CN116997362A - Fusion comprising CD8 antigen binding molecules that modulate immune cell function - Google Patents

Fusion comprising CD8 antigen binding molecules that modulate immune cell function Download PDF

Info

Publication number
CN116997362A
CN116997362A CN202180084033.7A CN202180084033A CN116997362A CN 116997362 A CN116997362 A CN 116997362A CN 202180084033 A CN202180084033 A CN 202180084033A CN 116997362 A CN116997362 A CN 116997362A
Authority
CN
China
Prior art keywords
amino acid
acid sequence
sequence seq
cdr
seq
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202180084033.7A
Other languages
Chinese (zh)
Inventor
杨翊
I·德瑞蒂克
P·贝塞特
陈薇
李景良
K·D·莫伊尼汉
H·C·阮
倪芸琦
D·C·帕帕斯
T·帕克
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Asher Biotherapy Co
Original Assignee
Asher Biotherapy Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Asher Biotherapy Co filed Critical Asher Biotherapy Co
Priority claimed from PCT/US2021/056312 external-priority patent/WO2022087458A1/en
Publication of CN116997362A publication Critical patent/CN116997362A/en
Pending legal-status Critical Current

Links

Landscapes

  • Peptides Or Proteins (AREA)

Abstract

Provided herein are anti-CD 8 antigen binding molecules and fusion polypeptides comprising the same for selectively modulating the function of cd8+ T cells relative to other immune cells. In addition, the disclosure also provides polynucleotides encoding the disclosed antigen binding molecules and fusion polypeptides, as well as vectors and host cells comprising such polynucleotides. The present disclosure further provides methods for producing the antigen binding molecules and fusion polypeptides, pharmaceutical compositions comprising the antigen binding molecules and fusion polypeptides, and uses thereof.

Description

Fusion comprising CD8 antigen binding molecules that modulate immune cell function
Cross reference to related applications
The present application claims priority from U.S. provisional application number 63/105,162 filed on day 10 and 23 of 2020, U.S. provisional application number 63/121,663 filed on day 12 and 4 of 2020, and U.S. provisional application number 63/190,669 filed on day 5 and 19 of 2021, each of which is incorporated herein by reference in its entirety.
Submission of sequence listing in ASCII text file
The following submissions in ASCII text files are incorporated herein by reference in their entirety: a Computer Readable Form (CRF) of the sequence listing (file name: 182842000440seqlist. Txt, recording date: 2021, 10 months 21, size: 557,283 bytes).
Technical Field
The present disclosure discloses CD8 antigen binding molecules and fusion polypeptides comprising the CD8 antigen binding molecules for selectively modulating the function of cd8+ T cells relative to other immune cells. In addition, the disclosure also provides polynucleotides encoding the disclosed antigen binding molecules and fusion polypeptides, as well as vectors and host cells comprising such polynucleotides. The present disclosure further provides methods for producing the antigen binding molecules and fusion polypeptides, pharmaceutical compositions comprising the antigen binding molecules and fusion polypeptides, and uses thereof.
Background
Cd8+ T cells expressing the αβ T cell receptor are a large subset of Major Histocompatibility (MHC) class I restricted T cells that mediate adaptive immunity to a variety of pathogens and cancers. In addition, they may also be pathogenic and cause disease in certain autoimmune and inflammatory disorders. Modulating the function of cd8+ T cells by activating the function of cd8+ T cells in the case of infection and cancer or by inhibiting their function in the case of certain autoimmune diseases may have therapeutic benefit.
Cd8+ T cell activation and differentiation is largely controlled by soluble immunomodulatory proteins such as cytokines. The biological activity of cytokines is mediated by their respective cytokine receptors, which typically bind with extremely high affinity to the cell surface, enabling them to strongly stimulate signal transduction downstream of their receptors, triggering various cellular processes that regulate immune cell phenotype and function. Cytokines often have pleiotropic effects, causing a number of downstream cellular events such as activation, proliferation, survival, apoptosis, and secretion of other immunomodulatory proteins. In addition, since its receptor is expressed on multiple immune cell subsets, cytokines act not only on cd8+ T cells, but also on other immune and non-immune cells that express its receptor.
For example, interleukin-2 (IL-2) is a cytokine that regulates many lymphocyte subsets including αβcd4+ and cd8t+ cells and various congenital and congenital-like lymphocytes such as NK cells, NK T cells, γδ T cells (tγδ) cells, and congenital lymphoid cells (ILC 1, ILC2, and ILC3 cells).
IL-2 can be signaled by binding with moderate affinity to a receptor complex consisting of IL-2Rbeta and IL-2Rgamma subunits (IL-2Rbeta gamma, moderate affinity receptor), which are both required for triggering downstream signaling in immune cells and are sufficient for triggering. In addition, IL-2 binds with high affinity to a receptor complex consisting of IL-2Rα, IL-2Rβ and IL-2Rγ subunits (IL-2Rαβγ, high affinity receptor) (Stauber et al Proc Natl Acad Sci U S A.2006, 21; 103 (8): 2788-93). IL-2Rα expression is limited by CD4+ Treg cells, activated T lymphocytes, and ILC2 and ILC3 cells, making these subsets most susceptible to IL-2 signaling. IL-2Rβ and IL-2Rγ subunits are shared with another related cytokine IL-15, and IL-2Rγ subunits are shared among other common gamma chain cytokines (IL-4, IL-7, IL-9, and IL-21). Most congenital and congenital-like lymphocytes, including NK cells, NK T cells, tγδ cells, and ILC1, ILC2 and ILC3 cells, express high levels of IL-2rβ (ImmGen consortium; heng TS et al Immunological Genome Project Consortium. Nat immunol.2008, month 10; 9 (10): 1091-4), which also makes them sensitive to both IL-2 and IL-15 cytokines.
Binding of IL-2 to its receptor induces phosphorylation of receptor-associated Janus kinases JAK3 and JAK1 that promote phosphorylation of STAT5 transcription factor (pSTAT 5) that regulates transcription of many genes in lymphocytes. IL-2 signaling in lymphocytes promotes cell survival, proliferation, and increased effector functions, including pro-inflammatory cytokine secretion and cytotoxicity, and in some cases, activation-induced cell death (reviewed in Ross and Cantrell, annu Rev immunol.2018, month 4, 26; 36:411-433).
Cd8+ T cells express CD8, CD8 being a type I transmembrane glycoprotein found on the cell surface in the form of CD8a (CD 8a ) homodimers and CD8 a-CD 8 β (CD 8 β, CD8 b) heterodimers. The CD8 dimer interacts with MHC class I molecules on the target cells and this interaction causes the TCR to tightly bind to MHC during cd8+ T cell activation. The cytoplasmic tail of CD 8. Alpha. Contains a binding site for T cell kinase (Lck) which initiates signal transduction downstream of TCR during T cell activation, while CD 8. Beta. Is thought to have the effect of increasing CD8 binding affinity to MHC class I and affecting the specificity of the CD8/MHC/TCR interaction (Bosselout et al, immunity. 4. 2000; 12 (4): 409-18). Cd8+ T cells expressing tcrαβ typically express both CD8ab and CD8aa dimers, however high levels of CD8aa, but not CD8ab dimers, can be found on some congenital lymphocytes, such as NK cells, mucosa-associated constant T (MAIT) cells, and γδ T cells.
Thus, there is a need for antibodies that selectively bind to CD8ab heterodimers over CD8aa homodimers. These antibodies can be used, for example, to target certain immunomodulatory polypeptides such as IL-2 to cd8ab+ T cells, and to limit their activity on CD 8-immune cells and cd8aa+ immune cells (such as NK cells).
All references cited herein, including patent applications, patent publications, and UniProtKB/Swiss-Prot register numbers, are incorporated by reference in their entirety as if each individual reference were specifically and individually indicated to be incorporated by reference.
Disclosure of Invention
The present disclosure describes, inter alia, human or humanized antibodies, antigen-binding fragments, and fusion proteins that bind to human CD8 b. In some embodiments, the human or humanized antibody, antigen binding fragment, and fusion protein preferentially bind to human CD8b or human CD8ab heterodimer over to human CD8aa homodimer. In some embodiments, the human or humanized antibodies, antigen binding fragments, and fusion proteins bind CD8b, CD8ab, or both.
Certain aspects of the disclosure relate to human or humanized antibodies or antigen binding fragments thereof. In some embodiments, the antibody or fragment specifically binds human CD8b and/or human CD8ab with at least 10-fold higher affinity than it binds human CD8a and/or human CD8 aa. In some embodiments, the antibody or fragment specifically binds to the extracellular domain of human CD8b and/or human CD8ab with at least 10-fold higher affinity than it binds to the extracellular domain of human CD8a and/or human CD8 aa. In some embodiments, the antibody or fragment binds to a cell expressing a human CD8ab heterodimer on the surface with an EC50 of less than 1000 nM. In some embodiments, the antibody or fragment binds to human cd8+ T cells. In some embodiments, the antibody or fragment specifically binds human CD8b and/or human CD8ab with at least 10-fold higher affinity than it binds human CD8a and/or human CD8aa expressed on the surface of Natural Killer (NK) cells. In some embodiments, the antibody or fragment specifically binds to a cell (e.g., a T cell) expressing human CD8b and/or human CD8ab on a surface with at least 10-fold higher affinity than it binds to a cell (e.g., NK cell) expressing human CD8a and/or human CD8aa on a surface.
