CLEC9A-based chimeric protein complex

Abstract

The present invention relates in part to chimeric protein complexes and their use as therapeutic agents, the chimeric protein complexes comprising an anti-Clec9A targeting moiety, a modified Fc domain, and a modified human IFNα. The present invention also relates to pharmaceutical compositions comprising the chimeric protein complexes and the use of the pharmaceutical compositions in the treatment of various diseases.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 906,442, filed on September 26, 2019, and U.S. Provisional Patent Application No. 62 / 825,584, filed on March 28, 2019, the contents of which are hereby incorporated by reference in their entirety. Technical field

[0003] The present invention relates in part to chimeric protein complexes that include a fragment crystallizable domain (Fc), a Clec9A VHH as a targeting moiety, and a modified interferon alpha 2 (IFNα2) as a signaling agent. The use of these chimeric protein complexes as therapeutic agents is also disclosed.

[0004] Sequence listing

[0005] This application contains a sequence listing that has been submitted in ASCII format via EFS - Web, which is hereby incorporated by reference in its entirety. The ASCII copy was created on March 26, 2020, has the name ORN - 063PC_ST25.txt and is 139,264 bytes in size. Background art

[0006] Biological agents with effector functions are a class of biological agents with many potential therapeutic applications. In some cases, these biological agents, such as cytokines, encode an effector function when administered to a human body, and this effector function may cause systemic toxicity. Therefore, it is crucial to maximize the tolerance and therapeutic index of these biological agents in the human body so as to reduce the systemic toxicity of the human body or subject.

[0007] Generally, it is necessary to deliver these biological agents to one or more targets in a subject's body with high precision and in a regulated manner in order to make these biological agents effective. Therefore, there is a need for engineered biomolecules with high inherent safety characteristics, capable of reaching the targets in a subject's body with high precision and capable of functioning in a regulated manner.

[0008] An example of such biological agents is a chimeric protein having a signaling agent (having an effector function, such as a cytokine) linked to a targeting element (capable of finding its target with high precision). In these biological agents, the signaling agent can be a wild - type signaling agent or a modified signaling agent (e.g., by mutation). The modified signaling agent is generally modified to cause a decrease in the activity of the signaling agent (e.g., substantially reducing its ability to interact / bind with its receptor) in such a way that the effector function of the signaling agent can be restored after the targeting element binds to its target (e.g., an antigen on a target cell).

[0009] However, such chimeric proteins are suitable for therapeutic use only when certain conditions are met, such as the ability to be produced on a large scale, an in vivo half-life ensuring sufficient time for exposure to the drug to elicit a therapeutically beneficial effect, an appropriate size to avoid rapid clearance or limited tissue penetration and biodistribution, and other properties ensuring sufficient solubility, stability, and storage characteristics without significant loss of function. Importantly, all or substantially most of the above properties should be achieved without loss of effector function while conditionally targeting and maintaining the conditional engagement of the modified signaling agent with its receptor. Generally, it is difficult to achieve all these goals with a chimeric protein encoded or presented by a single continuous polypeptide chain. There is a need in the art to achieve such desired properties of biologics while maintaining the tolerability and therapeutic index of the biologics. SUMMARY OF THE INVENTION

[0010] The present invention provides a chimeric protein complex that includes a biotherapeutic agent, the effector function of which can be delivered to a selected target in a highly precise manner, with limited or no cross-reactivity and limited or no systemic adverse events, and also provides functions that confer drug-like properties, enabling the production of a therapeutic agent with a desired in vivo exposure time (e.g., half-life), size (e.g., for biodistribution and clearance characteristics), and large-scale production and / or purification scale for commercial production (e.g., with sufficient solubility, stability, and storage characteristics).

[0011] In one aspect, the present invention relates to a heterodimeric protein complex and its individual polypeptide chain subunits (components), and wherein the protein complex includes a targeting moiety that specifically binds to C-type lectin domain family 9 member A (CleC9A), a modified human IFNα2, and a modified Fc domain.

[0012] In one aspect, the present invention relates to a chimeric protein complex comprising: (i) a targeting moiety that specifically binds to C-type lectin domain family 9 member A (CleC9A), (ii) a modified human IFNα2, and (iii) a modified Fc domain.

[0013] In one aspect, the present invention relates to a chimeric protein complex, wherein the chimeric protein complex includes a targeting moiety that specifically binds to C-type lectin domain family 9 member A (CleC9A), a modified human IFNα2, and a modified Fc domain.

[0014] In some embodiments, the chimeric protein complex comprises a polypeptide having at least 95% identity to any one of SEQ ID NOs: 1-4 and 43, or having at least 98% identity to any one of SEQ ID NOs: 1-4 and 43, or having at least 99% identity to any one of SEQ ID NOs: 1-4 and 43. In some embodiments, the chimeric protein complex comprises a polypeptide of any one of SEQ ID NOs: 1-4 and 43, optionally having 0, or 1, or 2, or 3, or 4, or 5 mutations. In some embodiments, the chimeric protein complex comprises a polypeptide of any one of SEQ ID NOs: 1-4 and 43.

[0015] In some embodiments, the chimeric protein complex comprises a polypeptide incorporating a contiguous amino acid sequence having at least 95% identity to any one of SEQ ID NOs: 1-4 and 43, or having at least 98% identity to any one of SEQ ID NOs: 1-4 and 43.

[0016] In another aspect, the present invention relates to a method of treating or preventing cancer, the method comprising administering to a patient in need thereof an effective amount of a chimeric protein complex as disclosed herein.

[0017] Another aspect of the present invention relates to a pharmaceutical composition comprising a chimeric protein complex as disclosed herein and a pharmaceutically acceptable carrier. In another aspect, the present invention relates to a method for treating or preventing cancer, the method comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition as disclosed herein. In another aspect, the present invention relates to a recombinant nucleic acid composition encoding one or more polypeptide chain subunits of the chimeric protein complex as disclosed herein. In another aspect, the present invention relates to a host cell comprising a nucleic acid composition encoding one or more of the chimeric protein complexes as disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Shows various non-limiting illustrative schematics of the chimeric protein complex of the present invention. In multiple embodiments, each schematic is a composition of the present invention. Herein, "IFN" refers to IFNα2 as described herein; "VHH" refers to the anti-Clec9A VHH as described herein. is an optional "linker" as described herein; and the two long parallel rectangles (one with a protrusion and the other with a recess) are the human Fc domain from IgG1 with a knob-into-hole mutation as described herein and optionally with effector knockout and / or stabilization mutations also as described herein. Although SEQ ID Nos are shown, these are illustrative only and will change, for example, if alternative mutations other than R149A as described herein are used.

[0019] Figure 2 The plasma concentration of Fc-AFN after intravenous administration in mice is shown. The mean (+SEM) of 3 individual samples at each time point is plotted.

[0020] Figure 3 The plasma concentration of CLEC9A AFN (Fc-lacking construct) after intravenous administration in mice is shown. The mean (+SEM) of 3 individual samples at each time point is plotted.

[0021] Figures 4A to 4D The specific binding of the CLEC9A-AFN Fc construct to cells expressing human CLEC9A (HL116-hCLEC9a) compared to control cells (HL116 and HEK293T) is shown.

[0022] Figure 5 The tumor growth curves in humanized mice after treatment with buffer or four different CLEC9A-AFN Fc constructs are shown. The mean of 5 animals at each time point (mm 3 )(+SEM) is plotted.

[0023] Figure 6 The tumor growth curves in humanized mice after treatment with buffer or increasing doses of a single CLEC9A-AFN Fc construct are shown. The mean of 5 animals at each time point (mm 3 )(+SEM) is plotted.

[0024] Figure 7 The various bivalent orientations and / or configurations encompassed by the present invention are shown. The second VHH portion that achieves bivalency is shaded and forms an N-terminal or C-terminal extension of the SEQ ID mentioned in the figure together with the linked linker. Although SEQ ID Nos are shown, these are illustrative only and will change, for example, if alternative mutations other than R149A as described herein are used. Additionally, the VHHs can be the same. See Figure 1 the description.

[0025] Figure 8AShows the results of pSTAT1 phosphorylation of IFNa2 in Clec9A- / CD141- and Clec9A+ / CD141+ PBMCs.

[0026] Figure 8B Shows the results of pSTAT1 phosphorylation of AFN with A145G or M148A mutations in Clec9A- / CD141- and Clec9A+ / CD141+ PBMCs.

[0027] Figure 9 Shows the tumor growth curves in humanized mice after treatment with buffer or two different CLEC9A-AFN Fc constructs at a dose of 7.5 μg. The tumor sizes (mm 3 ) of 6 animals at each time point were averaged (+SEM).

[0028] Figures 10A to 10C Shows pSTAT1 activity in CLEC9A- / CD141- and CLEC9A+ / CD141+ PBMCs after treatment with Clec9A-targeted AFN with T106 O-glycosylation in IFNα2 ( Figure 10A ) and Clec9A-targeted AFN without T106 O-glycosylation in IFNα2 ( Figure 10B ) and untargeted variants ( Figure 10C ).

[0029] Figure 11 Shows the anti-tumor activity of Clec9A-targeted AFN Fc with A145G mutation of IFNα2. DETAILED DESCRIPTION

[0030] In one aspect, the present invention relates to a chimeric protein complex, wherein the chimeric protein complex comprises a targeting moiety that specifically binds to C-type lectin domain family 9 member A (Clec9A), a modified human IFNα2, and a modified Fc domain. In various embodiments, the chimeric protein complex comprises a polypeptide having at least 95% identity to any one of SEQ ID NOs: 1-4 and 43. In various embodiments, the chimeric protein complex comprises a polypeptide having at least 98% identity or at least 99% identity to any one of SEQ ID NOs: 1-4 and 43. In various embodiments, the chimeric protein complex comprises the polypeptides of SEQ ID NOs: 1-4 and 43, wherein the sequence has fewer than 10 mutations compared to the selected sequence. In various embodiments, the chimeric protein complex comprises the polypeptides of SEQ ID NOs: 1-4 and 43, wherein the sequence has fewer than 5 mutations compared to the selected sequence.

[0031] In multiple embodiments, the chimeric protein complex comprises a polypeptide having the amino acid sequence SEQ ID NO: 1. This sequence includes a single domain antibody (VHH) against Clec9A (i.e., R1CHCL50 (opt4)), a linker (i.e., 5*GGS), and an Fc hole Ridgway sequence with LALA-KQ mutation (i.e., Fc hole Ridgway (LALA-KQ), see Ridgway et al., Protein Engineering 1996; 9: 617-621, which is incorporated herein by reference in its entirety). Such a construct having the sequence SEQ ID NO: 1 is represented as follows: Variant 1 VHH-Fc R1CHCL50 (opt4)-5*GGS-Fc hole Ridgway (LALA-KQ).

[0032] In multiple embodiments, the chimeric protein complex comprises a polypeptide having the amino acid sequence SEQ ID NO: 2. This sequence includes a single domain antibody (VHH) against Clec9A (i.e., R1CHCL50 (opt4)), a linker (i.e., 5*GGS), and an Fc hole Merchant sequence with LALA-KQ mutation (i.e., Fc hole Merchant (LALA-KQ), see Merchant et al., Nature Biotechnology 1998; 16: 677-681, which is incorporated herein by reference in its entirety). Such a construct having SEQ ID NO: 2 is represented as follows: VHH-Fc: R1CHCL50 (opt4)-5*GGS-Fc hole Merchant (LALA-KQ).

