims

1. An isolated antibody or antigen-binding fragment thereof that specifically binds to a yellow fever virus (YFV) protein, wherein the antibody comprises a heavy chain variable region as shown in SEQ ID NO: 308 and a light chain variable region as shown in SEQ ID NO:

460.

2. An isolated antibody or antigen-binding fragment thereof that specifically binds to a yellow fever virus (YFV) protein, wherein the antibody comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, wherein: The amino acid sequence of CDRH1 is FTFNSHGMH, The amino acid sequence of CDRH2 is VISYDGTKKYFADSVKG, The amino acid sequence of CDRH3 is AKDSSTSWYQVVYHIDY, The amino acid sequence of CDRL1 is SGSSSNIGNNYVA, The amino acid sequence of CDRL2 is DNKKRPS, and The amino acid sequence of CDRL3 is ETWDSSLNAVV.

3. The isolated antibody or antigen-binding fragment thereof according to claim 1 or 2, wherein: a) The isolated antibody or antigen-binding fragment thereof exhibits neutralizing activity against YFV in vitro; and / or b) The isolated antibody or antigen-binding fragment thereof binds to the envelope protein of YFV.

4. The isolated antibody or antigen-binding fragment thereof according to claim 3, wherein the isolated antibody or antigen-binding fragment thereof exhibits an in vitro neutralizing potency IC of 0.5 µg / ml to 5 µg / ml against YFV 50 .

5. The isolated antibody or antigen-binding fragment thereof according to claim 3, wherein the isolated antibody or antigen-binding fragment thereof exhibits an in vitro neutralizing potency IC of 0.05 µg / ml to 0.5 µg / ml against YFV 50 .

6. The isolated antibody or antigen-binding fragment thereof according to claim 3, wherein the isolated antibody and antigen-binding fragment exhibit an in vitro neutralizing potency IC against YFV of less than 0.05 mg / ml 50 .

7. The isolated antibody or antigen-binding fragment thereof according to claim 3, wherein the antibody exhibits an equilibrium dissociation constant of 1×10 -6 M to 1×10 -10 M.

8. A pharmaceutical composition comprising: one or more isolated antibodies or antigen-binding fragments thereof according to any one of claims 1-7, and a pharmaceutically acceptable excipient.

9. Use of an isolated antibody or antigen-binding fragment thereof in the preparation of a drug for treating or preventing yellow fever virus (YFV) infection or at least one symptom caused thereby, wherein the antibody or antigen-binding fragment thereof specifically binds to a YFV protein, and wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region as shown in SEQ ID NO: 308 and a light chain variable region as shown in SEQ ID NO:

460.

10. Use of an isolated antibody or antigen-binding fragment thereof in the preparation of a drug for treating or preventing yellow fever virus (YFV) infection or at least one symptom caused thereby, wherein the antibody or antigen-binding fragment thereof specifically binds to a YFV protein, and wherein the antibody or antigen-binding fragment thereof comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, wherein: The amino acid sequence of CDRH1 is FTFNSHGMH, The amino acid sequence of CDRH2 is VISYDGTKKYFADSVKG, The amino acid sequence of CDRH3 is AKDSSTSWYQVVYHIDY, The amino acid sequence of CDRL1 is SGSSSNIGNNYVA, The amino acid sequence of CDRL2 is DNKKRPS, and The amino acid sequence of CDRL3 is ETWDSSLNAVV.

11. The use according to claim 9 or 10, wherein at least one symptom associated with YFV infection is treated, improved, or the severity is reduced.

12. Use according to any one of claims 9-11, wherein at least one symptom associated with YFV infection is fever, chills, headache, low back pain, myalgia, loss of appetite, nausea, vomiting or fatigue.

13. Use according to any one of claims 9-12, wherein the isolated antibody or antigen-binding fragment thereof: (a) exhibits neutralizing activity against YFV in vitro; and / or (b) binds to the envelope protein of YFV.

14. Use according to claim 13, wherein the isolated antibody or antigen-binding fragment thereof exhibits an in vitro neutralizing potency IC of 0.5 µg / ml to 5 µg / ml against YFV 50 .

15. Use according to claim 13, wherein the isolated antibody or antigen-binding fragment thereof exhibits an in vitro neutralizing potency IC of 0.05 µg / ml to 0.5 µg / ml against YFV 50 .

16. The use according to claim 13, wherein the isolated antibody or antigen-binding fragment thereof exhibits an in vitro neutralization potency IC against YFV of less than 0.05 mg / ml 50 .