In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 13, CDR-H2 comprising amino acid sequence SEQ ID NO. 14 and CDR-H3 comprising amino acid sequence SEQ ID NO. 15; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 51, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 15; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 62, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 63. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 19, CDR-H2 comprising amino acid sequence SEQ ID NO. 20 and CDR-H3 comprising amino acid sequence SEQ ID NO. 21; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 53, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 21; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 64, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 65. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 25, CDR-H2 comprising amino acid sequence SEQ ID NO. 26 and CDR-H3 comprising amino acid sequence SEQ ID NO. 27; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 49, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 27; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 66, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 67. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 31, CDR-H2 comprising amino acid sequence SEQ ID NO. 32 and CDR-H3 comprising amino acid sequence SEQ ID NO. 33; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 54, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 33; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 68, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 69. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 37, CDR-H2 comprising amino acid sequence SEQ ID NO. 38 and CDR-H3 comprising amino acid sequence SEQ ID NO. 39; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 55, CDR-H2 comprising amino acid sequence SEQ ID NO. 56 and CDR-H3 comprising amino acid sequence SEQ ID NO. 39; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO. 70, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO. 71. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 43, CDR-H2 comprising amino acid sequence SEQ ID NO. 44 and CDR-H3 comprising amino acid sequence SEQ ID NO. 45; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 55, CDR-H2 comprising amino acid sequence SEQ ID NO. 57 and CDR-H3 comprising amino acid sequence SEQ ID NO. 45; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 72, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 73. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 1, CDR-H2 comprising amino acid sequence SEQ ID NO. 2 and CDR-H3 comprising amino acid sequence SEQ ID NO. 3; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 49, CDR-H2 comprising amino acid sequence SEQ ID NO. 50 and CDR-H3 comprising amino acid sequence SEQ ID NO. 3; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 177, CDR-H2 comprising amino acid sequence SEQ ID NO. 178 and CDR-H3 comprising amino acid sequence SEQ ID NO. 179; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 183, CDR-H2 comprising amino acid sequence SEQ ID NO. 184 and CDR-H3 comprising amino acid sequence SEQ ID NO. 179; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO. 185, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO. 186.
In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising the amino acid sequence X 1 X 2 AIS, wherein X 1 S, K, G, N, R, D, T or G, and wherein X 2 Y, L, H or F (SEQ ID NO: 259); CDR-H2 comprising the amino acid sequence X 1 X 2 X 3 PX 4 X 5 X 6 X 7 X 8 X 9 YX 10 QKFX 11 G, wherein X 1 Is G or H, X 2 Is I or F, X 3 I, N or M, X 4 G, N, H, S, R, I or A, X 5 A, N, H, S, T, F or Y, X 6 A, D or G, X 7 T, E, K, V, Q or A, X 8 Is A or T, X 9 Is N or K, X 10 Is A or N, and X 11 Q or T (SEQ ID NO: 260); and CDR-H3 comprising the amino acid sequence X 1 X 2 X 3 GX 4 X 5 LFX 6 X 7 Wherein X is 1 Is D or A, X 2 A, G, E, R, Y, K, N, Q, L or F, X 3 A, L, P or Y, X 4 Is I or L, X 5 R, A, Q or S, X 6 Is A or D, and X 7 D, E, A or S (SEQ ID NO: 261); and wherein the VL domain comprises: CDR-L1 comprising the amino acid sequence X 1 X 2 SX 3 X 4 IX 5 GX 6 LN, wherein X 1 R or G, X 2 Is A or T, X 3 Q or E, X 4 E, N, T, S, A, K, D, G, R or Q, X 5 Is Y or S, and X 6 A or V (SEQ ID NO: 262); CDR-L2 comprising the amino acid sequence GX 1 X 2 X 3 LX 4 X 5 Wherein X is 1 Is A or S, X 2 T, S, E, Q or D, X 3 N, R, A, E or H, X 4 Q or A, and X 5 S or D (SEQ ID NO: 263); and CDR-L3 comprising the amino acid sequence QX 1 X 2 X 3 X 4 X 5 PWT, wherein X 1 S, N, D, Q, A or E, X 2 T, I or S, X 3 Y, L or F, X 4 D, G, T, E, Q, A or Y, and X 5 A, T, R, S, K or Y (SEQ ID NO: 264). In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 226 and CDR-H3 comprising amino acid sequence SEQ ID NO. 227; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO 245, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO 246. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: comprising the amino acid sequence SEQ ID NO. 2 25, CDR-H2 comprising the amino acid sequence SEQ ID No. 232 and CDR-H3 comprising the amino acid sequence SEQ ID No. 233. And wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 251, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 252. In some embodiments, the VH domain comprises the amino acid sequence SEQ ID NO 251; and the VL domain comprises the amino acid sequence SEQ ID NO. 252. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 232 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 253, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 254. In some embodiments, the VH domain further comprises: FW-1 comprising sequence QVQLVQSGAEVKKPGSSVKVSCKASGGTFS (SEQ ID NO: 274), FW-2 comprising sequence WVRQAPGQGLEWMG (SEQ ID NO: 275), FW-3 comprising sequence RVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 276) and/or FW-4 comprising sequence WGQGTLVTVSS (SEQ ID NO: 277). In some embodiments, the VL domain further comprises: FW-1 comprising sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 289), FW-2 comprising sequence WYQQKPGKAPKLLIY (SEQ ID NO: 290), FW-3 comprising sequence GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 291) and/or FW-4 comprising sequence FGGGTKVEIK (SEQ ID NO: 292).
In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domainAnd a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising the amino acid sequence GX 1 X 2 FX 3 X 4 X 5 Wherein X is 1 G, Y, S or A, X 2 T, S, G, R, N or H, X 3 S, T, R, H, Y, G or P, X 4 S, K, G, N, R, D, T or G, and X 5 Y, L, H or F (SEQ ID NO: 265); CDR-H2 comprising the amino acid sequence X 1 PX 2 X 3 X 4 X 5 Wherein X is 1 I, N or M, X 2 G, N, H, S, R, I or A, X 3 A, N, H, S, T, F or Y, X 4 A, D or G, and X 5 T, E, K, V, Q or A (SEQ ID NO: 266); and CDR-H3 comprising the amino acid sequence X 1 X 2 X 3 GX 4 X 5 LFX 6 X 7 Wherein X is 1 Is D or A, X 2 A, G, E, R, Y, K, N, Q, L or F, X 3 A, L, P or Y, X 4 Is I or L, X 5 R, A, Q or S, X 6 Is A or D, and X 7 D, E, A or S (SEQ ID NO: 267); and wherein the VL domain comprises: CDR-L1 comprising the amino acid sequence X 1 X 2 SX 3 X 4 IX 5 GX 6 LN, wherein X 1 R or G, X 2 Is A or T, X 3 Q or E, X 4 E, N, T, S, A, K, D, G, R or Q, X 5 Is Y or S, and X 6 A or V (SEQ ID NO: 262); CDR-L2 comprising the amino acid sequence GX 1 X 2 X 3 LX 4 X 5 Wherein X is 1 Is A or S, X 2 T, S, E, Q or D, X 3 N, R, A, E or H, X 4 Q or A, and X 5 S or D (SEQ ID NO: 263); and CDR-L3 comprising the amino acid sequence QX 1 X 2 X 3 X 4 X 5 PWT, wherein X 1 S, N, D, Q, A or E, X 2 T, I or S, X 3 Y, L or F, X 4 D, G, T, E, Q, A or Y, and X 5 A, T, R, S, K or Y (SEQ ID NO: 264). In some embodiments, theThe VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 239 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO 245; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO 246. In some embodiments, the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 243 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 251; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 252. In some embodiments, the VH domain comprises the amino acid sequence SEQ ID NO 251; and the VL domain comprises the amino acid sequence SEQ ID NO. 252. In some embodiments, the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 243 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 253; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SE Q ID NO. 254. In some embodiments, the VH domain further comprises: comprises the sequence QVQLVQS GAEVKKPGSSVKVSCKAS (SEQ ID NO:27 8) FW-1 comprising sequence AISWVRQAPGQGLEWMGGI (SEQ ID NO: 279), FW-3 comprising sequence ANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 280) and/or FW-4 comprising sequence WGQGTLVTVSS (SEQ ID NO: 277). In some embodiments, the VL domain further comprises: FW-1 comprising sequence DIQ MTQSPSSLSASVGDRVTITC (SEQ ID NO: 289), FW-2 comprising sequence WYQQKPGKAPKLLIY (SEQ ID NO: 290), FW-3 comprising sequence GVPS RFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 291) and/or FW-4 comprising sequence FGGGTKVEIK (SEQ ID NO: 292).
In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising the amino acid sequence X 1 YX 2 MS, wherein X 1 S, D, E, A or Q, and X 2 A, G or T (SEQ ID NO: 268); CDR-H2 comprising the amino acid sequence DIX 1 X 2 X 3 GX 4 X 5 TX 6 YA DSVKG, wherein X 1 T, N, S, Q, E, H, R or A, X 2 Y, W, F or H, X 3 A, S, Q, E or T, X 4 Is G or E, X 5 Is S or I, and X 6 Is A or G (SEQ ID NO: 269); and CDR-H3 comprising the amino acid sequence X 1 X 2 X 3 YX 4 WX 5 X 6 AX 7 DX 8 Wherein X is 1 Is S or A, X 2 N, H, A, D, L, Q, Y or R, X 3 A, N, S or G, X 4 A, V, R, E or S, X 5 Is D or S, X 6 D, N, Q, E, S, T or L, X 7 L, F or M, and X 8 I, Y or V (SEQ ID NO: 270); and the VL domain comprises: CDR-L1 comprising amino acid sequence RASQSVSSNLA (SEQ ID NO: 40), CDR-L2 comprising amino acid sequence GASS RAT (SEQ ID NO: 41) and CDR-L3 comprising amino acid sequence QQYGSSPPVT (SEQ ID NO: 42). In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 229, CDR-H2 comprising amino acid sequence SEQ ID NO. 230 and CDR-H3 comprising amino acid sequence SEQ ID NO. 231; and wherein the VLThe domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 247, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 248. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 249, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 250. In some embodiments, the VH domain comprises the amino acid sequence SEQ ID NO 249; and wherein the VL domain comprises the amino acid sequence SEQ ID NO. 250. In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 229, CDR-H2 comprising amino acid sequence SEQ ID NO. 237 and CDR-H3 comprising amino acid sequence SEQ ID NO. 231; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 255, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 256. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 257, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 258. In some embodiments, the VH domain further comprises: FW-1 comprising sequence EVQLVESGGGLVQP GGSLRLSCAASGFTFS (SEQ ID NO: 281), FW-2 comprising sequence WVR QAPGKGLEWVS (SEQ ID NO: 282), FW-3 comprising sequence RFTISRDN AKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 283) and/or FW-3 comprising sequence WGQGTMVTVSS (S) EQ ID NO: 284) or WGQGTLVTVS S (SEQ ID NO: 285). In some embodiments, the VL domain further comprises: FW-1 comprising sequence EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising sequence WYQQKPGQAPRLLIY (SEQ ID NO: 294), FW-3 comprising sequence GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 295) and/or FW-4 comprising sequence FGQGTKVEIK (SEQ ID NO: 296).