[0033] In multiple embodiments, the chimeric protein complex comprises a polypeptide having the amino acid sequence SEQ ID NO: 3. This sequence includes a single domain antibody (VHH) against Clec9A (i.e., 3LEC89 (opt4)), a linker (i.e., 5*GGS), and an Fc hole Ridgway sequence with LALA-KQ mutation (i.e., Fc hole Ridgway (LALA-KQ), see Ridgway et al., Protein Engineering 1996; 9: 617-621, which is incorporated herein by reference in its entirety). Such a construct having SEQ ID NO: 3 is represented as follows: VHH-Fc: 3LEC89 (opt4)-5*GGS-Fc hole Ridgway (LALA-KQ).

[0034] In multiple embodiments, the chimeric protein complex comprises a polypeptide having the amino acid sequence SEQ ID NO:4. This sequence includes a single-domain antibody (VHH) against Clec9A (i.e., 3LEC89(opt4)), a linker (i.e., 5*GGS), and an Fc pore Merchant sequence with a LALA-KQ mutation (i.e., Fc pore Merchant (LALA-KQ), see Merchant et al., Nature Biotechnology 1998; 16:677-681, which is incorporated herein by reference in its entirety). This construct with SEQ ID NO:4 is represented as: VHH-Fc: 3LEC89(opt4)-5*GGS-Fc pore Merchant (LALA-KQ).

[0035] In multiple embodiments, the chimeric protein complex comprises a polypeptide having the amino acid sequence SEQ ID NO:43. This sequence includes a single-domain antibody (VHH) against Clec9A (i.e., R1CHCL50(opt4)), a linker (i.e., 5*GGS), and an Fc pore Merchant sequence with a LALA-KQ mutation and no C-terminal lysine (i.e., Fc pore Merchant (LALA-KQ), see Merchant et al., Nature Biotechnology 1998; 16:677-681, which is incorporated herein by reference in its entirety).

[0036] The chimeric protein complex of the present invention may also include an amino acid sequence having at least 95% identity to any one of SEQ ID NOs: 5-8, 29-36, or 41-42. In multiple embodiments, the chimeric protein complex comprises a polypeptide having an amino acid sequence having at least 98% identity to any one of SEQ ID NOs: 5-8, 29-36, or 41-42 or having at least 99% identity to any one of SEQ ID NOs: 5-8, 29-36, or 41-42. In multiple embodiments, the chimeric protein complex comprises a polypeptide having an amino acid sequence selected from SEQ ID NOs: 5-8, 29-36, or 41-42, wherein the sequence has fewer than 10 mutations compared to the selected sequence. In multiple embodiments, the chimeric protein complex comprises a polypeptide having an amino acid sequence selected from SEQ ID NOs: 5-8, 29-36, or 41-42, wherein the sequence has fewer than 5 mutations compared to the selected sequence.

[0037] In multiple embodiments, the chimeric protein complex comprises a polypeptide having the amino acid sequence of SEQ ID NO:5. This sequence includes a modified human interferon alpha 2b with an R149A mutation (i.e., huIFNa2B_R149A), a linker (i.e., 10*GGS-G), and an Fc knob Ridgway sequence with an LALA-KQ mutation (i.e., Fc knob Ridgway (LALA-KQ), see Ridgway et al., Protein Engineering 1996; 9:617-621, which is incorporated herein by reference in its entirety). Such a construct with the SEQ ID NO:5 sequence is represented as follows: Variant 1 Fc-AFN: Fc knob Ridgway (LALA-KQ)-10*GGS-G-huIFNa2B_R149A.

[0038] In multiple embodiments, the chimeric protein complex comprises a polypeptide having the amino acid sequence of SEQ ID NO:6. This sequence includes a modified human interferon alpha 2b with R149A and T106E mutations (i.e., huIFNa2B_R149A_T106E), a linker (i.e., 10*GGS-G), and an Fc knob Ridgway sequence with an LALA-KQ mutation (i.e., Fc knob Ridgway (LALA-KQ), see Ridgway et al., Protein Engineering 1996; 9:617-621, which is incorporated herein by reference in its entirety). Such a construct with the SEQ ID NO:6 sequence is represented as follows: Variant 2 Fc-AFN: Fc knob Ridgway (LALA-KQ)-10*GGS-G-huIFNa2B_R149A_T106E.

[0039] In multiple embodiments, the chimeric protein complex comprises a polypeptide having the amino acid sequence of SEQ ID NO:7. This sequence includes a modified human interferon alpha 2b with an R149A mutation (i.e., huIFNa2B_R149A), a linker (i.e., 10*GGS-G), and an Fc knob Merchant sequence with an LALA-KQ mutation (i.e., Fc knob Merchant (LALA-KQ), see Merchant et al., Nature Biotechnology 1998; 16:677-681, which is incorporated herein by reference in its entirety). Such a construct with the SEQ ID NO:7 sequence is represented as follows: Variant 3 Fc-AFN: Fc knob Merchant (LALA-KQ)-10*GGS-G-huIFNa2B_R149A.

[0040] In multiple embodiments, the chimeric protein complex comprises a polypeptide having the amino acid sequence SEQ ID NO:8. This sequence includes a modified human interferon α2b with R149A and T106E mutations (i.e., huIFNa2B_R149A_T106E), a linker (i.e., 10*GGS-G), and an Fc-knob Merchant sequence with LALA-KQ mutations (i.e., Fc-knob Merchant (LALA-KQ), see Merchant et al., Nature Biotechnology 1998; 16:677-681, which is incorporated herein by reference in its entirety). This construct with the SEQ ID NO:8 sequence is represented as follows: Variant 4Fc-AFN: Fc-knob Merchant (LALA-KQ)-10*GGS-G-huIFNa2B_R149A_T106E.

[0041] In multiple embodiments, the chimeric protein complex comprises a polypeptide having the amino acid sequence SEQ ID NO:41. This sequence includes a modified interferon α2b with A145G mutation, a linker (i.e., 10*GGS-G), and an Fc-knob Merchant sequence with LALA-KQ mutations (i.e., Fc-knob Merchant (LALA-KQ), see Merchant et al., Nature Biotechnology 1998; 16:677-681, which is incorporated herein by reference in its entirety). This construct with the sequence SEQ ID NO:41 is represented as follows: Fc4’-IFNa2b_A145G.

[0042] In multiple embodiments, the chimeric protein complex comprises a polypeptide having the amino acid sequence SEQ ID NO:42. This sequence includes a modified interferon α2b with T106A and A145G mutations, a linker (i.e., 10*GGS-G), and an Fc-knob Merchant sequence with LALA-KQ mutations (i.e., Fc-knob Merchant (LALA-KQ), see Merchant et al., Nature Biotechnology 1998; 16:677-681, which is incorporated herein by reference in its entirety). This construct with the sequence SEQ ID NO:42 is represented as follows: Fc4’-IFNa2a_T106E_A145G.

[0043] In one embodiment, the chimeric protein complex comprises: (i) an amino acid sequence having at least 95% identity to any one of SEQ ID NO: 1 or 3 and (ii) an amino acid sequence having at least 95% identity to any one of SEQ ID NO: 5 or 6. In another embodiment, the chimeric protein complex comprises: (i) an amino acid sequence having at least 98% identity to any one of SEQ ID NO: 1 or 3 and (ii) an amino acid sequence having at least 98% identity to any one of SEQ ID NO: 5 or 6. In another embodiment, the chimeric protein complex comprises: (i) an amino acid sequence having at least 99% identity to any one of SEQ ID NO: 1 or 3 and (ii) an amino acid sequence having at least 99% identity to any one of SEQ ID NO: 5 or 6. In one embodiment, the chimeric protein complex comprises: (i) an amino acid sequence having at least 95% identity to any one of SEQ ID NO: 2 or 4 and (ii) an amino acid sequence having at least 95% identity to any one of SEQ ID NO: 7 or 8. In one embodiment, the chimeric protein complex comprises: (i) an amino acid sequence having at least 98% identity to any one of SEQ ID NO: 2 or 4 and (ii) an amino acid sequence having at least 98% identity to any one of SEQ ID NO: 7 or 8. In another embodiment, the chimeric protein complex comprises: (i) an amino acid sequence having at least 99% identity to any one of SEQ ID NO: 2 or 4 and (ii) an amino acid sequence having at least 99% identity to any one of SEQ ID NO: 7 or 8.

[0044] In some embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence that is at least 95% identical to SEQ ID NO:2 and (ii) a polypeptide having an amino acid sequence that is at least 95% identical to either SEQ ID NO:31 or 32. In some embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence that is at least 98% identical to SEQ ID NO:2 and (ii) a polypeptide having an amino acid sequence that is at least 98% identical to either SEQ ID NO:31 or 32. In some embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence that is at least 99% identical to SEQ ID NO:2 and (ii) a polypeptide having an amino acid sequence that is at least 99% identical to either SEQ ID NO:31 or 32. In some embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence that is at least 95% identical to SEQ ID NO:43 and (ii) a polypeptide having an amino acid sequence that is at least 95% identical to either SEQ ID NO:41 or 42. In some embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence that is at least 98% identical to SEQ ID NO:43 and (ii) a polypeptide having an amino acid sequence that is at least 98% identical to either SEQ ID NO:41 or 42. In some embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence that is at least 99% identical to SEQ ID NO:43 and (ii) a polypeptide having an amino acid sequence that is at least 99% identical to either SEQ ID NO:41 or 42.

[0045] In some embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence that is at least 95% identical to either SEQ ID NO:1 or 3 and (ii) a polypeptide having an amino acid sequence that is at least 95% identical to either SEQ ID NO:5 or 6.

[0046] In some embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence that is at least 98% identical to either SEQ ID NO:1 or 3 and (ii) a polypeptide having an amino acid sequence that is at least 98% identical to either SEQ ID NO:5 or 6.

[0047] In some embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence with at least 99% identity to any one of SEQ ID NO:1 or 3 and (ii) a polypeptide having an amino acid sequence with at least 99% identity to any one of SEQ ID NO:5 or 6.

[0048] In some embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence with at least 95% identity to any one of SEQ ID NO:2 or 4 and (ii) a polypeptide having an amino acid sequence with at least 95% identity to any one of SEQ ID NO:7 or 8.

[0049] In some embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence with at least 98% identity to any one of SEQ ID NO:2 or 4 and (ii) a polypeptide having an amino acid sequence with at least 98% identity to any one of SEQ ID NO:7 or 8.

[0050] In some embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence with at least 99% identity to any one of SEQ ID NO:2 or 4 and (ii) a polypeptide having an amino acid sequence with at least 99% identity to any one of SEQ ID NO:7 or 8.

[0051] In some embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence with at least 95% identity to SEQ ID NO:2 and (ii) a polypeptide having an amino acid sequence with at least 95% identity to any one of SEQ ID NO:31 or 32.

[0052] In some embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence with at least 98% identity to SEQ ID NO:2 and (ii) a polypeptide having an amino acid sequence with at least 98% identity to any one of SEQ ID NO:31 or 32.

[0053] In some embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence with at least 99% identity to SEQ ID NO:2 and (ii) a polypeptide having an amino acid sequence with at least 99% identity to any one of SEQ ID NO:31 or 32.

[0054] In multiple embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence with at least 95% identity to SEQ ID NO: 43 and (ii) a polypeptide having an amino acid sequence with at least 95% identity to either SEQ ID NO: 41 or 42.

[0055] In multiple embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence with at least 98% identity to SEQ ID NO: 43 and (ii) a polypeptide having an amino acid sequence with at least 98% identity to either SEQ ID NO: 41 or 42.