17. Use according to any one of claims 9-16, wherein the isolated antibody or antigen-binding fragment thereof exhibits an equilibrium dissociation constant of 1×10 -6 M to 1×10 -10 M.

18. Use of an isolated nucleic acid in the preparation of a medicament for the treatment or prevention of yellow fever virus (YFV) infection or at least one symptom caused thereby, wherein the isolated nucleic acid encodes an antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof specifically binds to a YFV protein, and wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region as shown in SEQ ID NO: 308 and a light chain variable region as shown in SEQ ID NO:

460.

19. Use of an isolated nucleic acid in the preparation of a medicament for the treatment or prevention of yellow fever virus (YFV) infection or at least one symptom caused thereby, wherein the isolated nucleic acid encodes an antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof specifically binds to a YFV protein, and wherein the antibody or antigen-binding fragment thereof comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3, wherein: The amino acid sequence of CDRH1 is FTFNSHGMH, The amino acid sequence of CDRH2 is VISYDGTKKYFADSVKG, The amino acid sequence of CDRH3 is AKDSSTSWYQVVYHIDY, The amino acid sequence of CDRL1 is SGSSSNIGNNYVA, The amino acid sequence of CDRL2 is DNKKRPS, and The amino acid sequence of CDRL3 is ETWDSSLNAVV.

20. Use according to claim 18 or 19, wherein at least one symptom associated with YFV infection is fever, chills, headache, low back pain, myalgia, loss of appetite, nausea, vomiting or fatigue.

21. Use of a pharmaceutical composition in the preparation of a medicament for the treatment or prevention of yellow fever virus (YFV) infection or at least one symptom caused thereby, wherein the pharmaceutical composition comprises an isolated antibody or antigen-binding fragment thereof and a pharmaceutically acceptable excipient, wherein the antibody or antigen-binding fragment thereof specifically binds to a YFV protein, and wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region as shown in SEQ ID NO: 308 and a light chain variable region as shown in SEQ ID NO:

460.

22. Use of a pharmaceutical composition in the preparation of a medicament for the treatment or prevention of yellow fever virus (YFV) infection or at least one symptom caused thereby, wherein the pharmaceutical composition comprises an isolated antibody or antigen-binding fragment thereof and a pharmaceutically acceptable excipient, wherein the antibody or antigen-binding fragment thereof specifically binds to a YFV protein, and wherein the antibody or antigen-binding fragment thereof comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, wherein: the amino acid sequence of CDRH1 is FTFNSHGMH, the amino acid sequence of CDRH2 is VISYDGTKKYFADSVKG, the amino acid sequence of CDRH3 is AKDSSTSWYQVVYHIDY, the amino acid sequence of CDRL1 is SGSSSNIGNNYVA, the amino acid sequence of CDRL2 is DNKKRPS, and the amino acid sequence of CDRL3 is ETWDSSLNAVV.

23. The use according to claim 21 or 22, wherein at least one symptom associated with YFV infection is fever, chills, headache, low back pain, myalgia, anorexia, nausea, vomiting, or fatigue.

24. Use of a pharmaceutical composition in the preparation of a medicament for treating or preventing yellow fever virus (YFV) infection or at least one symptom caused thereby, wherein the pharmaceutical composition comprises an isolated nucleic acid encoding an antibody or antigen-binding fragment thereof and a pharmaceutically acceptable excipient, wherein the antibody or antigen-binding fragment thereof specifically binds to a YFV protein, and wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region as shown in SEQ ID NO: 308 and a light chain variable region as shown in SEQ ID NO:

460.

25. Use of a pharmaceutical composition in the preparation of a medicament for treating or preventing yellow fever virus (YFV) infection or at least one symptom caused thereby, wherein the pharmaceutical composition comprises an isolated nucleic acid encoding an antibody or antigen-binding fragment thereof and a pharmaceutically acceptable excipient, wherein the antibody or antigen-binding fragment thereof specifically binds to a YFV protein, and wherein the antibody or antigen-binding fragment thereof comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, wherein: the amino acid sequence of CDRH1 is FTFNSHGMH, the amino acid sequence of CDRH2 is VISYDGTKKYFADSVKG, the amino acid sequence of CDRH3 is AKDSSTSWYQVVYHIDY, the amino acid sequence of CDRL1 is SGSSSNIGNNYVA, the amino acid sequence of CDRL2 is DNKKRPS, and the amino acid sequence of CDRL3 is ETWDSSLNAVV.

26. The use according to claim 24 or 25, wherein at least one symptom associated with YFV infection is fever, chills, headache, low back pain, myalgia, anorexia, nausea, vomiting, or fatigue.

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