In some embodiments, the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising the amino acid sequence GFTFX 1 X 2 Y, wherein X 1 S, D, E, Q, S or A, and X 2 S, D, E, A or Q (SEQ ID NO: 271); CDR-H2 comprising the amino acid sequence X 1 X 2 X 3 GX 4 X 5 Wherein X is 1 T, N, S, Q, E, H, R or A, X 2 Y, W, F or H, X 3 A, S, Q, E or T, X 4 Is G or E, and X 5 S or I (SEQ ID NO: 272); and CDR-H3 comprising the amino acid sequence X 1 X 2 X 3 YX 4 WX 5 X 6 AX 7 DX 8 Wherein X is 1 Is S or A, X 2 N, H, A, D, L, Q, Y or R, X 3 A, N, S or G, X 4 A, V, R, E or S, X 5 Is D or S, X 6 D, N, Q, E, S, T or L, X 7 L, F or M, and X 8 I, Y or V (SEQ ID NO: 273); and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence RASQSVSSNLA (SEQ ID NO: 40); CDR-L2 comprising the amino acid sequence GASSRAT (SEQ ID NO: 41); and CDR-L3 comprising amino acid sequence QQYGSSPPVT (SEQ ID NO: 42). In some embodiments, the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 240, CDR-H2 comprising amino acid sequence SEQ ID NO. 241 and CDR-H3 comprising amino acid sequence SEQ ID NO. 242; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the VH domain comprises at least 90%, at least 95% of the sequence SEQ ID NO 247, An amino acid sequence that is at least 99% or 100% identical; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO 248. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 249; and wherein the VL domain comprises an amino acid sequence at least 90%, at least 95%, at least 99% or 100% identical to sequence SE Q ID NO:250. In some embodiments, the VH domain comprises the amino acid sequence SEQ ID NO 249; and wherein the VL domain comprises the amino acid sequence SEQ ID NO. 250. In some embodiments, the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 240, CDR-H2 comprising amino acid sequence SEQ ID NO. 244 and CDR-H3 comprising amino acid sequence SEQ ID NO. 242; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 255; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO. 256. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 257; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO 258. In some embodiments, the VH domain further comprises: FW-1 comprising sequence EVQLVESGGGLVQPGGSLRLS CAAS (SEQ ID NO: 286), FW-2 comprising sequence AMSWVRQAPGKGLE WVSDI (SEQ ID NO: 287), FW-3 comprising sequence TAYADSVKGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 288) and/or FW-4 comprising sequence WGQGTMVTVSS (SEQ ID NO: 284) or WGQGTLVT VSS (SEQ ID NO: 285). In some embodiments, the VL domain further comprises: FW-1 comprising sequence EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising sequence WYQQKPGQAPRLLIY (SEQ ID NO: 294), FW-3 comprising sequence GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 295) and FW-3 comprising sequence FGQGTKVEIK (S) EQ ID NO: 296) FW-4.
In some embodiments according to any one of the embodiments described herein, the antibody is a multispecific antibody (e.g., bispecific antibody).
Further provided herein are fusion proteins comprising: a first portion comprising an antibody or fragment of any one of the above embodiments and a second portion comprising a cytokine, chemokine or growth factor. In some embodiments, the first moiety is fused to the second moiety directly or via a linker. In some embodiments, the first portion comprises a human or humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain, wherein: the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 13, CDR-H2 comprising amino acid sequence SEQ ID NO. 14 and CDR-H3 comprising amino acid sequence SEQ ID NO. 15; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18; the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 19, CDR-H2 comprising amino acid sequence SEQ ID NO. 20 and CDR-H3 comprising amino acid sequence SEQ ID NO. 21; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24; the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 25, CDR-H2 comprising amino acid sequence SEQ ID NO. 26 and CDR-H3 comprising amino acid sequence SEQ ID NO. 27; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30; the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 31, CDR-H2 comprising amino acid sequence SEQ ID NO. 32 and CDR-H3 comprising amino acid sequence SEQ ID NO. 33; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36; the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 37, CDR-H2 comprising amino acid sequence SEQ ID NO. 38 and CDR-H3 comprising amino acid sequence SEQ ID NO. 39; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42; the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 43, CDR-H2 comprising amino acid sequence SEQ ID NO. 44 and CDR-H3 comprising amino acid sequence SEQ ID NO. 45; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48; the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 1, CDR-H2 comprising amino acid sequence SEQ ID NO. 2 and CDR-H3 comprising amino acid sequence SEQ ID NO. 3; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6; the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 177, CDR-H2 comprising amino acid sequence SEQ ID NO. 178 and CDR-H3 comprising amino acid sequence SEQ ID NO. 179; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182; the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 226 and CDR-H3 comprising amino acid sequence SEQ ID NO. 227; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 229, CDR-H2 comprising amino acid sequence SEQ ID NO. 230 and CDR-H3 comprising amino acid sequence SEQ ID NO. 231; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence RASQSVSSNLA (SEQ ID NO: 40), CDR-L2 comprising amino acid sequence GASSRAT (SEQ ID NO: 41) and CDR-L3 comprising amino acid sequence QQYGSSPPVT (SEQ ID NO: 42); the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 232 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236; the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 232 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; or the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO:229, a CDR-H2 comprising amino acid sequence SEQ ID NO:237 and a CDR-H3 comprising amino acid sequence SEQ ID NO:231, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence RASQSVSSNLA (SEQ ID NO: 40), CDR-L2 comprising amino acid sequence GASSRAT (SEQ ID NO: 41) and CDR-L3 comprising amino acid sequence QQYGSSPPVT (SEQ ID NO: 42). In some embodiments, the first portion comprises a human or humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain, wherein: the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO:51, a CDR-H2 comprising amino acid sequence SEQ ID NO:52 and a CDR-H3 comprising amino acid sequence SEQ ID NO:15, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO:53, a CDR-H2 comprising amino acid sequence SEQ ID NO:52 and a CDR-H3 comprising amino acid sequence SEQ ID NO:21, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 49, a CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 27, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 54, a CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 33, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO:55, a CDR-H2 comprising amino acid sequence SEQ ID NO:56 and a CDR-H3 comprising amino acid sequence SEQ ID NO:39, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO:55, a CDR-H2 comprising amino acid sequence SEQ ID NO:57 and a CDR-H3 comprising amino acid sequence SEQ ID NO:45, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 49, a CDR-H2 comprising amino acid sequence SEQ ID NO. 50 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 3, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 183, a CDR-H2 comprising amino acid sequence SEQ ID NO. 184 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 179, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 238, a CDR-H2 comprising amino acid sequence SEQ ID NO. 239 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 233, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 240, a CDR-H2 comprising amino acid sequence SEQ ID NO. 241 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 242, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42; the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID No. 238, CDR-H2 comprising amino acid sequence SEQ ID No. 243, and CDR-H3 comprising amino acid sequence SEQ ID No. 233, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236; the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID No. 238, CDR-H2 comprising amino acid sequence SEQ ID No. 243, and CDR-H3 comprising amino acid sequence SEQ ID No. 233, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; or the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 240, a CDR-H2 comprising amino acid sequence SEQ ID NO. 244 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 242, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42.
In some embodiments (e.g., fusion proteins of the disclosure) according to any of the embodiments described herein, the second moiety induces activation of cd8+ T cells. In some embodiments, the fusion protein induces activation of cells expressing human CD8ab heterodimer with at least 10-fold greater potency than activation of cells expressing human CD8aa homodimer. In some embodiments, the fusion protein induces activation of cd8+ T cells with at least 10-fold greater potency than activation of NK cells. In some embodiments, the activation efficacy is measured by EC50 as assessed by cell proliferation. In some embodiments, the first portion comprises: two antibody heavy chain polypeptides comprising from N-terminus to C-terminus a structure according to formula [ I ]:
VH-CH 1-hinge-CH 2-CH3 [ I ]
And two antibody light chain polypeptides comprising a structure according to formula [ II ] from N-terminus to C-terminus:
VL-CL [II]
wherein VH is an antibody heavy chain Variable (VH) domain, wherein CH1 is an antibody CH1 domain, wherein the hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is an antibody light chain Variable (VL) domain, and wherein CL is an antibody constant light chain domain; and wherein the N-terminus of the second moiety is fused to the C-terminus of one of the two CH3 domains (e.g., via a linker of the present disclosure). In some embodiments, the first portion comprises: a first antibody heavy chain polypeptide comprising from N-terminus to C-terminus a structure according to formula [ I ]:
VH-CH 1-hinge-CH 2-CH 3I,
an antibody light chain polypeptide comprising a structure according to formula [ II ] from N-terminus to C-terminus:
VL-CL [II]，
and a second antibody heavy chain polypeptide comprising from N-terminus to C-terminus a structure according to formula [ III ]:
hinge-CH 2-CH3 III,
wherein VH is an antibody heavy chain Variable (VH) domain, wherein CH1 is an antibody CH1 domain, wherein the hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is an antibody light chain Variable (VL) domain, and wherein CL is an antibody constant light chain domain; and wherein the N-terminus of the second portion is fused to the C-terminus of the CH3 domain of the second antibody heavy chain polypeptide (e.g., via a linker of the present disclosure). In some embodiments, the N-terminus of the second portion is fused to the C-terminus of the CH3 domain of the first antibody heavy chain polypeptide (e.g., via a linker of the disclosure). In some embodiments, the first portion comprises a first antibody heavy chain polypeptide comprising a structure according to formula [ I ] from N-terminus to C-terminus:
VH-CH 1-hinge-CH 2-CH 3I,
an antibody light chain polypeptide comprising a structure according to formula [ II ] from N-terminus to C-terminus:
VL-CL [II]，
And a second antibody heavy chain polypeptide comprising from N-terminus to C-terminus a structure according to formula [ III ]:
hinge-CH 2-CH3 III,
wherein VH is an antibody heavy chain Variable (VH) domain, wherein CH1 is an antibody CH1 domain, wherein the hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is an antibody light chain Variable (VL) domain, and wherein CL is an antibody constant light chain domain; and wherein the C-terminus of the second portion is fused to the N-terminus of the hinge domain of the second antibody heavy chain polypeptide (e.g., via a linker of the present disclosure). In some embodiments, the first portion comprises one or two antibody heavy chain polypeptides and one or two antibody light chain polypeptides. In some embodiments, the first portion comprises a single chain antibody or single chain variable fragment (scFv). In some embodiments, the first moiety comprises a VHH antibody. In some embodiments according to any one of the embodiments described herein (e.g., the fusion proteins described above), the VH and VL form an antigen binding site (e.g., specifically bind CD8b and/or CD8 ab). In some embodiments, the first portion comprises: a first antibody heavy chain polypeptide comprising from N-terminus to C-terminus a structure according to formula [ I ]:
VH-CH 1-hinge-CH 2-CH 3I,
an antibody light chain polypeptide comprising a structure according to formula [ II ] from N-terminus to C-terminus:
VL-CL [II]，
and a second antibody heavy chain polypeptide comprising from N-terminus to C-terminus a structure according to formula [ III ]:
hinge-CH 2-CH3 III,