[0056] In some embodiments, the chimeric protein complex comprises: (i) a polypeptide having an amino acid sequence with at least 99% identity to SEQ ID NO: 43 and (ii) a polypeptide having an amino acid sequence with at least 99% identity to either SEQ ID NO: 41 or 42.

[0057] In some embodiments, the present invention relates to a multivalent or bivalent chimeric protein complex, the chimeric protein complex comprising: a polypeptide having a sequence that is at least 95%, or 97%, or 98%, or 99% identical to the amino acid sequence SEQ ID NO:17 and a polypeptide having a sequence that is at least 95%, or 97%, or 98%, or 99% identical to the amino acid sequence SEQ ID NO:7; a polypeptide having a sequence that is at least 95%, or 97%, or 98%, or 99% identical to the amino acid sequence SEQ ID NO:2 and a polypeptide having a sequence that is at least 95%, or 97%, or 98%, or 99% identical to the amino acid sequence SEQ ID NO:19; a polypeptide having a sequence that is at least 95%, or 97%, or 98%, or 99% identical to the amino acid sequence SEQ ID NO:18 and a polypeptide having a sequence that is at least 95%, or 97%, or 98%, or 99% identical to the amino acid sequence SEQ ID NO:7; a polypeptide having a sequence that is at least 95%, or 97%, or 98%, or 99% identical to the amino acid sequence SEQ ID NO:20 and a polypeptide having a sequence that is at least 95%, or 97%, or 98%, or 99% identical to the amino acid sequence SEQ ID NO:7; a polypeptide having a sequence that is at least 95%, or 97%, or 98%, or 99% identical to the amino acid sequence SEQ ID NO:2 and a polypeptide having a sequence that is at least 95%, or 97%, or 98%, or 99% identical to the amino acid sequence SEQ ID NO:22; or a polypeptide having a sequence that is at least 95%, or 97%, or 98%, or 99% identical to the amino acid sequence SEQ ID NO:21 and a polypeptide having a sequence that is at least 95%, or 97%, or 98%, or 99% identical to the amino acid sequence SEQ ID NO:7. In some embodiments, the present invention relates to a method for treating or preventing cancer, the method comprising administering to a patient in need thereof an effective amount of the multivalent or bivalent chimeric protein complex described herein.

[0058] In some embodiments, the present invention relates to a chimeric protein complex comprising at least two polypeptides having a sequence that is at least 95%, or 97%, or 98%, or 99%, or 100% identical to the amino acid sequence of any one of SEQ ID No:1-43. In various embodiments, the present invention relates to a method for treating or preventing cancer, the method comprising administering to a patient in need thereof an effective amount of a chimeric protein complex comprising at least two polypeptides having a sequence that is at least 95%, or 97%, or 98%, or 99%, or 100% identical to the amino acid sequence of any one of SEQ ID No:1-43.

[0059] In some embodiments, the chimeric protein complex comprises a modified human interferon α2. In various embodiments, the modified IFN-α2 agent has reduced affinity and / or activity for the IFN-α / β receptor (IFNAR), namely the IFNAR1 and / or IFNAR2 chains. In some embodiments, the modified IFN-α2 agent has substantially reduced or eliminated affinity and / or activity for the IFN-α / β receptor (IFNAR), namely the IFNAR1 and / or IFNAR2 chains. In some embodiments, the modified human interferon α2 as disclosed herein has an amino acid sequence having at least 95% identity with SEQ ID NO:9 or 10. In other embodiments, the modified human IFNα2 has an amino acid sequence having at least 98% or at least 99% identity with SEQ ID NO:9 or 10. In some embodiments, the modified human IFNα2 has 1-3 mutations relative to the amino acid sequence SEQ ID NO:9 or 10. In one embodiment, the modified human IFNα2 comprises the R149A mutation relative to SEQ ID NO:9 or 10. In one embodiment, the modified human IFNα2 comprises the A145G mutation relative to SEQ ID NO:9 or 10.

[0060] In some embodiments, the targeting moiety of the chimeric protein complex disclosed herein comprises a recombinant single-chain antibody variable fragment (VHH). In some embodiments, the VHH has an amino acid sequence having at least 95% identity with one of SEQ ID NO:11 or 12. In other embodiments, the VHH comprises an amino acid sequence having at least 98% identity with one of SEQ ID NO:11 or 12 or having at least 99% identity with one of SEQ ID NO:11 or 12. In some embodiments, the VHH has the amino acid sequence of either SEQ ID NO:11 or 12.

[0061] In some embodiments, the chimeric protein complex disclosed herein comprises two targeting moieties. In some embodiments, the chimeric protein complex disclosed herein comprises two identical targeting moieties. In various embodiments, the orientation of these bivalent modes is as Figure 7 shown.

[0062] In some embodiments, the chimeric protein complex disclosed herein comprises two targeting moieties. In some embodiments, the chimeric protein complex disclosed herein comprises two different targeting moieties. In various embodiments, the orientation of these bivalent modes is as Figure 7as shown. For example, in some embodiments, the chimeric protein complexes disclosed herein comprise targeting moieties (but not limited to, VHHs) against Clec9A and PD-L1.

[0063] In multiple embodiments, the R149A mutation is present in IFN-α2.

[0064] In multiple embodiments, the R149A mutation is not present in IFN-α2, but rather another mutation is present. For example, such an alternative mutation may be at one of positions R33, R144, A145, M148, and L153. In multiple embodiments, the alternative mutation is one of R33A, R144A, R144I, R144L, R144S, R144T, R144Y, A145D, A145G, A145H, A145K, A145Y, M148A, and L153A. For clarity, in multiple embodiments, any reference to R149A herein may be replaced by one of R33A, R144A, R144I, R144L, R144S, R144T, R144Y, A145D, A145G, A145H, A145K, A145Y, M148A, and L153A. In multiple embodiments, any reference to R149A herein may be replaced by A145G.

[0065] In some embodiments, the chimeric protein complexes disclosed herein comprise at least one Fc domain. In some embodiments, the chimeric protein complex comprises a modified Fc domain, wherein the modified Fc domain comprises one or more of the following mutations relative to any of SEQ ID NOs: 13-16: P329G, K322Q, K322A, or P331S. In other embodiments, the modified Fc domain comprises one or more of the following mutations relative to human IgG1 Fc: P329G, K322Q, K322A, or P331S.

[0066] In some embodiments, the chimeric protein complex comprises a modified Fc domain having an amino acid sequence with at least 90% identity to SEQ ID NOs: 13-16. In other embodiments, the modified Fc domain has an amino acid sequence with at least 93% identity to SEQ ID NOs: 13-16. In other embodiments, the modified Fc domain has an amino acid sequence with at least 95% identity to SEQ ID NOs: 13-16.

[0067] In another aspect, the present invention relates to a method for treating or preventing cancer, the method comprising administering to a patient in need thereof an effective amount of a chimeric protein complex as disclosed herein. The method can be used to treat or prevent cancer selected from one or more of the following: basal cell carcinoma; biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancers; breast cancer; peritoneal cancer; cervical cancer; choriocarcinoma; colorectal cancer; connective tissue cancer; digestive system cancers; endometrial cancer; esophageal cancer; eye cancer; head and neck cancer; gastric cancer (including gastrointestinal cancer); glioblastoma; liver cancer; hepatoma; intraepithelial neoplasia; kidney cancer or renal carcinoma; laryngeal cancer; leukemia; liver cancer; lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma); melanoma; myeloma; neuroblastoma; oral cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; respiratory system cancers; salivary gland cancer; sarcoma (e.g., Kaposi's sarcoma); skin cancer; squamous cell carcinoma; gastric cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; urinary system cancers; vulvar cancer; lymphoma, including Hodgkin's lymphoma and non-Hodgkin's lymphoma, and B-cell lymphoma (including low-grade / follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate / follicular NHL; intermediate diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small non-cleaved cell NHL; large mass NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenström macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia; chronic myelogenous leukemia; and other carcinomas and sarcomas; and post-transplant lymphoproliferative disorder (PTLD), and abnormal vascular proliferation associated with phakomatosis; edema (e.g., edema associated with brain tumors); and Meigs' syndrome.

[0068] Another aspect of the present invention relates to a pharmaceutical composition comprising a chimeric protein complex as disclosed herein and a pharmaceutically acceptable carrier. In some embodiments, the present invention relates to a pharmaceutical composition comprising the chimeric protein complex of the present invention.

[0069] Another aspect of the present invention relates to a method for treating or preventing cancer, the method comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition as disclosed herein. The pharmaceutical composition can be used to treat or prevent cancer selected from one or more of the following: basal cell carcinoma; biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancer; breast cancer; peritoneal cancer; cervical cancer; choriocarcinoma; colorectal cancer; connective tissue cancer; digestive system cancer; endometrial cancer; esophageal cancer; eye cancer; head and neck cancer; gastric cancer (including gastrointestinal cancer); glioblastoma; liver cancer; hepatoma; intraepithelial neoplasia; kidney cancer or renal carcinoma; laryngeal cancer; leukemia; liver cancer; lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma); melanoma; myeloma; neuroblastoma; oral cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; respiratory system cancer; salivary gland cancer; sarcoma (e.g., Kaposi's sarcoma); skin cancer; squamous cell carcinoma; gastric cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; urinary system cancer; vulvar cancer; lymphoma, including Hodgkin's lymphoma and non-Hodgkin's lymphoma, and B-cell lymphoma (including low grade / follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate / follicular NHL; intermediate diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; large mass NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenström's macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia; chronic myelogenous leukemia; and other carcinomas and sarcomas; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal blood vessel proliferation associated with phakomatosis; edema (e.g., edema associated with brain tumors); and Meigs' syndrome.

[0070] In another aspect, the present invention relates to a recombinant nucleic acid composition encoding one or more chimeric protein complexes as disclosed herein, e.g., encoding the entire chimeric protein complex or its constituent polypeptides. In another aspect, the present invention relates to a host cell comprising the recombinant nucleic acid composition complex as disclosed herein.

[0071] Definition

[0072] As used herein, "a / an" or "the" can mean one or more than one.

[0073] In addition, the term "about" when used in conjunction with a recited numerical indication means the recited numerical indication plus or minus up to 10% of the recited numerical indication. For example, the language "about 50" encompasses a range from 45 to 55.

[0074] As used herein, the term "effective amount" means an amount sufficient to achieve the desired therapeutic and / or prophylactic effect, e.g., an amount that results in the prevention or reduction of a disease or disorder or one or more signs or symptoms associated with a disease or disorder. In the context of a therapeutic or prophylactic application, the amount of the composition administered to a subject will depend on the degree, type, and severity of the disease, as well as the characteristics of the individual (such as general health, age, sex, weight, and resistance to drugs). One of ordinary skill in the art will be able to determine an appropriate dosage based on these and other factors. The composition may also be administered in combination with one or more other therapeutic compounds. In the methods described herein, the therapeutic compound may be administered to a subject having one or more signs or symptoms of a disease or disorder. As used herein, a property "decreases" if the readout of an activity and / or effect is decreased by a significant amount in the presence of an agent or stimulus relative to the absence of such modulation, such as decreased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98% or more, up to and including at least about 100%. As will be understood by one of ordinary skill in the art, in some embodiments, the activity decreases and some downstream readouts will decrease but other downstream readouts may increase.

[0075] Conversely, an activity "increases" if the readout of an activity and / or effect is increased by a significant amount in the presence of an agent or stimulus relative to the absence of such agent or stimulus, e.g., increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98% or more, up to and including at least about 100% or more, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 50-fold, at least about 100-fold.