wherein VH is said VH domain, wherein CH1 is an antibody CH1 domain, wherein the hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is said VL domain, and wherein CL is an antibody constant light chain domain; and wherein the N-terminus of the second portion is fused to the C-terminus of the CH3 domain of the first antibody heavy chain polypeptide. In some embodiments, the VH domains of both antibody heavy chain polypeptides comprise: a CDR-H1 comprising amino acid sequence SEQ ID No. 13, a CDR-H2 comprising amino acid sequence SEQ ID No. 14, and a CDR-H3 comprising amino acid sequence SEQ ID No. 15, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18; the VH domains of both antibody heavy chain polypeptides comprise: a CDR-H1 comprising amino acid sequence SEQ ID No. 19, a CDR-H2 comprising amino acid sequence SEQ ID No. 20, and a CDR-H3 comprising amino acid sequence SEQ ID No. 21, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24; the VH domains of both antibody heavy chain polypeptides comprise: a CDR-H1 comprising amino acid sequence SEQ ID No. 25, a CDR-H2 comprising amino acid sequence SEQ ID No. 26, and a CDR-H3 comprising amino acid sequence SEQ ID No. 27, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30; the VH domains of both antibody heavy chain polypeptides comprise: a CDR-H1 comprising amino acid sequence SEQ ID No. 31, a CDR-H2 comprising amino acid sequence SEQ ID No. 32, and a CDR-H3 comprising amino acid sequence SEQ ID No. 33, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36; the VH domains of both antibody heavy chain polypeptides comprise: a CDR-H1 comprising amino acid sequence SEQ ID No. 37, a CDR-H2 comprising amino acid sequence SEQ ID No. 38, and a CDR-H3 comprising amino acid sequence SEQ ID No. 39, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42; the VH domains of both antibody heavy chain polypeptides comprise: a CDR-H1 comprising amino acid sequence SEQ ID No. 43, a CDR-H2 comprising amino acid sequence SEQ ID No. 44, and a CDR-H3 comprising amino acid sequence SEQ ID No. 45, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48; the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID No. 1, CDR-H2 comprising amino acid sequence SEQ ID No. 2 and CDR-H3 comprising amino acid sequence SEQ ID No. 3, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6; the VH domains of both antibody heavy chain polypeptides comprise: a CDR-H1 comprising amino acid sequence SEQ ID No. 177, a CDR-H2 comprising amino acid sequence SEQ ID No. 178, and a CDR-H3 comprising amino acid sequence SEQ ID No. 179, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182; the VH domains of both antibody heavy chain polypeptides comprise: a CDR-H1 comprising amino acid sequence SEQ ID No. 225, a CDR-H2 comprising amino acid sequence SEQ ID No. 226, and a CDR-H3 comprising amino acid sequence SEQ ID No. 227, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID No. 229, CDR-H2 comprising amino acid sequence SEQ ID No. 230, and CDR-H3 comprising amino acid sequence SEQ ID No. 231, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42; the VH domains of both antibody heavy chain polypeptides comprise: a CDR-H1 comprising amino acid sequence SEQ ID No. 225, a CDR-H2 comprising amino acid sequence SEQ ID No. 232, and a CDR-H3 comprising amino acid sequence SEQ ID No. 233, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236; the VH domains of both antibody heavy chain polypeptides comprise: a CDR-H1 comprising amino acid sequence SEQ ID No. 225, a CDR-H2 comprising amino acid sequence SEQ ID No. 232, and a CDR-H3 comprising amino acid sequence SEQ ID No. 233, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; or both antibody heavy chain polypeptides comprising: CDR-H1 comprising amino acid sequence SEQ ID No. 229, CDR-H2 comprising amino acid sequence SEQ ID No. 237 and CDR-H3 comprising amino acid sequence SEQ ID No. 231, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the VH domains of both antibody heavy chain polypeptides comprise: a CDR-H1 comprising amino acid sequence SEQ ID No. 51, a CDR-H2 comprising amino acid sequence SEQ ID No. 52, and a CDR-H3 comprising amino acid sequence SEQ ID No. 15, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18; the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID No. 53, CDR-H2 comprising amino acid sequence SEQ ID No. 52, and CDR-H3 comprising amino acid sequence SEQ ID No. 21, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24; the VH domains of both antibody heavy chain polypeptides comprise: a CDR-H1 comprising amino acid sequence SEQ ID No. 49, a CDR-H2 comprising amino acid sequence SEQ ID No. 52, and a CDR-H3 comprising amino acid sequence SEQ ID No. 27, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30; the VH domains of both antibody heavy chain polypeptides comprise: a CDR-H1 comprising amino acid sequence SEQ ID No. 54, a CDR-H2 comprising amino acid sequence SEQ ID No. 52, and a CDR-H3 comprising amino acid sequence SEQ ID No. 33, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36; the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 55, CDR-H2 comprising amino acid sequence SEQ ID NO. 56 and CDR-H3 comprising amino acid sequence SEQ ID NO. 39; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42; the VH domains of both antibody heavy chain polypeptides comprise: a CDR-H1 comprising amino acid sequence SEQ ID No. 55, a CDR-H2 comprising amino acid sequence SEQ ID No. 57, and a CDR-H3 comprising amino acid sequence SEQ ID No. 45, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48; the VH domains of both antibody heavy chain polypeptides comprise: a CDR-H1 comprising amino acid sequence SEQ ID No. 49, a CDR-H2 comprising amino acid sequence SEQ ID No. 50, and a CDR-H3 comprising amino acid sequence SEQ ID No. 3, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6; the VH domains of both antibody heavy chain polypeptides comprise: a CDR-H1 comprising amino acid sequence SEQ ID No. 183, a CDR-H2 comprising amino acid sequence SEQ ID No. 184, and a CDR-H3 comprising amino acid sequence SEQ ID No. 179, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182; the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID No. 238, CDR-H2 comprising amino acid sequence SEQ ID No. 239, and CDR-H3 comprising amino acid sequence SEQ ID No. 233, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID No. 240, CDR-H2 comprising amino acid sequence SEQ ID No. 241, and CDR-H3 comprising amino acid sequence SEQ ID No. 242, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42; the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID No. 238, CDR-H2 comprising amino acid sequence SEQ ID No. 243, and CDR-H3 comprising amino acid sequence SEQ ID No. 233, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236; the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID No. 238, CDR-H2 comprising amino acid sequence SEQ ID No. 243, and CDR-H3 comprising amino acid sequence SEQ ID No. 233, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; or both antibody heavy chain polypeptides comprising: a CDR-H1 comprising amino acid sequence SEQ ID No. 240, a CDR-H2 comprising amino acid sequence SEQ ID No. 244, and a CDR-H3 comprising amino acid sequence SEQ ID No. 242, and wherein said VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO 13, a CDR-H2 comprising amino acid sequence SEQ ID NO 14 and a CDR-H3 comprising amino acid sequence SEQ ID NO 15, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 19, a CDR-H2 comprising amino acid sequence SEQ ID NO. 20 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 21, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 25, a CDR-H2 comprising amino acid sequence SEQ ID NO. 26 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 27, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 31, a CDR-H2 comprising amino acid sequence SEQ ID NO. 32 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 33, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO:37, a CDR-H2 comprising amino acid sequence SEQ ID NO:38 and a CDR-H3 comprising amino acid sequence SEQ ID NO:39, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 43, a CDR-H2 comprising amino acid sequence SEQ ID NO. 44 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 45, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48; the VH domain comprises: a CDR-H1 comprising the amino acid sequence SEQ ID No. 1, a CDR-H2 comprising the amino acid sequence SEQ ID No. 2 and a CDR-H3 comprising the amino acid sequence SEQ ID No. 3, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO:177, a CDR-H2 comprising amino acid sequence SEQ ID NO:178 and a CDR-H3 comprising amino acid sequence SEQ ID NO:179, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO:225, a CDR-H2 comprising amino acid sequence SEQ ID NO:226 and a CDR-H3 comprising amino acid sequence SEQ ID NO:227, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 229, a CDR-H2 comprising amino acid sequence SEQ ID NO. 230 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 231, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO:225, a CDR-H2 comprising amino acid sequence SEQ ID NO:232 and a CDR-H3 comprising amino acid sequence SEQ ID NO:233, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO:225, a CDR-H2 comprising amino acid sequence SEQ ID NO:232 and a CDR-H3 comprising amino acid sequence SEQ ID NO:233, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; or the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO:229, a CDR-H2 comprising amino acid sequence SEQ ID NO:237 and a CDR-H3 comprising amino acid sequence SEQ ID NO:231, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO:51, a CDR-H2 comprising amino acid sequence SEQ ID NO:52 and a CDR-H3 comprising amino acid sequence SEQ ID NO:15, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO:53, a CDR-H2 comprising amino acid sequence SEQ ID NO:52 and a CDR-H3 comprising amino acid sequence SEQ ID NO:21, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 49, a CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 27, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 54, a CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 33, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO:55, a CDR-H2 comprising amino acid sequence SEQ ID NO:56 and a CDR-H3 comprising amino acid sequence SEQ ID NO:39, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO:55, a CDR-H2 comprising amino acid sequence SEQ ID NO:57 and a CDR-H3 comprising amino acid sequence SEQ ID NO:45, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 49, a CDR-H2 comprising amino acid sequence SEQ ID NO. 50 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 3, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 183, a CDR-H2 comprising amino acid sequence SEQ ID NO. 184 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 179, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 238, a CDR-H2 comprising amino acid sequence SEQ ID NO. 239 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 233, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 240, a CDR-H2 comprising amino acid sequence SEQ ID NO. 241 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 242, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42; the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID No. 238, CDR-H2 comprising amino acid sequence SEQ ID No. 243, and CDR-H3 comprising amino acid sequence SEQ ID No. 233, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236; the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID No. 238, CDR-H2 comprising amino acid sequence SEQ ID No. 243, and CDR-H3 comprising amino acid sequence SEQ ID No. 233, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; or the VH domain comprises: a CDR-H1 comprising amino acid sequence SEQ ID NO. 240, a CDR-H2 comprising amino acid sequence SEQ ID NO. 244 and a CDR-H3 comprising amino acid sequence SEQ ID NO. 242, and wherein said VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to sequence SEQ ID No. 62, and wherein the VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to sequence SEQ ID No. 63; said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 64, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 65; said VH domain of two antibody heavy chain polypeptides comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 66, and wherein said VL domain of two antibody light chain polypeptides comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 67; said VH domain of both antibody heavy chain polypeptides comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 68, and wherein said VL domains of both antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 69; said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 70, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 71; said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 72, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 73; said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 185, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 186; said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 245, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 246; said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 251, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 252; the VH domain comprises the amino acid sequence SEQ ID No. 251, and wherein the VL domain comprises the amino acid sequence SEQ ID No. 252; said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 253, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 254; said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 247, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 248; said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 249, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 250; the VH domain comprises the amino acid sequence SEQ ID No. 249, and wherein the VL domain comprises the amino acid sequence SEQ ID No. 250; said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 255, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 256; or both antibody heavy chain polypeptides comprising an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 257, and wherein both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 258. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 62, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 63; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 64, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 65; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 66, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 67; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 68, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 69; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 70, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 71; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 72, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 73; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 185, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 186; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 245, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 246; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 251, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 252; the VH domain comprises the amino acid sequence SEQ ID No. 251, and wherein the VL domain comprises the amino acid sequence SEQ ID No. 252; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 253, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 254; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 247, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 248; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 249, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 250; the VH domain comprises the amino acid sequence SEQ ID No. 249, and wherein the VL domain comprises the amino acid sequence SEQ ID No. 250; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 255, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 256; or the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 257, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 258. In some embodiments, one or both of the antibody heavy chain polypeptides comprises the following amino acid substitutions: L234A, L a and G237A, numbered according to EU index. In some embodiments, a first one of the antibody heavy chain polypeptides comprises amino acid substitutions Y349C and T366W, and a second one of the antibody heavy chain polypeptides comprises amino acid substitutions S354C, T366S, L a and Y407V, numbered according to the EU index.
In some embodiments according to any of the embodiments described herein, the second moiety comprises an IL-2 polypeptide. In some embodiments, the IL-2 polypeptide is a mutant IL-2 polypeptide comprising one or more mutations relative to a human IL-2 polypeptide, which human IL-2 polypeptide comprises sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 81). In some embodiments, the mutant IL-2 polypeptide has a binding affinity for IL-2Rα that is 50% or more reduced compared to the binding affinity for IL-2Rα of a wild-type IL-2 polypeptide comprising sequence SEQ ID: 81. In some embodiments, the mutant IL-2 polypeptide has a binding affinity for IL-2Rβ that is 50% or more lower than the binding affinity for IL-2Rβ of a wild-type IL-2 polypeptide comprising the sequence SEQ ID 81; and/or the binding affinity of the mutant IL-2 polypeptide for IL-2rγ is reduced by 50% or more compared to the binding affinity of a wild-type IL-2 polypeptide comprising the sequence SEQ ID:81 for IL-2rγ. In some embodiments, the IL-2 polypeptide comprises the sequence of SEQ ID NO:81 having one, two, three, four, or five amino acid substitutions relative to SEQ ID NO:81, and wherein the one, two, three, four, or five substitutions comprise a substitution at a position of SEQ ID NO:81 selected from the group consisting of: q11, H16, L18, L19, D20, Q22, R38, F42, K43, Y45, E62, P65, E68, V69, L72, D84, S87, N88, V91, I92, T123, Q126, S127, I129, and S130. In some embodiments, the IL-2 polypeptide comprises the sequence of SEQ ID NO:81 having one of the following sets of amino acid substitutions (relative to sequence SEQ ID NO: 81): R38E and F42A; R38D and F42A; F42A and E62Q; R38A and F42K; R38E, F a and N88S; R38E, F a and N88A; R38E, F a and N88G; R38E, F a and N88R; R38E, F a and N88T; R38E, F a and N88D; R38E, F a and V91E; R38E, F a and D84H; R38E, F a and D84K; R38E, F a and D84R; H16D, R E and F42A; H16E, R E and F42A; R38E, F a and Q126S; R38D, F a and N88S; R38D, F a and N88A; R38D, F a and N88G; R38D, F a and N88R; R38D, F a and N88T; R38D, F a and N88D; R38D, F a and V91E; R38D, F a and D84H; R38D, F a and D84K; R38D, F a and D84R; H16D, R D and F42A; H16E, R D and F42A; R38D, F a and Q126S; R38A, F K and N88S; R38A, F K and N88A; R38A, F K and N88G; R38A, F K and N88R; R38A, F K and N88T; R38A, F K and N88D; R38A, F K and V91E; R38A, F K and D84H; R38A, F K and D84K; R38A, F K and D84R; H16D, R a and F42K; H16E, R a and F42K; R38A, F K and Q126S; F42A, E Q and N88S; F42A, E Q and N88A; F42A, E Q and N88G; F42A, E Q and N88R; F42A, E Q and N88T; F42A, E Q and N88D; f42A, E Q and V91E; F42A, E Q and D84H; F42A, E Q and D84K; F42A, E Q and D84R; H16D, F a and E62Q; H16E, F a and E62Q; F42A, E Q and Q126S. In some embodiments, the IL-2 polypeptide comprises the sequence of SEQ ID NO:81 having another amino acid substitution at position C125 relative to SE Q ID NO: 81. In some embodiments, the IL-2 polypeptide comprises the sequence of SEQ ID NO:81 having one of the following sets of amino acid substitutions (relative to sequence SEQ ID NO: 81): R38E, F a and C125A; R38D, F a and C125A; F42A, E Q and C125A; R38A, F K and C125A; R38E, F42A, N S and C125A; R38E, F42A, N a and C125A; R38E, F42A, N G and C125A; R38E, F42A, N R and C125A; R38E, F42A, N T and C125A; R38E, F42A, N D and C125A; R38E, F, 42, A, V E and C125A; R38E, F42A, D H and C125A; R38E, F42A, D K and C125A; R38E, F42A, D R and C125A; H16D, R E, F a and C125A; H16E, R E, F a and C125A; R38E, F42A, C a and Q126S; R38D, F42A, N S and C125A; R38D, F42A, N a and C125A; R38D, F42A, N G and C125A; R38D, F42A, N R and C125A; R38D, F42A, N T and C125A; R38D, F42A, N D and C125A; R38D, F, 42, A, V E and C125A; R38D, F42A, D H and C125A; R38D, F42A, D K and C125A; R38D, F42A, D R and C125A; H16D, R D, F a and C125A; H16E, R D, F a and C125A; R38D, F42A, C a and Q126S; R38A, F42K, N S and C125A; R38A, F42K, N G and C125A; R38A, F42K, N R and C125A; R38A, F42K, N T and C125A; R38A, F42K, N D and C125A; R38A, F42K, N a and C125A; R38A, F, 42, K, V E and C125A; R38A, F42K, D H and C125A; R38A, F42K, D K and C125A; R38A, F42K, D R and C125A; H16D, R A, F K and C125A; H16E, R A, F K and C125A; R38A, F42K, C a and Q126S; F42A, E62Q, N S and C125A; F42A, E62Q, N a and C125A; F42A, E62Q, N G and C125A; F42A, E62Q, N88R and C125A; F42A, E62Q, N T and C125A; F42A, E62Q, N88D and C125A; F42A, E62Q, V E and C125A; F42A, E Q and D84H and C125A; F42A, E Q and D84K and C125A; F42A, E Q and D84R and C125A; H16D, F a and E62Q and C125A; H16E, F, 42, A, E Q and C125A; F42A, E62Q, C a and Q126S; F42A, N S and C125A; F42A, N a and C125A; F42A, N G and C125A; F42A, N R and C125A; F42A, N T and C125A; F42A, N D and C125A; F42A, V91E and C125A; F42A, D H and C125A; F42A, D K and C125A; F42A, D R and C125A; H16D, F a and C125A; H16E, F a and C125A; and F42A, C125A and Q126S. In some embodiments, the IL-2 polypeptide comprises the sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNY KNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSK NFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITF AQSIISTLT (SEQ ID NO: 80). In some embodiments, the IL-2 polypeptide comprises the sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 297). In some embodiments, the IL-2 polypeptide comprises a sequence selected from the group consisting of SEQ ID Nos 85-155 and 190-216. In some embodiments, the IL-2 polypeptide comprises a sequence selected from the group consisting of SEQ ID No. 80, 85-155, 190-216, 297 and 354-383. In some embodiments, the second moiety comprises a polypeptide that induces signaling via IL2rβγ. In some embodiments, the second portion comprises an IL-21 polypeptide.
In some embodiments (e.g., fusion proteins of the disclosure) according to any of the embodiments described herein, one or both of the antibody Fc domains comprises a human IgG1 Fc domain with the following amino acid substitutions: L234A, L235A, G a and K322A, numbered according to EU index. In some embodiments, one or both of the antibody Fc domains does not have a C-terminal lysine. In some embodiments, one or both of the antibody Fc domains comprises a human IgG1 Fc domain with the following amino acid substitutions: L234A, L a and G237A, numbered according to EU index. In some embodiments, one or both of the antibody Fc domains does not have a C-terminal lysine. In some embodiments, the first of the two Fc domains comprises a human IgG1 Fc domain having amino acid substitutions Y349C and T366W, and the second of the two Fc domains comprises a human IgG1 Fc domain having amino acid substitutions S354C, T366S, L368A and Y407V, numbered according to the EU index. In some embodiments, one or both of the antibody Fc domains does not have a C-terminal lysine. In some embodiments (e.g., fusion proteins of the present disclosure), the linker comprises the sequence (GGGS) xGn (SEQ ID NO: 74), (GGGGS) xGn (SEQ ID NO: 75) or (GGGGS) xGn (SEQ ID NO: 76), S (GGGS) xGn (SEQ ID NO: 386), S (GGGGS) xGn (SEQ ID NO: 387) or S (GGGGS) xGn (SEQ ID NO: 388), wherein x = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and wherein n = 0, 1, 2, or 3. In some embodiments, the linker comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 79) or SGGGGSGGGGSGGGGS (SEQ ID NO: 389). In some embodiments (e.g., in a fusion protein of the disclosure), the linker connects a first portion of the disclosure (e.g., a human or humanized antibody or antigen binding fragment thereof that specifically binds CD8b and/or CD8 ab) to a second portion of the disclosure (e.g., an IL-2 polypeptide of the disclosure, an IL-21 polypeptide of the disclosure, or a polypeptide of the disclosure that induces signaling via IL2rβγ).