[0076] Although the open-ended term "comprising" is used herein as a synonym for terms such as including, containing, or having to describe and claim the invention, the invention or its embodiments may optionally be described using alternative terms such as "consisting of" or "consisting essentially of".

[0077] The amount of the compositions described herein required to achieve a therapeutic effect can be determined empirically according to conventional procedures for a particular purpose. Generally, for the administration of a therapeutic agent for therapeutic purposes, the therapeutic agent is administered at a pharmacologically effective dose. "Pharmacologically effective amount", "pharmacologically effective dose", "therapeutically effective amount" or "effective amount" means an amount sufficient to produce the desired physiological effect or an amount capable of achieving the desired result, particularly for treating a disorder or disease. As used herein, an effective amount will include an amount sufficient to, for example, delay the development of symptoms of a disorder or disease, alter the course of symptoms of a disorder or disease (e.g., slow the progression of symptoms of a disease), reduce or eliminate one or more symptoms or manifestations of a disorder or disease, and reverse the symptoms of a disorder or disease. Therapeutic benefits also include interrupting or slowing the progression of a potential disease or disorder, regardless of whether improvement is achieved.

[0078] As used herein, "method of treatment" equally applies to the use of a composition for treating a disease or disorder described herein and / or one and / or more uses of a composition for manufacturing a medicament for treating a disease or disorder described herein.

[0079] As used herein, Fc domain mutations are numbered according to the EU convention (Edelman et al., PNAS 1969; 63(1) 78-85, which is incorporated herein by reference in its entirety). As used herein, the term "LALA" mutation refers to a double mutant Fc domain having L234A and L235A mutations. As used herein, the term "KQ" mutation refers to a mutant Fc domain having a K322Q mutation.

[0080] Knob-into-hole mutants are those described in Ridgway et al., Protein Engineering 1996; 9: 617-621 (which is incorporated herein by reference), i.e., Y407T / T366Y.

[0081] Alternatively, knob-into-hole mutants are those described in Merchant et al., Nature Biotechnology 1998; 16: 677-681 (which is incorporated herein by reference), i.e., S354C:T366W / Y349C:T366S:L368A:Y407V.

[0082] Unless otherwise specified, Fc is from human IgG1.

[0083] Sequence

[0084] SEQ ID NO:1 Variant 1 VHH-Fc: R1CHCL50(opt4)-5*GGS-Fc hole Ridgway (LALA-KQ)

[0085]

[0086] SEQ ID NO:2 Variant 2 VHH-Fc: R1CHCL50 (opt4)-5*GGS-Fc pore Merchant (LALA-KQ)

[0087]

[0088] SEQ ID NO:3 Variant 3 VHH-Fc: 3LEC89 (opt4)-5*GGS-Fc pore Ridgway (LALA-KQ)

[0089] D

[0090]

[0091] SEQ ID NO:4 Variant 4 VHH-Fc: 3LEC89 (opt4)-5*GGS-Fc pore Merchant (LALA-KQ)

[0092]

[0093] SEQ ID NO:5 Variant 1 Fc-AFN: Fc knob Ridgway (LALA-KQ)-10*GGS-G-huIFNa2B_R149A

[0094]

[0095] SEQ ID NO:6 Variant 2 Fc-AFN: Fc knob Ridgway (LALA-KQ)-10*GGS-G-huIFNa2B_R149A_T106E

[0096]

[0097] SEQ ID NO:7 Variant 3 Fc-AFN: Fc knob Merchant (LALA-KQ)-10*GGS-G-huIFNa2B_R149A

[0098]

[0099] SEQ ID NO:8 Variant 4 Fc-AFN: Fc knob Merchant (LALA-KQ)-10*GGS-G-huIFNa2B_R149A_T106E

[0100]

[0101] SEQ ID NO:9 Human IFNα2a (Amino Acid Sequence)

[0102]

[0103] SEQ ID NO:10 Human IFNα2b (Amino Acid Sequence)

[0104]

[0105] SEQ ID NO:11 R1CHCL50_opt4 (Anti-human Clec9a VHH)

[0106]

[0107] SEQ ID NO:12 3LEC89_opt4 (Anti-human Clec9a VHH)

[0108]

[0109] SEQ ID NO:13 Amino Acid Sequence of Fc (Human IgG1) - with LALA Mutation and Ridgway Hole

[0110]

[0111] SEQ ID NO:14 Amino Acid Sequence of Fc (Human IgG1) - with LALA Mutation and Ridgway Knob

[0112]

[0113] SEQ ID NO:15 Amino Acid Sequence of Fc (Human IgG1) - with LALA Mutation and Merchant Hole

[0114]

[0115] SEQ ID NO:16 Amino Acid Sequence of Fc (Human IgG1) - with LALA Mutation and Merchant Knob

[0116]

[0117] Other sequences are identified elsewhere in the text.

[0118] Examples

[0119] In some embodiments, two variants of the knob-into-hole technology were used: Ridgway (from Ridgway et al., Protein Engineering 1996; 9:617-621) and Merchant (from Merchant et al., Nature Biotechnology 1998; 16:677-681).

[0120] The "standard" effector mutation in the Ridgway construct is LALA-PG (P329G), which is described herein. The "standard" effector mutation in the Merchant construct is LALA-KQ (K322Q), which is described herein.

[0121] The terms "ActaFeron (AFN)" or "ActaKine" are occasionally used herein to refer to the chimeric proteins described herein (detailed information on the chimeric protein forms is provided in the examples).

[0122] Example 1: Fc-based AcTaferon

[0123] To increase the half-life of AcTaferon with CLEC9A specificity (CLEC9A is a highly specific cDC1 marker), the human CLEC9A-VHH_huIFNa2 fusion protein was converted into an Fc fusion. For this purpose, human IgG1-Fc was fused to AcTaferon (VHH 3LEC89-20*GGS-huIFNa2_R149) via a 20*GGS linker. In a second format, the Fc domain was constructed between the VHH and the IFN portion. The effector function of human IgG1-Fc was reduced by introducing the LALA-P329G mutation.

[0124] The relevant sequences for expression in mammalian cells are:

[0125] P-956: pcDNA3.4 - murine light chain κ - hIgG1 - LALA - PG - 20*GGS - 3LEC89 -20*GGS + G - IFNa2 R149A

[0126]

[0127] P-957: pcDNA3.4 - murine Ig heavy chain - 3LEC89 -20*GGS - hIgG1 - LALA - PG - 20*GGS + G -IFNa2 R149A

[0128]

[0129] These constructs were prepared by GeneArt (Thermo Fisher) and transiently expressed in the ExpiCHO expression system (Thermo Fisher) according to the manufacturer's guidelines. Ten days after transfection, the supernatant was collected and cells were removed by centrifugation. The recombinant protein was purified from the medium using rProtein A Sepharose Fast Flow resin (GE Healthcare) according to the manufacturer's guidelines. Unexpectedly, the proteins expressed at 70 - 170 mg / L showed severe solubility problems and tended to aggregate and precipitate even at concentrations below 1 mg / ml when stored at 4 °C or after undergoing a single freeze-thaw cycle. Similar observations when VHH 3LEC89 was replaced with an irrelevant VHH 2LIG99 specific for human PD-L1 indicated the manufacturability of the Fc-based AcTakine format.

[0130] Surprisingly, the solubility problem was solved by designing different types of Fc constructs. In this new format, a heterodimeric Fc complex was generated by binding the VHH-Fc fusion with the Fc-IFN fusion using the knob-into-hole mutations Y407T / T366Y or S354C:T366W / Y349C:T366S:L368A:Y407V. Other variants included selectively knocking out the O-glycosylation site in huIFNa2 by the T106E mutation. A total of 8 constructs were designed based on 2 different humanized human CLEC9A-specific VHHs. To reduce the effector function of the IgG1-Fc protein, the mutation LALA-K322Q was used. The sequences of the mature proteins are represented by SEQ ID NO:1 - 8. This resulted in a total of 8 different Fc complexes that could be generated by combining the knob and hole structures as Figure 1 shown.

[0131] For expression in mammalian cells, the sequences were ligated to a leader sequence and constructs were prepared by GeneArt (ThermoFisher). Production was carried out in ExpiCHO cells as described above. The recombinant protein was purified from the supernatant on HiTrap Protein A HP (GE Healthcare), the eluted protein was desalted on a G25 column (GE Healthcare) after neutralization, and then subjected to a final 0.22 μm filtration. The protein remained soluble at concentrations of at least 10 mg / mL at 4 °C or after undergoing repeated freeze / thaw cycles.

[0132] Example 2: PK effects of chimeras with or without Fc

[0133] PK (pharmacokinetics) studies were conducted in mice using 4 different variants of the Fc protein based on R1CHCL50.

[0134] Each construct was administered intravenously at 1 mg / kg to a total of 9 mice. K-EDTA blood was drawn from the first group of 3 mice at 5 minutes, 8 hours, and 6 days, from the second group of 3 mice at 15 minutes, 1 day, and 10 days, and from the third group of 3 mice at 2 hours, 3 days, and 14 days. The concentration of intact CLEC9A-AFN Fc was measured by ELISA. Briefly, MAXISORP Nunc immunoplates (Thermo Scientific) were coated overnight with 0.5 μg / ml anti-human interferon α mAb (clone MMHA-13; PBL Assay Science) in PBS. After washing the plates four times with PBS + 0.05% Tween-20, they were blocked with PBS containing 0.1% casein for at least 1 hour at room temperature. Subsequently, diluted samples and standards were incubated in PBS containing 0.1% casein for 2 hours at room temperature. After another washing cycle, custom rabbit anti-VHH (diluted 1 / 20000 in PBS containing 0.1% casein) was incubated for 2 hours at room temperature, followed by another washing cycle and incubation with HRP-conjugated goat anti-rabbit (Jackson-111-035-144; 1:5000, 0.1% casein) for 1 hour at room temperature. After the final washing cycle, peroxidase activity was measured using a KPL substrate (5120-0047; SeraCare) according to the manufacturer's instructions. Concentrations in the samples were calculated using GraphPad Prism. The measured concentrations were plotted in Figure 2 which showed that all 4 constructs had similar PK curves, except that at the last sampling time point, the clearance rate of the Ridgway-based Fc construct was faster. It was estimated that the terminal half-life of the Ridgway construct was on average about 3 days, while that of the Merchant construct was on average about 4.5 days.

[0135] PK studies were conducted in mice using CLEC9A AcTaferon without an Fc fusion.

[0136] In a separate study, the PK of AFN without Fc (3LEC89-20*GGS-huIFNa2_R149A-his6) was evaluated in mice. The sequence of this chimera was:

[0137] P-602 sequence

[0138]

[0139] Nine animals were dosed intravenously at 3 mg / kg. K-EDTA blood was drawn from the first group of 3 mice at 5 minutes and 1 hour, from the second group of 3 mice at 15 minutes and 3 hours, and finally from the last group of mice at 8 hours. Plasma samples were assayed for concentration using the same ELISA described for Fc fusion proteins. The measured concentrations ( Figure 3 ) showed rapid clearance of this type of molecule, resulting in concentrations below the limit of detection (0.12 μg / ml) at the 8-hour time point. The estimated terminal half-life was in the range of only 2 hours, clearly demonstrating the superior half-life properties of Fc-based AcTakine.

[0140] Example 3: Binding and in vivo effects of constructs

[0141] To measure relative binding affinity, the same 4 molecules as shown in Example 2 were incubated with serial dilutions of the CLEC9A-AFN Fc construct on HL116-hClec9A cells. To assess binding specificity, parental HL116 cells and parental HEK293T cells (both lacking detectable Clec9A expression) were also incubated with the same serial dilutions of the CLEC9A-AFN Fc construct. Binding was detected by subsequent incubation with FITC-conjugated anti-human secondary Ab and measured on a MACSQuant X instrument (Miltenyi Biotech) and analyzed using FlowLogic software (Miltenyi Biotech). The data in Figure 4 show that Fc-based AFN has a similar binding EC50 for HL116-hClec9A cells, while no binding was detected on cell lines that do not express Clec9A.

[0142] To evaluate the efficacy of Fc-based AFN, these molecules were tested in a tumor model of humanized mice. Briefly, neonatal NSG mice (1 - 2 days old) were given a sublethal irradiation of 100 cGy and then 1 x 10 5 CD34+ human stem cells (from HLA-A2 positive cord blood) were delivered into the liver. At 13 weeks post-stem cell transfer, mice were inoculated subcutaneously with 25 x 10 5 human RL follicular lymphoma cells (ATCC CRL-2261; not sensitive to the direct anti-proliferative effect of IFN). From day 10 to day 19 post-tumor inoculation, mice were treated intraperitoneally with 30 μg of human Flt3L protein daily. At 11 days post-tumor inoculation, when palpable tumors were visible, intravenous injections of buffer or Fc-AFN (8 or 75 μg) were started once a week (n = 5 mice / group). Tumor size (measured with calipers), body weight, and temperature were assessed daily. Figure 5 and Figure 6The data in show tumor growth up to 6 days after the second treatment. Figure 5 It was shown that all constructs induced similar levels of tumor growth inhibition at the lower dose of 8 μg. Figure 6 The results in show that higher doses of the Merchant construct led to increased tumor growth inhibition. Data on body weight and temperature did not show any significant differences between buffer treatment and AFN treatment, confirming that all AFN treatments were well tolerated.

[0143] Example 4: Bivalent and bispecific variants

[0144] To further improve the targeting ability of the molecule, additional VHH moieties were added to generate constructs, non-limiting configurational examples of which are shown in Figure 7 These novel constructs target CLEC9A in a bivalent mode or co-target, for example, both CLEC9A and PD-L1. As an example, the following constructs are based on the R1CHCL50(opt4) VHH against CLEC9A and / or the 2LIG99 VHH against PD-L1 and huIFNa2B_R149A. Similar series can be generated by replacing R1CHCL50(opt4) with 3LEC89(opt4). Alternatively, huIFNa2B_R149A can be replaced with huIFNa2B_R149A_T106E. Finally, the following examples are based on an Fc moiety containing a Merchant-based knob-in-hole mutation, which can be exchanged with an Fc moiety having a Ridgway-based knob-in-hole mutation.

[0145] Novel constructs

[0146] A. Bivalent CLEC9A-targeting hole chain with additional VHH at the N-terminus of Fc(Merchant)

[0147] VHH-VHH-Fc: R1CHCL50(opt4)-5*GGS-R1CHCL50(opt4)-5*GGS-Fc(LALA-KQ)

[0148]

[0149] B. Bivalent CLEC9A-targeting hole chain with additional VHH at the C-terminus of Fc(Merchant)

[0150] VHH-Fc-VHH: R1CHCL50(opt4)-5*GGS-Fc(LALA-KQ)-5*GGS-R1CHCL50(opt4)

[0151]

[0152] Bivalent CLEC9A-targeted knob-linker with an additional VHH at the N-terminus of Fc(Merchant)

[0153] VHH-Fc-AFN: R1CHCL50(opt4)-5*GGS-Fc(LALA-KQ)-10*GGS-G-hulFNa2B_R149A

[0154]

[0155] Bispecific CLEC9A-PDL1-targeted hole-linker with an additional VHH at the N-terminus of Fc(Merchant)

[0156] VHH-VHH-Fc: 2LIG99-5*GGS-R1CHCL50(opt4)-5*GGS-Fc(LALA-KQ)

[0157]

[0158] Bispecific CLEC9A-PD-L1-targeted hole-linker with an additional VHH at the C-terminus of Fc(Merchant)

[0159] VHH-Fc-VHH: R1CHCL50(opt4)-5*GGS-Fc(LALA-KQ)-5*GGS-2LIG99

[0160]

[0161] Bispecific CLEC9A-PD-L1-targeted knob-linker with an additional VHH at the N-terminus of Fc(Merchant)

[0162] VHH-Fc-AFN: 2LIG99-5*GGS-Fc(LALA-KQ)-10*GGS-G-hulFNa2B_R149A

[0163]

[0164] For expression in mammalian cells, the sequences were ligated to a leader sequence and expression constructs were prepared by GeneArt (ThermoFisher). Production was carried out in ExpiCHO cells as described above. Recombinant proteins were purified from the supernatant on HiTrap Protein A HP (GE Healthcare), and the eluted proteins were desalted on a G25 column (GE Healthcare) after neutralization, followed by a final 0.22 μm filtration. More specifically, the following expression constructs were combined to produce Fc-based AcTaferon.

[0165] · Construct containing SEQ ID NO:17 + construct containing SEQ ID NO:7

[0166] · Construct containing SEQ ID NO:2 + construct containing SEQ ID NO:19

[0167] · Construct containing SEQ ID NO:18 + construct containing SEQ ID NO:7

[0168] · Construct containing SEQ ID NO:20 + construct containing SEQ ID NO:7

[0169] · Construct containing SEQ ID NO:2 + construct containing SEQ ID NO:22

[0170] · Construct containing SEQ ID NO:21 + construct containing SEQ ID NO:7

[0171] Example 5: A145G and M148A AFN mutation

[0172] In this example, the potential of IFN variants A145G and M148A as AFN mutations (i.e., warhead mutations that result in loss of biological activity and can be restored after targeting the warhead) was evaluated.

[0173] Mutations were evaluated in the "knobs-into-holes" Fc AFN of the heterodimer. Here, the Clec9A VHHR1CHCL50 sequence was fused via a flexible 20*GGS linker to a human IgG1 Fc sequence containing the L234A_L235A_K322Q effector mutation and the "hole" modification Y349C_T366S_L368A_Y407V in the pcDNA3.4 expression vector (see sequence R1CHCL50-Fc3 below). The second AFN partner (also cloned into the pcDNA3.4 vector) consisted of a fusion between a human IgG1 Fc sequence containing the L234A_L235A_K322Q effector mutation and the "knob" modification S354C_T366W and an hIFNa2 sequence with the AFN mutations A145G or M148A and the O-glycosylation mutation T106E (see sequences below).

[0174] To generate these "knobs-into-holes" Fc AFNs, a combination of the "hole" and "knob" plasmids was transfected into ExpiCHO according to the manufacturer's instructions. TMIn cells (ThermoFisher). Seven days after transfection, the recombinant protein was purified using a Protein A spin plate (ThermoFisher), quantified, and purity tested using SDS-PAGE.

[0175] STAT1 phosphorylation of the resulting A145G and M148 AFNs was tested in primary cDC1 cells (expressing Clec9A, the target of AFN) compared to other PBMC populations. Briefly, PBMCs were isolated from the buffy coat of healthy donors using Lymphoprep TM (StemCell technologies) by density gradient centrifugation. The cells were washed twice with FACS buffer (PBS with 2% FBS, 1 mM EDTA) and stained with anti-Clec9A and anti-CD141 Ab (both from Miltenyi) for 20 minutes at 4 °C to identify the cDC1 population. After two washes, the cells were stimulated with serial dilutions of wild-type IFNa2 or the two AFNs for 15 minutes at 37 °C. After fixation (10 minutes, 37 °C, Fixation Buffer I; BD Biosciences), permeabilization (30 minutes, on ice, Perm III Buffer I; BD Biosciences), and washing, the cells were stained with anti-STAT1 pY701 Ab (BD Biosciences). Samples were acquired using X instrument (Miltenyi Biotec) and analyzed using FlowLogic TM software (Miltenyi Biotec). Figures 8A to 8B The data in clearly illustrate that (i) Clec9A− / CD141− and Clec9A+ / CD141+ cells are equally sensitive to wild-type IFNa2, and (ii) both the A145G and M148A mutations abolish most signaling in non-cDC1 PBMCs (Clec9A− / CD141−), but targeting Clec9A-positive cells (Clec9A+ / CD141+) largely restores this signaling. This results in an AFN effect of at least 100-fold for the A145G or M148A mutations and illustrates the potential of these mutations in AFN design.

[0176] Sequence:

[0177] P-1451: -20*GGS-hlgG1 Fc_L234A_L235A_K322Q_Y349C_T366S_L368A_Y407V (abbreviation: R1CHCL50-Fc3)

[0178]

[0179] P-1846: hlgG1 Fc_L234A_L235A_K322Q_S354C_T366W-20*GGS-

[0180] (Abbreviation: Fc4-hlFNa2_A145G)

[0181]

[0182] P-1850: hlgG1 Fc_L234A_L235A_K322Q_S354C_T366W-20*GGS-

[0183] (Abbreviation: Fc4-hlFNa2_M148A)

[0184]

[0185] Example 6: In vivo A145G and M148A AFN mutations

[0186] To evaluate the efficacy of Fc-based AFNs, these molecules were tested in a tumor model of humanized mice. Briefly, neonatal NSG mice (1 - 2 days old) were given a sublethal irradiation of 100 cGy and then 1x10 5 CD34+ human stem cells (from HLA-A2 positive cord blood) were delivered into the liver. At the 13th week after stem cell transfer, mice were subcutaneously inoculated with 25x10 5 human RL follicular lymphoma cells (ATCC CRL-2261; not sensitive to the direct anti-proliferative effect of IFN). From day 9 to day 22 after tumor inoculation, mice were treated intraperitoneally with 30 μg of human Flt3L protein. At day 9 after tumor inoculation, when palpable tumors were visible, treatment with buffer or Fc-AFN (7.5 μg) constructs as described in Example 5 was started once a week by intravenous injection (n = 6 mice / group). Tumor size (measured with calipers), body weight, and temperature were assessed daily. Figure 9 The data in show tumor growth up to one week after the third treatment and indicate that both constructs induced a strong level of tumor growth inhibition. Data on body weight and temperature did not show any significant difference between buffer treatment and AFN treatment, confirming that all AFN treatments were well tolerated.

[0187] Example 7: Additional Fc-AFN constructs based on A145G and M148A mutations The following additional Fc constructs with attenuated human interferon alpha 2 were generated:

[0188] A. hlgG1 Fc_L234A_L235A_K322Q_S354C_T366W-10*GGS-G-hlFNa2_T106E_M148A

[0189]

[0190] B. hlgG1 Fc_L234A_L235A_K322Q_S354C_T366W-10*GGS-G-hlFNa2_M148A

[0191]

[0192]

[0193] C. hlgG1 Fc_L234A_L235A_K322Q_S354C_T366W-10*GGS-G-hlFNa2_T106E_A145G

[0194]

[0195] D. hlgG1 Fc_L234A_L235A_K322Q_S354C_T366W-10*GGS-G-hlFNa2_A145G

[0196]

[0197] E. hlgG1 Fc-L234A-L235A_K322Q_T366Y-10*GGS-G-hlFNa2_T106E-M148A

[0198]

[0199] F. hlgG1 Fc_L234A_L235A_K322Q_T366Y-10*GGS-G-hlFNa2_M148A

[0200]

[0201]

[0202] G. hlgG1 Fc_L234A_L235A_K322Q_T366Y-10*GGS-G-hlFNa2_T106E_A145G

[0203]

[0204] H, hlgG1 Fc_L234A_L235A_K322Q_T366Y-10*GGS-G-hlFNa2_A145G

[0205]

[0206] To generate human CLEC9A targeted AFNs, any of the above constructs AD were combined with the CLEC9A VHH-Fc fusions of SEQ ID 2 or 4, resulting in 8 novel constructs. In addition, any of the above constructs EH were combined with the CLEC9A VHH-Fc fusions of SEQ ID 1 or 3, resulting in another set of 8 novel constructs. Proteins were expressed and purified as described in Example 5.