In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 156, a heavy chain comprising the amino acid sequence SEQ ID NO. 157, and a heavy chain comprising the amino acid sequence SEQ ID NO. 158. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 156, a heavy chain comprising the amino acid sequence SEQ ID NO. 157, and a heavy chain comprising the amino acid sequence SEQ ID NO. 217. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 159, a heavy chain comprising the amino acid sequence SEQ ID NO. 160, and a heavy chain comprising the amino acid sequence SEQ ID NO. 161. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 159, a heavy chain comprising the amino acid sequence SEQ ID NO. 160, and a heavy chain comprising the amino acid sequence SEQ ID NO. 218. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 162, a heavy chain comprising the amino acid sequence SEQ ID NO. 163, and a heavy chain comprising the amino acid sequence SEQ ID NO. 164. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 162, a heavy chain comprising the amino acid sequence SEQ ID NO. 163, and a heavy chain comprising the amino acid sequence SEQ ID NO. 219. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 165, a heavy chain comprising the amino acid sequence SEQ ID NO. 166, and a heavy chain comprising the amino acid sequence SEQ ID NO. 167. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 165, a heavy chain comprising the amino acid sequence SEQ ID NO. 166, and a heavy chain comprising the amino acid sequence SEQ ID NO. 220. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 168, a heavy chain comprising the amino acid sequence SEQ ID NO. 169, and a heavy chain comprising the amino acid sequence SEQ ID NO. 170. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 168, a heavy chain comprising the amino acid sequence SEQ ID NO. 169, and a heavy chain comprising the amino acid sequence SEQ ID NO. 221. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 171, a heavy chain comprising the amino acid sequence SEQ ID NO. 172, and a heavy chain comprising the amino acid sequence SEQ ID NO. 173. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 171, a heavy chain comprising the amino acid sequence SEQ ID NO. 172, and a heavy chain comprising the amino acid sequence SEQ ID NO. 222. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO:174, a heavy chain comprising amino acid sequence SEQ ID NO:175, and a heavy chain comprising amino acid sequence SEQ ID NO: 176. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 174, a heavy chain comprising the amino acid sequence SEQ ID NO. 175, and a heavy chain comprising the amino acid sequence SEQ ID NO. 223. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 187, a heavy chain comprising the amino acid sequence SEQ ID NO. 188, and a heavy chain comprising the amino acid sequence SEQ ID NO. 189. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 187, a heavy chain comprising the amino acid sequence SEQ ID NO. 188, and a heavy chain comprising the amino acid sequence SEQ ID NO. 224. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 298, a heavy chain comprising the amino acid sequence SEQ ID NO. 299, and a heavy chain comprising the amino acid sequence SEQ ID NO. 300. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 298, a heavy chain comprising the amino acid sequence SEQ ID NO. 299, and a heavy chain comprising the amino acid sequence SEQ ID NO. 301. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 302, a heavy chain comprising amino acid sequence SEQ ID NO. 303, and a heavy chain comprising amino acid sequence SEQ ID NO. 304. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 302, a heavy chain comprising amino acid sequence SEQ ID NO. 303, and a heavy chain comprising amino acid sequence SEQ ID NO. 305. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 306, a heavy chain comprising amino acid sequence SEQ ID NO. 307, and a heavy chain comprising amino acid sequence SEQ ID NO. 308. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 306, a heavy chain comprising amino acid sequence SEQ ID NO. 307, and a heavy chain comprising amino acid sequence SEQ ID NO. 309. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 310, a heavy chain comprising amino acid sequence SEQ ID NO. 311, and a heavy chain comprising amino acid sequence SEQ ID NO. 312. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 310, a heavy chain comprising amino acid sequence SEQ ID NO. 311, and a heavy chain comprising amino acid sequence SEQ ID NO. 313. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 314, a heavy chain comprising amino acid sequence SEQ ID NO. 315, and a heavy chain comprising amino acid sequence SEQ ID NO. 316. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 314, a heavy chain comprising amino acid sequence SEQ ID NO. 315, and a heavy chain comprising amino acid sequence SEQ ID NO. 317. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 318, a heavy chain comprising the amino acid sequence SEQ ID NO. 319, and a heavy chain comprising the amino acid sequence SEQ ID NO. 320. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 318, a heavy chain comprising amino acid sequence SEQ ID NO. 319, and a heavy chain comprising amino acid sequence SEQ ID NO. 321. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 322, a heavy chain comprising the amino acid sequence SEQ ID NO. 323, and a heavy chain comprising the amino acid sequence SEQ ID NO. 324. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 322, a heavy chain comprising the amino acid sequence SEQ ID NO. 323, and a heavy chain comprising the amino acid sequence SEQ ID NO. 325. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO:326, a heavy chain comprising the amino acid sequence SEQ ID NO:327, and a heavy chain comprising the amino acid sequence SEQ ID NO: 328. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 326, a heavy chain comprising the amino acid sequence SEQ ID NO. 327, and a heavy chain comprising the amino acid sequence SEQ ID NO. 329. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 330, a heavy chain comprising amino acid sequence SEQ ID NO. 331, and a heavy chain comprising amino acid sequence SEQ ID NO. 332. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 330, a heavy chain comprising amino acid sequence SEQ ID NO. 331, and a heavy chain comprising amino acid sequence SEQ ID NO. 333. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 334, a heavy chain comprising the amino acid sequence SEQ ID NO. 335, and a heavy chain comprising the amino acid sequence SEQ ID NO. 336. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 334, a heavy chain comprising the amino acid sequence SEQ ID NO. 335, and a heavy chain comprising the amino acid sequence SEQ ID NO. 337. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 338, a heavy chain comprising the amino acid sequence SEQ ID NO. 339, and a heavy chain comprising the amino acid sequence SEQ ID NO. 340. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 338, a heavy chain comprising the amino acid sequence SEQ ID NO. 339, and a heavy chain comprising the amino acid sequence SEQ ID NO. 341. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 342, a heavy chain comprising the amino acid sequence SEQ ID NO. 343, and a heavy chain comprising the amino acid sequence SEQ ID NO. 344. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 342, a heavy chain comprising the amino acid sequence SEQ ID NO. 343, and a heavy chain comprising the amino acid sequence SEQ ID NO. 345. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 346, a heavy chain comprising the amino acid sequence SEQ ID NO. 347, and a heavy chain comprising the amino acid sequence SEQ ID NO. 348. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 346, a heavy chain comprising the amino acid sequence SEQ ID NO. 347, and a heavy chain comprising the amino acid sequence SEQ ID NO. 349. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 350, a heavy chain comprising the amino acid sequence SEQ ID NO. 351, and a heavy chain comprising the amino acid sequence SEQ ID NO. 352. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 156, a heavy chain comprising the amino acid sequence SEQ ID NO. 157, and a heavy chain comprising the amino acid sequence SEQ ID NO. 217. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 159, a heavy chain comprising the amino acid sequence SEQ ID NO. 160, and a heavy chain comprising the amino acid sequence SEQ ID NO. 218. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 162, a heavy chain comprising the amino acid sequence SEQ ID NO. 163, and a heavy chain comprising the amino acid sequence SEQ ID NO. 219. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 165, a heavy chain comprising the amino acid sequence SEQ ID NO. 166, and a heavy chain comprising the amino acid sequence SEQ ID NO. 220. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 168, a heavy chain comprising the amino acid sequence SEQ ID NO. 169, and a heavy chain comprising the amino acid sequence SEQ ID NO. 221. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 171, a heavy chain comprising the amino acid sequence SEQ ID NO. 172, and a heavy chain comprising the amino acid sequence SEQ ID NO. 222. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 174, a heavy chain comprising the amino acid sequence SEQ ID NO. 175, and a heavy chain comprising the amino acid sequence SEQ ID NO. 223. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 187, a heavy chain comprising the amino acid sequence SEQ ID NO. 188, and a heavy chain comprising the amino acid sequence SEQ ID NO. 224. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 298, a heavy chain comprising the amino acid sequence SEQ ID NO. 299, and a heavy chain comprising the amino acid sequence SEQ ID NO. 301. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 302, a heavy chain comprising amino acid sequence SEQ ID NO. 303, and a heavy chain comprising amino acid sequence SEQ ID NO. 305. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 306, a heavy chain comprising amino acid sequence SEQ ID NO. 307, and a heavy chain comprising amino acid sequence SEQ ID NO. 309. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 310, a heavy chain comprising the amino acid sequence SEQ ID NO. 311, and a heavy chain comprising the amino acid sequence SEQ ID NO. 313. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 314, a heavy chain comprising amino acid sequence SEQ ID NO. 315, and a heavy chain comprising amino acid sequence SEQ ID NO. 317. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 318, a heavy chain comprising amino acid sequence SEQ ID NO. 319, and a heavy chain comprising amino acid sequence SEQ ID NO. 321. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 322, a heavy chain comprising the amino acid sequence SEQ ID NO. 323, and a heavy chain comprising the amino acid sequence SEQ ID NO. 325. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 326, a heavy chain comprising the amino acid sequence SEQ ID NO. 327, and a heavy chain comprising the amino acid sequence SEQ ID NO. 329. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 330, a heavy chain comprising amino acid sequence SEQ ID NO. 331, and a heavy chain comprising amino acid sequence SEQ ID NO. 333. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 334, a heavy chain comprising the amino acid sequence SEQ ID NO. 335, and a heavy chain comprising the amino acid sequence SEQ ID NO. 337. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 338, a heavy chain comprising the amino acid sequence SEQ ID NO. 339, and a heavy chain comprising the amino acid sequence SEQ ID NO. 341. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 342, a heavy chain comprising the amino acid sequence SEQ ID NO. 343, and a heavy chain comprising the amino acid sequence SEQ ID NO. 345. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 346, a heavy chain comprising the amino acid sequence SEQ ID NO. 347, and a heavy chain comprising the amino acid sequence SEQ ID NO. 349. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 350, a heavy chain comprising amino acid sequence SEQ ID NO. 351, and a heavy chain comprising amino acid sequence SEQ ID NO. 353. In some embodiments, the fusion protein comprises one or two antigen binding sites, each antigen binding site comprising a VL domain from one of the light chains and a VH domain from one of the heavy chains (e.g., the fusion protein comprises two antigen binding sites: one comprising a VL domain from one of the two light chains and a VH domain from one of the heavy chains, and the other comprising a VL domain from the other light chain and a VH domain from the other heavy chain).