[0207] Example 8: A145G mutation with or without T106 O-glycosylation

[0208] In this experiment, Clec9A-targeted AFN (R1CHCl50-Fc3+Fc4-IFNa2_A145G and R1CHCl50-Fc3+Fc4-IFNa2_T106E_A145G) with or without T106O-glycosylation in IFNa2 was compared with a non-targeted variant (Fc3+Fc4-IFNa2_A145G). Proteins were produced as described in Example 5 and purified by protein A chromatography followed by size exclusion.

[0209] To assess efficacy, constructs were tested for STAT1 phosphorylation in primary cDC1 (CLEC9A+ / CD141+) and non-cDC1 (CLEC9A- / CD141-) populations in human PBMCs as described in Example 5. Figure 10 shows the specificity of CLEC9A targeting constructs with or without T106 O-glycosylation, showing that the constructs activated IFN signaling more efficiently in cDC1 cells than non-cDC1 cells, and were more effective on cDC1 cells than cDC1 cells treated with non-targeted variants.

[0210] To evaluate the in vivo efficacy of the aforementioned heterodimeric "knobs-in-holes" Fc AFN constructs, they were tested in a humanized mouse tumor model. Briefly, newborn NSG mice (1-2 days old) were sublethally irradiated with 100 cGy, followed by intrahepatic delivery of 1x10 5 CD34+ human stem cells (from HLA-A2 positive umbilical cord blood). At week 13 after stem cell transfer, mice were subcutaneously inoculated with 25x10 5Personal RL follicular lymphoma cells (ATCC CRL-2261; insensitive to the direct anti-proliferative effect of IFN). From day 7 to day 17 after tumor inoculation, mice were treated intraperitoneally with 30 μg of human Flt3L protein. On day 9 after tumor inoculation, when palpable tumors were visible, buffer or Fc-AFN (2.5 μg) constructs were injected intravenously once a week (n = 5 mice / group). Tumor size (measured with calipers), body weight, and temperature were assessed daily. Figure 11 The data in

[0211] Sequence

[0212] 1. P-1479: R1CHCL50-Fc3

[0213]

[0214] 2. P-1542: Fc3

[0215]

[0216] 3. P-2157: Fc4-IFNa2_

[0217]

[0218] 4. P-2158: Fc4-IFNa2_

[0219]

[0220] Example 9: Fc-AFN constructs

[0221] Mass spectrometry analysis showed that in almost all mature proteins, the C-terminal lysine K residue in the R1CHCL50-Fc3 chain was cleaved off. Therefore, variants were constructed in which this lysine residue in two of the Fc chains was removed. The resulting proteins will be referred to as Fc′ proteins. As an example, the sequences of chimeric protein combinations of R1CHCL50-Fc3′ and Fc4′-AFN fusions are shown below, where the residue A145 in IFNa2b is mutated to G, or where the residues T106 and A145 in IFNa2a are mutated to E and G, respectively.

[0222] Sequence:

[0223] P-2379: Fc4'-IFNa2b-A145G

[0224]

[0225] P-2380: Fc4'-IFNa2a_T106E_A145G

[0226]

[0227] P-1479b: R1CHCL50-Fc3″

[0228] Sequence Listing <110> Orionis Biosciences, Inc. Orionis Biosciences BV Nikolai Kley Erik Depla Lennart Zabeau Jan Tavernier <120> CLEC9A-based Chimeric Protein Complex <130> ORN-063PC / 114384-5063 <150> US 62 / 906,442 <151> 2019-09-26 <150> US 62 / 825,584 <151> 2019-03-28 <160> 43 <170> PatentIn version 3.5 <210> 1 <211> 357 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 1 Asp 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 Ser Phe Ser Ser Ile Asn 20 25 30 Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val 35 40 45 Ala Arg Ile Thr Asn Leu Gly Leu Pro Asn Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Tyr 85 90 95 Leu Val Ala Leu Lys Ala Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 115 120 125 Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 130 135 140 Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 145 150 155 160 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 165 170 175 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 180 185 190 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 195 200 205 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 210 215 220 Asn Gly Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala 225 230 235 240 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 245 250 255 Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 260 265 270 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 275 280 285 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 290 295 300 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Thr Ser Lys Leu 305 310 315 320 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 325 330 335 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 340 345 350 Leu Ser Pro Gly Lys 355 <210> 2 <211> 357 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 2 Asp 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 Ser Phe Ser Ser Ile Asn 20 25 30 Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val 35 40 45 Ala Arg Ile Thr Asn Leu Gly Leu Pro Asn Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Tyr 85 90 95 Leu Val Ala Leu Lys Ala Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 115 120 125 Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 130 135 140 Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 145 150 155 160 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 165 170 175 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 180 185 190 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 195 200 205 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 210 215 220 Asn Gly Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala 225 230 235 240 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 245 250 255 Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 260 265 270 Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 275 280 285 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 290 295 300 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu 305 310 315 320 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 325 330 335 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 340 345 350 Leu Ser Pro Gly Lys 355 <210> 3 <211> 357 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 3 Asp 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 Arg Ile Phe Ser Val Asn 20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala Ala Ile Thr Asn Gln Gly Ala Pro Thr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Lys 85 90 95 Ala Phe Thr Arg Gly Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 115 120 125 Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 130 135 140 Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 145 150 155 160 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 165 170 175 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 180 185 190 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 195 200 205 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 210 215 220 Asn Gly Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala 225 230 235 240 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 245 250 255 Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 260 265 270 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 275 280 285 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 290 295 300 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Thr Ser Lys Leu 305 310 315 320 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 325 330 335 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 340 345 350 Leu Ser Pro Gly Lys 355 <210> 4 <211> 357 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 4 Asp 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 Arg Ile Phe Ser Val Asn 20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala Ala Ile Thr Asn Gln Gly Ala Pro Thr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Lys 85 90 95 Ala Phe Thr Arg Gly Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 115 120 125 Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 130 135 140 Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 145 150 155 160 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 165 170 175 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 180 185 190 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 195 200 205 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 210 215 220 Asn Gly Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala 225 230 235 240 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 245 250 255 Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 260 265 270 Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 275 280 285 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 290 295 300 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu 305 310 315 320 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 325 330 335 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 340 345 350 Leu Ser Pro Gly Lys 355 <210> 5 <211> 423 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 5 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Tyr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 225 230 235 240 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 245 250 255 Ser Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr 260 265 270 Leu Met Leu Leu Ala Gln Met Arg Arg Ile Ser Leu Phe Ser Cys Leu 275 280 285 Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln 290 295 300 Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln 305 310 315 320 Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu 325 330 335 Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp 340 345 350 Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr Pro Leu 355 360 365 Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile 370 375 380 Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val 385 390 395 400 Val Arg Ala Glu Ile Met Ala Ser Phe Ser Leu Ser Thr Asn Leu Gln 405 410 415 Glu Ser Leu Arg Ser Lys Glu 420 <210> 6 <211> 423 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 6 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Tyr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 225 230 235 240 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 245 250 255 Ser Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr 260 265 270 Leu Met Leu Leu Ala Gln Met Arg Arg Ile Ser Leu Phe Ser Cys Leu 275 280 285 Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln 290 295 300 Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln 305 310 315 320 Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu 325 330 335 Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp 340 345 350 Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Glu Glu Thr Pro Leu 355 360 365 Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile 370 375 380 Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val 385 390 395 400 Val Arg Ala Glu Ile Met Ala Ser Phe Ser Leu Ser Thr Asn Leu Gln 405 410 415 Glu Ser Leu Arg Ser Lys Glu 420 <210> 7 <211> 423 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 7 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 225 230 235 240 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 245 250 255 Ser Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr 260 265 270 Leu Met Leu Leu Ala Gln Met Arg Arg Ile Ser Leu Phe Ser Cys Leu 275 280 285 Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln 290 295 300 Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln 305 310 315 320 Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu 325 330 335 Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp 340 345 350 Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr Pro Leu 355 360 365 Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile 370 375 380 Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val 385 390 395 400 Val Arg Ala Glu Ile Met Ala Ser Phe Ser Leu Ser Thr Asn Leu Gln 405 410 415 Glu Ser Leu Arg Ser Lys Glu 420 <210> 8 <211> 423 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 8 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 225 230 235 240 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 245 250 255 Ser Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr 260 265 270 Leu Met Leu Leu Ala Gln Met Arg Arg Ile Ser Leu Phe Ser Cys Leu 275 280 285 Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln 290 295 300 Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln 305 310 315 320 Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu 325 330 335 Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp 340 345 350 Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Glu Glu Thr Pro Leu 355 360 365 Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile 370 375 380 Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val 385 390 395 400 Val Arg Ala Glu Ile Met Ala Ser Phe Ser Leu Ser Thr Asn Leu Gln 405 410 415 Glu Ser Leu Arg Ser Lys Glu 420 <210> 9 <211> 165 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 9 Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr Leu Met 1 5 10 15 Leu Leu Ala Gln Met Arg Lys Ile Ser Leu Phe Ser Cys Leu Lys Asp 20 25 30 Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln Phe Gln 35 40 45 Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln Ile Phe 50 55 60 Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu Thr Leu 65 70 75 80 Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp Leu Glu 85 90 95 Ala Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr Pro Leu Met Lys 100 105 110 Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile Thr Leu 115 120 125 Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val Val Arg 130 135 140 Ala Glu Ile Met Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln Glu Ser 145 150 155 160 Leu Arg Ser Lys Glu 165 <210> 10 <211> 164 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 10 Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr Leu Met 1 5 10 15 Leu Leu Ala Gln Met Arg Arg Ile Ser Leu Phe Ser Cys Leu Lys Asp 20 25 30 Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln Phe Gln 35 40 45 Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln Ile Phe 50 55 60 Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu Thr Leu 65 70 75 80 Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp Leu Glu 85 90 95 Ala Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr Pro Leu Met Lys 100 105 110 Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile Thr Leu 115 120 125 Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Trp Arg Ala 130 135 140 Glu Ile Met Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln Glu Ser Leu 145 150 155 160 Arg Ser Lys Glu <210> 11 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 11 Asp 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 Ser Phe Ser Ser Ile Asn 20 25 30 Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val 35 40 45 Ala Arg Ile Thr Asn Leu Gly Leu Pro Asn Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Tyr 85 90 95 Leu Val Ala Leu Lys Ala Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> 12 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 12 Asp 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 Arg Ile Phe Ser Val Asn 20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala Ala Ile Thr Asn Gln Gly Ala Pro Thr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Lys 85 90 95 Ala Phe Thr Arg Gly Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> 13 <211> 227 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 13 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Thr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> 14 <211> 227 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 14 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Tyr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> 15 <211> 227 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 15 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> 16 <211> 227 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 16 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> 17 <211> 487 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 17 Asp 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 Ser Phe Ser Ser Ile Asn 20 25 30 Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val 35 40 45 Ala Arg Ile Thr Asn Leu Gly Leu Pro Asn Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Tyr 85 90 95 Leu Val Ala Leu Lys Ala Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 115 120 125 Gly Ser Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Phe Ser Ser 145 150 155 160 Ile Asn Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu 165 170 175 Leu Val Ala Arg Ile Thr Asn Leu Gly Leu Pro Asn Tyr Ala Asp Ser 180 185 190 Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val 195 200 205 Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr 210 215 220 Cys Tyr Leu Val Ala Leu Lys Ala Glu Tyr Trp Gly Gln Gly Thr Leu 225 230 235 240 Val Thr Val Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 245 250 255 Ser Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 260 265 270 Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 275 280 285 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 290 295 300 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 305 310 315 320 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 325 330 335 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 340 345 350 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu 355 360 365 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 370 375 380 Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 385 390 395 400 Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp 405 410 415 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 420 425 430 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser 435 440 445 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 450 455 460 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 465 470 475 480 Leu Ser Leu Ser Pro Gly Lys 485 <210> 18 <211> 487 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 18 Asp 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 Ser Phe Ser Ser Ile Asn 20 25 30 Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val 35 40 45 Ala Arg Ile Thr Asn Leu Gly Leu Pro Asn Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Tyr 85 90 95 Leu Val Ala Leu Lys Ala Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 115 120 125 Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 130 135 140 Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 145 150 155 160 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 165 170 175 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 180 185 190 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 195 200 205 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 210 215 220 Asn Gly Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala 225 230 235 240 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 245 250 255 Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 260 265 270 Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 275 280 285 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 290 295 300 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu 305 310 315 320 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 325 330 335 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 340 345 350 Leu Ser Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 355 360 365 Ser Gly Gly Ser Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 370 375 380 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Phe 385 390 395 400 Ser Ser Ile Asn Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu 405 410 415 Arg Glu Leu Val Ala Arg Ile Thr Asn Leu Gly Leu Pro Asn Tyr Ala 420 425 430 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 435 440 445 Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val 450 455 460 Tyr Tyr Cys Tyr Leu Val Ala Leu Lys Ala Glu Tyr Trp Gly Gln Gly 465 470 475 480 Thr Leu Val Thr Val Ser Ser 485 <210> 19 <211> 553 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 19 Asp 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 Ser Phe Ser Ser Ile Asn 20 25 30 Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val 35 40 45 Ala Arg Ile Thr Asn Leu Gly Leu Pro Asn Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Tyr 85 90 95 Leu Val Ala Leu Lys Ala Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 115 120 125 Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 130 135 140 Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 145 150 155 160 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 165 170 175 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 180 185 190 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 195 200 205 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 210 215 220 Asn Gly Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala 225 230 235 240 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 245 250 255 Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln 260 265 270 Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 275 280 285 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 290 295 300 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 305 310 315 320 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 325 330 335 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 340 345 350 Leu Ser Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 355 360 365 Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 370 375 380 Gly Gly Ser Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg 385 390 395 400 Arg Thr Leu Met Leu Leu Ala Gln Met Arg Arg Ile Ser Leu Phe Ser 405 410 415 Cys Leu Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly 420 425 430 Asn Gln Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile 435 440 445 Gln Gln Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp 450 455 460 Asp Glu Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu 465 470 475 480 Asn Asp Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr 485 490 495 Pro Leu Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln 500 505 510 Arg Ile Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp 515 520 525 Glu Val Val Arg Ala Glu Ile Met Ala Ser Phe Ser Leu Ser Thr Asn 530 535 540 Leu Gln Glu Ser Leu Arg Ser Lys Glu 545 550 <210> 20 <211> 487 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 20 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Thr Ile Phe Ser Ile Asn 20 25 30 Arg Met Asp Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala Leu Ile Thr Ser Asp Gly Thr Pro Ala Tyr Ala Asp Ser Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Lys Lys Thr Val Ser Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys His 85 90 95 Val Ser Ser Gly Val Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr 100 105 110 Val Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 115 120 125 Gly Ser Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Phe Ser Ser 145 150 155 160 Ile Asn Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu 165 170 175 Leu Val Ala Arg Ile Thr Asn Leu Gly Leu Pro Asn Tyr Ala Asp Ser 180 185 190 Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val 195 200 205 Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr 210 215 220 Cys Tyr Leu Val Ala Leu Lys Ala Glu Tyr Trp Gly Gln Gly Thr Leu 225 230 235 240 Val Thr Val Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 245 250 255 Ser Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 260 265 270 Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 275 280 285 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 290 295 300 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 305 310 315 320 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 325 330 335 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 340 345 350 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu 355 360 365 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 370 375 380 Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 385 390 395 400 Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp 405 410 415 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 420 425 430 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser 435 440 445 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 450 455 460 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 465 470 475 480 Leu Ser Leu Ser Pro Gly Lys 485 <210> 21 <211> 487 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 21 Asp 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 Ser Phe Ser Ser Ile Asn 20 25 30 Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val 35 40 45 Ala Arg Ile Thr Asn Leu Gly Leu Pro Asn Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Tyr 85 90 95 Leu Val Ala Leu Lys Ala Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 115 120 125 Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 130 135 140 Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 145 150 155 160 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 165 170 175 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 180 185 190 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 195 200 205 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 210 215 220 Asn Gly Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala 225 230 235 240 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 245 250 255 Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 260 265 270 Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 275 280 285 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 290 295 300 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu 305 310 315 320 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 325 330 335 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 340 345 350 Leu Ser Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 355 360 365 Ser Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val 370 375 380 Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Thr Ile 385 390 395 400 Phe Ser Ile Asn Arg Met Asp Trp Phe Arg Gln Ala Pro Gly Lys Gln 405 410 415 Arg Glu Leu Val Ala Leu Ile Thr Ser Asp Gly Thr Pro Ala Tyr Ala 420 425 430 Asp Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Lys Lys 435 440 445 Thr Val Ser Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val 450 455 460 Tyr Tyr Cys His Val Ser Ser Gly Val Tyr Asn Tyr Trp Gly Gln Gly 465 470 475 480 Thr Gln Val Thr Val Ser Ser 485 <210> 22 <211> 553 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 22 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Thr Ile Phe Ser Ile Asn 20 25 30 Arg Met Asp Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala Leu Ile Thr Ser Asp Gly Thr Pro Ala Tyr Ala Asp Ser Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Lys Lys Thr Val Ser Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys His 85 90 95 Val Ser Ser Gly Val Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr 100 105 110 Val Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 115 120 125 Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 130 135 140 Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 145 150 155 160 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 165 170 175 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 180 185 190 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 195 200 205 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 210 215 220 Asn Gly Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala 225 230 235 240 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 245 250 255 Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln 260 265 270 Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 275 280 285 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 290 295 300 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 305 310 315 320 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 325 330 335 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 340 345 350 Leu Ser Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 355 360 365 Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 370 375 380 Gly Gly Ser Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg 385 390 395 400 Arg Thr Leu Met Leu Leu Ala Gln Met Arg Arg Ile Ser Leu Phe Ser 405 410 415 Cys Leu Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly 420 425 430 Asn Gln Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile 435 440 445 Gln Gln Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp 450 455 460 Asp Glu Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu 465 470 475 480 Asn Asp Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr 485 490 495 Pro Leu Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln 500 505 510 Arg Ile Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp 515 520 525 Glu Val Val Arg Ala Glu Ile Met Ala Ser Phe Ser Leu Ser Thr Asn 530 535 540 Leu Gln Glu Ser Leu Arg Ser Lys Glu 545 550 <210> 23 <211> 647 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 23 Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 20 25 30 Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 35 40 45 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 50 55 60 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 65 70 75 80 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 85 90 95 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 100 105 110 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly 115 120 125 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 130 135 140 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 145 150 155 160 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 165 170 175 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 180 185 190 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 195 200 205 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 210 215 220 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 225 230 235 240 Ser Leu Ser Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 245 250 255 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 260 265 270 Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 275 280 285 Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 290 295 300 Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro 305 310 315 320 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser 325 330 335 Val Asn Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu 340 345 350 Leu Val Ala Ala Ile Thr Asn Gln Gly Ala Pro Thr Tyr Ala Asp Ser 355 360 365 Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Gly Asn Thr Val 370 375 380 Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr 385 390 395 400 Cys Lys Ala Phe Thr Arg Gly Asp Asp Tyr Trp Gly Gln Gly Thr Gln 405 410 415 Val Thr Val Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 420 425 430 Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 435 440 445 Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 450 455 460 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 465 470 475 480 Ser Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr 485 490 495 Leu Met Leu Leu Ala Gln Met Arg Lys Ile Ser Leu Phe Ser Cys Leu 500 505 510 Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln 515 520 525 Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln 530 535 540 Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu 545 550 555 560 Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp 565 570 575 Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr Pro Leu 580 585 590 Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile 595 600 605 Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val 610 615 620 Val Arg Ala Glu Ile Met Ala Ser Phe Ser Leu Ser Thr Asn Leu Gln 625 630 635 640 Glu Ser Leu Arg Ser Lys Glu 645 <210> 24 <211> 647 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 24 Met Gly Trp Ser Cys Ile Ile Phe Phe Leu Val Ala Thr Ala Thr Gly 1 5 10 15 Val His Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe 35 40 45 Ser Val Asn Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg 50 55 60 Glu Leu Val Ala Ala Ile Thr Asn Gln Gly Ala Pro Thr Tyr Ala Asp 65 70 75 80 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Gly Asn Thr 85 90 95 Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr 100 105 110 Tyr Cys Lys Ala Phe Thr Arg Gly Asp Asp Tyr Trp Gly Gln Gly Thr 115 120 125 Gln Val Thr Val Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 130 135 140 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 145 150 155 160 Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 165 170 175 Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 180 185 190 Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 195 200 205 Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 210 215 220 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 225 230 235 240 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 245 250 255 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 260 265 270 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 275 280 285 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala 290 295 300 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 305 310 315 320 Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 325 330 335 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 340 345 350 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 355 360 365 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 370 375 380 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 385 390 395 400 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 405 410 415 Leu Ser Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 420 425 430 Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 435 440 445 Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 450 455 460 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 465 470 475 480 Ser Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr 485 490 495 Leu Met Leu Leu Ala Gln Met Arg Lys Ile Ser Leu Phe Ser Cys Leu 500 505 510 Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln 515 520 525 Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln 530 535 540 Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu 545 550 555 560 Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp 565 570 575 Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr Pro Leu 580 585 590 Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile 595 600 605 Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val 610 615 620 Val Arg Ala Glu Ile Met Ala Ser Phe Ser Leu Ser Thr Asn Leu Gln 625 630 635 640 Glu Ser Leu Arg Ser Lys Glu 645 <210> 25 <211> 353 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 25 Gln Val Gln Leu Gln 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 Arg Ile Phe Ser Val Asn 20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala Ala Ile Thr Asn Gln Gly Ala Pro Thr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Gly Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Lys 85 90 95 Ala Phe Thr Arg Gly Asp Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr 100 105 110 Val Ser Ser Val Asp Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 115 120 125 Ser Gly Gly Ser Gly Gly Ser Arg Ser Gly Gly Ser Gly Gly Ser Gly 130 135 140 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 145 150 155 160 Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 165 170 175 Ala Ala Ala Met Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg 180 185 190 Arg Thr Leu Met Leu Leu Ala Gln Met Arg Arg Ile Ser Leu Phe Ser 195 200 205 Cys Leu Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly 210 215 220 Asn Gln Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile 225 230 235 240 Gln Gln Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp 245 250 255 Asp Glu Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu 260 265 270 Asn Asp Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr 275 280 285 Pro Leu Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln 290 295 300 Arg Ile Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp 305 310 315 320 Glu Val Val Arg Ala Glu Ile Met Ala Ser Phe Ser Leu Ser Thr Asn 325 330 335 Leu Gln Glu Ser Leu Arg Ser Lys Glu Leu Glu His His His His His 340 345 350 His <210> 26 <211> 402 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 26 Gln Val Gln Leu Gln 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 Ser Phe Ser Ser Ile Asn 20 25 30 Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val 35 40 45 Ala Arg Ile Thr Asn Leu Gly Leu Pro Asn Tyr Ala Asp Ser Val Thr 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Tyr 85 90 95 Leu Val Ala Leu Lys Ala Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr 100 105 110 Val Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 115 120 125 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 130 135 140 Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 145 150 155 160 Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Asp 165 170 175 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 180 185 190 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 195 200 205 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 210 215 220 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 225 230 235 240 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 245 250 255 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 260 265 270 Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 275 280 285 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 290 295 300 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 305 310 315 320 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 325 330 335 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 340 345 350 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 355 360 365 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 370 375 380 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 385 390 395 400 Gly Lys <210> 27 <211> 452 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 27 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 225 230 235 240 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 245 250 255 Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 260 265 270 Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Cys 275 280 285 Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr Leu Met Leu 290 295 300 Leu Ala Gln Met Arg Lys Ile Ser Leu Phe Ser Cys Leu Lys Asp Arg 305 310 315 320 His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln Phe Gln Lys 325 330 335 Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln Ile Phe Asn 340 345 350 Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu Thr Leu Leu 355 360 365 Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp Leu Glu Ala 370 375 380 Cys Val Ile Gln Gly Val Gly Val Glu Glu Thr Pro Leu Met Lys Glu 385 390 395 400 Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile Thr Leu Tyr 405 410 415 Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val Val Arg Gly 420 425 430 Glu Ile Met Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln Glu Ser Leu 435 440 445 Arg Ser Lys Glu 450 <210> 28 <211> 452 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 28 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 225 230 235 240 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 245 250 255 Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 260 265 270 Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Cys 275 280 285 Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr Leu Met Leu 290 295 300 Leu Ala Gln Met Arg Lys Ile Ser Leu Phe Ser Cys Leu Lys Asp Arg 305 310 315 320 His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln Phe Gln Lys 325 330 335 Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln Ile Phe Asn 340 345 350 Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu Thr Leu Leu 355 360 365 Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp Leu Glu Ala 370 375 380 Cys Val Ile Gln Gly Val Gly Val Glu Glu Thr Pro Leu Met Lys Glu 385 390 395 400 Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile Thr Leu Tyr 405 410 415 Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val Val Arg Ala 420 425 430 Glu Ile Ala Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln Glu Ser Leu 435 440 445 Arg Ser Lys Glu 450 <210> 29 <211> 423 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 29 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 225 230 235 240 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 245 250 255 Ser Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr 260 265 270 Leu Met Leu Leu Ala Gln Met Arg Lys Ile Ser Leu Phe Ser Cys Leu 275 280 285 Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln 290 295 300 Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln 305 310 315 320 Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu 325 330 335 Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp 340 345 350 Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Glu Glu Thr Pro Leu 355 360 365 Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile 370 375 380 Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val 385 390 395 400 Val Arg Ala Glu Ile Ala Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln 405 410 415 Glu Ser Leu Arg Ser Lys Glu 420 <210> 30 <211> 423 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 30 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 225 230 235 240 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 245 250 255 Ser Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr 260 265 270 Leu Met Leu Leu Ala Gln Met Arg Lys Ile Ser Leu Phe Ser Cys Leu 275 280 285 Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln 290 295 300 Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln 305 310 315 320 Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu 325 330 335 Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp 340 345 350 Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr Pro Leu 355 360 365 Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile 370 375 380 Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val 385 390 395 400 Val Arg Ala Glu Ile Ala Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln 405 410 415 Glu Ser Leu Arg Ser Lys Glu 420 <210> 31 <211> 423 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 31 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 225 230 235 240 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 245 250 255 Ser Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr 260 265 270 Leu Met Leu Leu Ala Gln Met Arg Lys Ile Ser Leu Phe Ser Cys Leu 275 280 285 Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln 290 295 300 Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln 305 310 315 320 Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu 325 330 335 Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp 340 345 350 Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Glu Glu Thr Pro Leu 355 360 365 Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile 370 375 380 Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val 385 390 395 400 Val Arg Gly Glu Ile Met Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln 405 410 415 Glu Ser Leu Arg Ser Lys Glu 420 <210> 32 <211> 423 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 32 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 225 230 235 240 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 245 250 255 Ser Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr 260 265 270 Leu Met Leu Leu Ala Gln Met Arg Lys Ile Ser Leu Phe Ser Cys Leu 275 280 285 Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln 290 295 300 Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln 305 310 315 320 Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu 325 330 335 Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp 340 345 350 Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr Pro Leu 355 360 365 Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile 370 375 380 Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val 385 390 395 400 Val Arg Gly Glu Ile Met Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln 405 410 415 Glu Ser Leu Arg Ser Lys Glu 420 <210> 33 <211> 423 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 33 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Tyr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 225 230 235 240 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 245 250 255 Ser Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr 260 265 270 Leu Met Leu Leu Ala Gln Met Arg Lys Ile Ser Leu Phe Ser Cys Leu 275 280 285 Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln 290 295 300 Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln 305 310 315 320 Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu 325 330 335 Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp 340 345 350 Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Glu Glu Thr Pro Leu 355 360 365 Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile 370 375 380 Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val 385 390 395 400 Val Arg Ala Glu Ile Ala Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln 405 410 415 Glu Ser Leu Arg Ser Lys Glu 420 <210> 34 <211> 423 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 34 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Tyr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 225 230 235 240 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 245 250 255 Ser Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr 260 265 270 Leu Met Leu Leu Ala Gln Met Arg Lys Ile Ser Leu Phe Ser Cys Leu 275 280 285 Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln 290 295 300 Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln 305 310 315 320 Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu 325 330 335 Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp 340 345 350 Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr Pro Leu 355 360 365 Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile 370 375 380 Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val 385 390 395 400 Val Arg Ala Glu Ile Ala Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln 405 410 415 Glu Ser Leu Arg Ser Lys Glu 420 <210> 35 <211> 423 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 35 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Tyr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 225 230 235 240 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 245 250 255 Ser Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr 260 265 270 Leu Met Leu Leu Ala Gln Met Arg Lys Ile Ser Leu Phe Ser Cys Leu 275 280 285 Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln 290 295 300 Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln 305 310 315 320 Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu 325 330 335 Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp 340 345 350 Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Glu Glu Thr Pro Leu 355 360 365 Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile 370 375 380 Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val 385 390 395 400 Val Arg Gly Glu Ile Met Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln 405 410 415 Glu Ser Leu Arg Ser Lys Glu 420 <210> 36 <211> 423 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 36 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Tyr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 225 230 235 240 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 245 250 255 Ser Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr 260 265 270 Leu Met Leu Leu Ala Gln Met Arg Lys Ile Ser Leu Phe Ser Cys Leu 275 280 285 Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln 290 295 300 Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln 305 310 315 320 Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu 325 330 335 Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp 340 345 350 Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr Pro Leu 355 360 365 Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile 370 375 380 Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val 385 390 395 400 Val Arg Gly Glu Ile Met Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln 405 410 415 Glu Ser Leu Arg Ser Lys Glu 420 <210> 37 <400> 37 000 <210> 38 <211> 227 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 38 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> 39 <400> 39 000 <210> 40 <400> 40 000 <210> 41 <211> 422 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 41 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 225 230 235 240 Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 245 250 255 Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr Leu 260 265 270 Met Leu Leu Ala Gln Met Arg Arg Ile Ser Leu Phe Ser Cys Leu Lys 275 280 285 Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln Phe 290 295 300 Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln Ile 305 310 315 320 Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu Thr 325 330 335 Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp Leu 340 345 350 Glu Ala Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr Pro Leu Met 355 360 365 Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile Thr 370 375 380 Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val Val 385 390 395 400 Arg Gly Glu Ile Met Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln Glu 405 410 415 Ser Leu Arg Ser Lys Glu 420 <210> 42 <211> 422 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 42 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly 225 230 235 240 Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 245 250 255 Gly Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr Leu 260 265 270 Met Leu Leu Ala Gln Met Arg Lys Ile Ser Leu Phe Ser Cys Leu Lys 275 280 285 Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln Phe 290 295 300 Gln Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln Ile 305 310 315 320 Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu Thr 325 330 335 Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp Leu 340 345 350 Glu Ala Cys Val Ile Gln Gly Val Gly Val Glu Glu Thr Pro Leu Met 355 360 365 Lys Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile Thr 370 375 380 Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val Val 385 390 395 400 Arg Gly Glu Ile Met Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln Glu 405 410 415 Ser Leu Arg Ser Lys Glu 420 <210> 43 <211> 356 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 43 Asp 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 Ser Phe Ser Ser Ile Asn 20 25 30 Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val 35 40 45 Ala Arg Ile Thr Asn Leu Gly Leu Pro Asn Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Tyr 85 90 95 Leu Val Ala Leu Lys Ala Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 115 120 125 Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 130 135 140 Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 145 150 155 160 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 165 170 175 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 180 185 190 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 195 200 205 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 210 215 220 Asn Gly Lys Glu Tyr Lys Cys Gln Val Ser Asn Lys Ala Leu Pro Ala 225 230 235 240 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 245 250 255 Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 260 265 270 Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 275 280 285 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 290 295 300 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu 305 310 315 320 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 325 330 335 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 340 345 350 Leu Ser Pro Gly 355