In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 156, a polypeptide comprising the amino acid sequence SEQ ID NO. 157, and a polypeptide comprising the amino acid sequence SEQ ID NO. 158. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 156, a polypeptide comprising the amino acid sequence SEQ ID NO. 157, and a polypeptide comprising the amino acid sequence SEQ ID NO. 217. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 159, a polypeptide comprising the amino acid sequence SEQ ID NO. 160, and a polypeptide comprising the amino acid sequence SEQ ID NO. 161. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 159, a polypeptide comprising the amino acid sequence SEQ ID NO. 160, and a polypeptide comprising the amino acid sequence SEQ ID NO. 218. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO:162, a polypeptide comprising the amino acid sequence SEQ ID NO:163, and a polypeptide comprising the amino acid sequence SEQ ID NO: 164. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO:162, a polypeptide comprising the amino acid sequence SEQ ID NO:163, and a polypeptide comprising the amino acid sequence SEQ ID NO: 219. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 165, a polypeptide comprising the amino acid sequence SEQ ID NO. 166, and a polypeptide comprising the amino acid sequence SEQ ID NO. 167. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 165, a polypeptide comprising the amino acid sequence SEQ ID NO. 166, and a polypeptide comprising the amino acid sequence SEQ ID NO. 220. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 168, a polypeptide comprising the amino acid sequence SEQ ID NO. 169, and a polypeptide comprising the amino acid sequence SEQ ID NO. 170. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 168, a polypeptide comprising the amino acid sequence SEQ ID NO. 169, and a polypeptide comprising the amino acid sequence SEQ ID NO. 221. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 171, a polypeptide comprising the amino acid sequence SEQ ID NO. 172, and a polypeptide comprising the amino acid sequence SEQ ID NO. 173. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 171, a polypeptide comprising the amino acid sequence SEQ ID NO. 172, and a polypeptide comprising the amino acid sequence SEQ ID NO. 222. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO:174, a polypeptide comprising the amino acid sequence SEQ ID NO:175, and a polypeptide comprising the amino acid sequence SEQ ID NO: 176. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO:174, a polypeptide comprising the amino acid sequence SEQ ID NO:175, and a polypeptide comprising the amino acid sequence SEQ ID NO: 223. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 187, a polypeptide comprising the amino acid sequence SEQ ID NO. 188, and a polypeptide comprising the amino acid sequence SEQ ID NO. 189. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 187, a polypeptide comprising the amino acid sequence SEQ ID NO. 188, and a polypeptide comprising the amino acid sequence SEQ ID NO. 224. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 298, a polypeptide comprising the amino acid sequence SEQ ID NO. 299, and a polypeptide comprising the amino acid sequence SEQ ID NO. 300. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 298, a polypeptide comprising the amino acid sequence SEQ ID NO. 299, and a polypeptide comprising the amino acid sequence SEQ ID NO. 301. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 302, a polypeptide comprising the amino acid sequence SEQ ID NO. 303, and a polypeptide comprising the amino acid sequence SEQ ID NO. 304. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 302, a polypeptide comprising the amino acid sequence SEQ ID NO. 303, and a polypeptide comprising the amino acid sequence SEQ ID NO. 305. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 306, a polypeptide comprising the amino acid sequence SEQ ID NO. 307, and a polypeptide comprising the amino acid sequence SEQ ID NO. 308. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising amino acid sequence SEQ ID NO. 306, a polypeptide comprising amino acid sequence SEQ ID NO. 307, and a polypeptide comprising amino acid sequence SEQ ID NO. 309. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO:310, a polypeptide comprising the amino acid sequence SEQ ID NO:311, and a polypeptide comprising the amino acid sequence SEQ ID NO: 312. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 310, a polypeptide comprising the amino acid sequence SEQ ID NO. 311, and a polypeptide comprising the amino acid sequence SEQ ID NO. 313. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 314, a polypeptide comprising the amino acid sequence SEQ ID NO. 315, and a polypeptide comprising the amino acid sequence SEQ ID NO. 316. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 314, a polypeptide comprising the amino acid sequence SEQ ID NO. 315, and a polypeptide comprising the amino acid sequence SEQ ID NO. 317. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 318, a polypeptide comprising the amino acid sequence SEQ ID NO. 319, and a polypeptide comprising the amino acid sequence SEQ ID NO. 320. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 318, a polypeptide comprising the amino acid sequence SEQ ID NO. 319, and a polypeptide comprising the amino acid sequence SEQ ID NO. 321. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 322, a polypeptide comprising the amino acid sequence SEQ ID NO. 323, and a polypeptide comprising the amino acid sequence SEQ ID NO. 324. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 322, a polypeptide comprising the amino acid sequence SEQ ID NO. 323, and a polypeptide comprising the amino acid sequence SEQ ID NO. 325. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO:326, a polypeptide comprising the amino acid sequence SEQ ID NO:327, and a polypeptide comprising the amino acid sequence SEQ ID NO: 328. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO:326, a polypeptide comprising the amino acid sequence SEQ ID NO:327, and a polypeptide comprising the amino acid sequence SEQ ID NO: 329. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO:330, a polypeptide comprising the amino acid sequence SEQ ID NO:331, and a polypeptide comprising the amino acid sequence SEQ ID NO: 332. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 330, a polypeptide comprising the amino acid sequence SEQ ID NO. 331, and a polypeptide comprising the amino acid sequence SEQ ID NO. 333. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO:334, a polypeptide comprising the amino acid sequence SEQ ID NO:335, and a polypeptide comprising the amino acid sequence SEQ ID NO: 336. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO:334, a polypeptide comprising the amino acid sequence SEQ ID NO:335, and a polypeptide comprising the amino acid sequence SEQ ID NO: 337. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 338, a polypeptide comprising the amino acid sequence SEQ ID NO. 339, and a polypeptide comprising the amino acid sequence SEQ ID NO. 340. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 338, a polypeptide comprising the amino acid sequence SEQ ID NO. 339, and a polypeptide comprising the amino acid sequence SEQ ID NO. 341. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 342, a polypeptide comprising the amino acid sequence SEQ ID NO. 343, and a polypeptide comprising the amino acid sequence SEQ ID NO. 344. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 342, a polypeptide comprising the amino acid sequence SEQ ID NO. 343, and a polypeptide comprising the amino acid sequence SEQ ID NO. 345. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 346, a polypeptide comprising the amino acid sequence SEQ ID NO. 347, and a polypeptide comprising the amino acid sequence SEQ ID NO. 348. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO. 346, a polypeptide comprising the amino acid sequence SEQ ID NO. 347, and a polypeptide comprising the amino acid sequence SEQ ID NO. 349. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO:350, a polypeptide comprising the amino acid sequence SEQ ID NO:351, and a polypeptide comprising the amino acid sequence SEQ ID NO: 352. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence SEQ ID NO:350, a polypeptide comprising the amino acid sequence SEQ ID NO:351, and a polypeptide comprising the amino acid sequence SEQ ID NO: 353.
Further provided herein are fusion proteins comprising a first portion that binds to human CD8b and a second portion comprising an IL2 polypeptide, wherein the fusion protein comprises four polypeptide chains, wherein: (1) The first polypeptide chain comprises the amino acid sequence SEQ ID NO. 334, the second polypeptide chain comprises the amino acid sequence SEQ ID NO. 335, the third polypeptide chain comprises the amino acid sequence SEQ ID NO. 336, and the fourth polypeptide chain comprises the amino acid sequence SEQ ID NO. 334; (2) The first polypeptide chain comprises the amino acid sequence SEQ ID NO. 334, the second polypeptide chain comprises the amino acid sequence SEQ ID NO. 335, the third polypeptide chain comprises the amino acid sequence SEQ ID NO. 337, and the fourth polypeptide chain comprises the amino acid sequence SEQ ID NO. 334; (3) The first polypeptide chain comprises the amino acid sequence SEQ ID NO. 338, the second polypeptide chain comprises the amino acid sequence SEQ ID NO. 339, the third polypeptide chain comprises the amino acid sequence SEQ ID NO. 340, and the fourth polypeptide chain comprises the amino acid sequence SEQ ID NO. 338; or (4) the first polypeptide chain comprises the amino acid sequence SEQ ID NO. 338, the second polypeptide chain comprises the amino acid sequence SEQ ID NO. 339, the third polypeptide chain comprises the amino acid sequence SEQ ID NO. 341, and the fourth polypeptide chain comprises the amino acid sequence SEQ ID NO. 338.
Further provided herein are polynucleotides (e.g., isolated polynucleotides) encoding antibodies or fusion proteins according to any of the above embodiments. Further provided herein are vectors (e.g., expression vectors) comprising a polynucleotide according to any of the above embodiments. Further provided herein are host cells (e.g., isolated host cells or cell lines) comprising a polynucleotide or vector according to any of the above embodiments. Further provided herein are methods of producing an antibody or fusion protein comprising culturing a host cell according to any of the above embodiments under conditions suitable for production of the antibody or fusion protein. In some embodiments, the method further comprises recovering the antibody or fusion protein from the host cell.
Further provided herein are pharmaceutical compositions comprising an antibody or fusion protein according to any of the above embodiments and a pharmaceutically acceptable carrier.
Further provided herein is the use of an antibody, fusion protein or composition according to any of the above embodiments as a medicament. Further provided herein is the use of an antibody, fusion protein or composition according to any of the above embodiments in a method of treating cancer or infection (e.g., chronic infection). Further provided herein is the use of an antibody, fusion protein or composition according to any of the above embodiments for the manufacture of a medicament for the treatment of cancer or infection (e.g., chronic infection). Further provided herein are methods of treating cancer comprising administering to an individual having cancer an effective amount of an antibody, fusion protein, or composition according to any of the above embodiments. In some embodiments, the method further comprises administering to the individual a T cell therapy, a cancer vaccine, a chemotherapeutic agent, or an Immune Checkpoint Inhibitor (ICI). Further provided herein are methods of treating an infection (e.g., chronic infection) comprising administering to an individual having an infection an effective amount of an antibody, fusion protein, or composition according to any of the above embodiments. Further provided herein are methods of expanding T cells (e.g., ex vivo), the methods comprising contacting one or more T cells (e.g., tumor-infiltrating lymphocytes) ex vivo (e.g., ex vivo) with an effective amount of an antibody, fusion protein, or composition according to any of the above embodiments.