Claims

1. A heterodimeric chimeric protein complex, the heterodimeric chimeric protein complex consisting of: (a) A polypeptide consisting of the amino acid sequence of SEQ ID NO: 43 and a polypeptide consisting of the amino acid sequence of SEQ ID NO: 7 or 8; (b) A polypeptide consisting of the amino acid sequence of SEQ ID NO: 2 or 4 and a polypeptide consisting of the amino acid sequence of SEQ ID NO: 7 or 8; (c) A polypeptide consisting of the amino acid sequence of SEQ ID NO: 1 or 3 and a polypeptide consisting of the amino acid sequence of SEQ ID NO: 5 or 6; (d) A polypeptide consisting of the amino acid sequence of SEQ ID NO: 2 and a polypeptide consisting of the amino acid sequence of SEQ ID NO: 31 or 32; or (e) A polypeptide consisting of the amino acid sequence of SEQ ID NO: 43 and a polypeptide consisting of the amino acid sequence of SEQ ID NO: 41 or 42.

2. A pharmaceutical composition, the pharmaceutical composition comprising the chimeric protein complex according to claim 1 and a pharmaceutically acceptable carrier.

3. A recombinant nucleic acid, the recombinant nucleic acid encoding one or more of the chimeric protein complexes according to claim 1.

4. A host cell, the host cell comprising the recombinant nucleic acid according to claim 3.

5. A multivalent chimeric protein complex, the multivalent chimeric protein complex consisting of: A polypeptide consisting of the amino acid sequence SEQ ID NO:17 and a polypeptide consisting of the amino acid sequence SEQ ID NO:7; A polypeptide consisting of the amino acid sequence SEQ ID NO:2 and a polypeptide consisting of the amino acid sequence SEQ ID NO:19; A polypeptide consisting of the amino acid sequence SEQ ID NO:18 and a polypeptide consisting of the amino acid sequence SEQ ID NO:7; A polypeptide consisting of the amino acid sequence SEQ ID NO:20 and a polypeptide consisting of the amino acid sequence SEQ ID NO:7; A polypeptide consisting of the amino acid sequence SEQ ID NO:2 and a polypeptide consisting of the amino acid sequence SEQ ID NO:22; or A polypeptide consisting of the amino acid sequence SEQ ID NO:21 and a polypeptide consisting of the amino acid sequence SEQ ID NO:7.

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