It is to be understood that one, some, or all of the features of the various embodiments described herein may be combined to form other embodiments of the present disclosure. These and other aspects of the present disclosure will become apparent to those skilled in the art. These and other embodiments of the disclosure are further described by the following detailed description.
Drawings
FIGS. 1A-1C depict three types of CD8ab antibodies that can be identified based on their binding preference for CD8a, CD8b and CD8ab heterodimers. Antibodies that bind to the CD8a epitope are shown in fig. 1A, antibodies that bind to an epitope spanning both CD8a and CD8B are shown in fig. 1B, and antibodies that bind to the CD8B epitope are shown in fig. 1C. The binding preference of each antibody type for CD8a, CD8b and CD8ab heterodimers is also depicted.
FIGS. 2A-2C show the results of ELISA assays for differentiating the three types of CD8ab antibodies depicted in FIGS. 1A-1C. Binding to recombinant CD8a (filled squares), CD8b (filled triangles), CD8ab heterodimer (filled circles) and the unrelated antigen ovalbumin (open triangles) was measured. The xhCD8a1 (clone OKT 8) and xhCD8a2 antibodies (clone SK 1) have been previously described.
FIGS. 3A-3C depict the binding preference of the three types of anti-CD 8ab antibodies depicted in FIGS. 2A-2C for various CD8+ immune cell types. The antibody that binds to the CD8a epitope depicted in fig. 1A binds to both cd8ab+ T cells and cd8aa+ NK cells, as depicted in fig. 3A. Antibodies that bind to an epitope spanning both CD8a and CD8B depicted in fig. 1B preferentially bind to cd8ab+ T cells over cd8aa+ NK cells, as depicted in fig. 3B. The antibody that binds to the CD8b epitope depicted in fig. 1C preferentially binds to cd8ab+ T cells over cd8aa+ NK cells, as depicted in fig. 3C.
FIGS. 4 and 5 depict the results of flow cytometry analysis to detect binding of CD8ab antibodies to human PBMC and to distinguish between the three types of CD8ab antibodies depicted in FIGS. 1A-1C. Binding of CD8ab antibodies to T cells (fig. 4) and NK cells (fig. 5) in hPBMC was detected by staining with anti-human Fc antibodies that bind to APC. anti-hFc was used to measure binding of CD8 antibodies containing hFc. The Mean Fluorescence Intensity (MFI) stained with anti-hFc was used to indicate binding. anti-hFc binding was measured in CD3+CD8a+CD8b+ cells (CD8+ T cells) and CD3-CD56+CD8a+ cells (CD8+ NK cells).
FIG. 6 depicts the results of a flow cytometry analysis measuring the binding of CD8ab antibodies xhCD8v1 to xhCD8v5 to CD8+ T cells that bind to the CD8b epitope. Negative control antibodies that bind HA antigen are also included.
Figure 7 depicts four different forms (forms A, B, C and D) of fusion proteins comprising a CD8ab antibody of the disclosure, according to some embodiments.
FIGS. 8A-8C depict fusion proteins comprising three types of CD8ab antibodies as depicted in FIGS. 1A-1C and 3A-3C, and IL-2Rbg binding polypeptides. Preferential activation of cd8ab+ T cells relative to cd8aa+ NK cells is shown.
FIG. 9 shows the results of an assay to determine the selectivity of fusion proteins comprising a CD8ab antibody and IL-2Rbg binding polypeptide IL2m 1. Five days after co-culture with the following fusion proteins, expression of proliferation marker Ki-67 in cd8+ T cells and NK cells from hPBMC donors was measured by flow cytometry: ctrl Ab-IL2v, comprising a control antibody and the previously disclosed IL-2 variant (Klein et al, oncoimmunol.2017;6 (3); e 1277306) (upper panel); an xhCD8a1-IL-2m1 comprising a CD8 antibody xhCD8a1 targeting the CD8a epitope and a mutant IL-2 polypeptide IL2m1 of the present disclosure (bottom left panel); and xhCD8v1-IL2m1, comprising the CD8ab antibodies xhCD8v1 and IL2m1 of the present disclosure (bottom right panel). xhCD8a1-IL-2m1 is form C, and Ctrl Ab-IL2v and xhCD8v1-IL2m1 are form A. Ki-67 expression was measured in cd8+ T cells (filled circles) and NK cells (filled squares). NK cells are defined as CD3-CD56+. CD8 expression was measured by staining with CD8 antibody SK 1.
FIGS. 10A-10C depict the expression of Ki-67 proliferation markers after five days of co-culture of hBMC from three different donors with indicated fusion proteins. All fusion proteins contained the mutant IL-2 polypeptide IL2m1 and the CD8ab antibodies xhCD8v1 to xhCD8v7 of the present disclosure and were form a. Ki-67 expression was measured in cd8+ T cells (solid line) and NK cells (dashed line).
FIGS. 11A-11D show the results of phospho-STAT 5 analysis with hBMC from one donor incubated with a designated fusion protein (both form C). The percentage of pSTAT5 expressing cells in the following hPBMC subpopulations is described: cd8+ T cells (fig. 11A), NK cells (fig. 11B), treg cells (fig. 11C), and cd4+ Foxp3-T cells (fig. 11D). NK cells were identified as CD 3-Perforin (Perforin) +. Treg cells were identified as cd4+foxp3+cd25+.
FIG. 12 shows the expression of Ki-67 proliferation markers after five days of co-culture of hBMC from one donor with the indicated fusion proteins. All fusion proteins contained the CD8ab antibody xhCD8v1 of the present disclosure and the various mutant IL-2 polypeptides IL2m1 to IL2m5 of the present disclosure and were form a. Ki-67 expression was measured in cd8+ T cells (left panel) and NK cells (right panel).
FIGS. 13A and 13B show the results of phospho-STAT 5 analysis with hBMC from one donor incubated with the indicated fusion proteins. The percentage of pSTAT5 expressing cells in the following hPBMC subpopulations is depicted: cd8+ T cells and NK cells. In fig. 13A, all fusion proteins contain the CD8ab antibody xhCD8v1 of the present disclosure and the various mutant IL-2 polypeptides IL2m1, IL2m2 and IL2m6 to IL2m10 of the present disclosure and are form a. In FIG. 13B, the fusion proteins contain the CD8ab antibodies xhCD8v11 and xhCD8v12 of the disclosure and the various mutant IL-2 polypeptides IL2m11, IL2m12, and IL2m13 of the disclosure and are form A. NK cells were identified as CD 3-perforin+.
FIG. 14A shows the expression of Ki-67 proliferation markers after five days of co-culture of hBMC from one donor with xhCD8v1-IL2m1 (left panel) and xhCD8v6-IL2m1 (right panel). Three different fusion protein forms as depicted in fig. 7 were tested: form a, form B and form C as indicated. The solid line depicts Ki-67 expression in CD8+ T cells, and the dashed line represents Ki-67 expression in NK cells. Form a significantly increased the activity of the two CD8ab antibodies tested on cd8+ T cells compared to NK cells, indicating that this is a preferred form of fusion protein containing a CD8ab antibody targeting an epitope between CD8a and CD8B (fig. 8B) or a CD8B epitope (fig. 8C). FIG. 14B depicts the binding of xhCD8v6-IL2m1 to CD8+ T cells from one donor (left panel) and induction of Ki67 therein (right panel). Four different fusion protein formats as depicted in fig. 7 were tested: form a, form B, form C and form D as indicated. Although form a was about 5-fold stronger in cell binding than the other forms, form a was 20-to 40-fold stronger in inducing Ki-67 than the other forms. Figure 14C depicts the results of nine fusion molecules of forms a and D as assessed for binding to cd8+ T cells and induction of Ki67 in cd8+ T cells. Examples of binding of xhCD8v12-IL2m4 and ki-67 curves are shown in the left panel. For a given binder and mutein pair, the EC50 ratio of form D to form a is shown in the right panel for binding and Ki 67. Form a shows about a 10-fold deviation in potency in binding EC50 versus form D for all molecules tested. However, upon assessing activation of another downstream proliferation marker Ki67, form a exhibited an approximately 1000-fold increase in potency over form D in inducing Ki-67.
FIG. 15 shows the expression of Ki-67 proliferation markers after five days of co-culturing hBMC with fusion protein xhCD8v8-IL2m1 comprising mutant IL-2 polypeptide IL2m1 and form A of the CD8ab antibody xhCD8v8 of the present disclosure. Ki-67 expression was measured in cd8+ T cells (squares) and NK cells (triangles).
FIG. 16A depicts Ki-67 expression in Tumor Infiltrating Lymphocytes (TILs) gated against CD8+ T cells (left panel) and NK cells (right panel). Prior to analysis, TIL was incubated with rhIL-2 or the indicated fusion protein (form A) for five days. Fig. 16B depicts the numbers of cd8+ T cells, NK cells, and cd4+ T cells per well under various specified conditions.
FIGS. 17A-17E show the expression of Ki-67 proliferation markers after five days of co-culturing hBMC with fusion proteins comprising a mutant IL-2 polypeptide (IL 2m1 or IL2m 4) and form A of the CD8ab antibodies of the disclosure. The CD8ab antibody xhCD8v9-14 was tested. Ki-67 expression was measured in cd8+ T cells (squares) and NK cells (triangles).
FIG. 18A shows the number of amino acid trends (e.g., putative N-linked glycosylation, deamination, or acid cleavage sites) and amino acid mismatches compared to the human germline of a given anti-CD 8ab antibody.
FIG. 18B shows an alignment illustrating how CDRs (italics) from xhCD8v1 VH (top) and VK (bottom) are grafted onto VH1-69 and VK1-39 human germline frameworks, respectively. The VH domain sequences (top) correspond to SEQ ID NOS 58, 384 and 60 (top to bottom), respectively. The VL domain sequences (bottom) correspond to SEQ ID NOS 59, 385 and 61, respectively (top to bottom). Underlined residues depict framework residues of the human germline.
Fig. 18C and 18D show an alignment of VH domains (fig. 18C) and VL domains (fig. 18D) of a given anti-CD 8ab antibody of the present disclosure. The VH domain sequences (FIG. 18C) correspond to SEQ ID NOS 60, 62, 64, 66, 68, 245, 251 and 253, respectively (from top to bottom). The VL domain sequences (FIG. 18D) correspond to SEQ ID NOS 61, 63, 65, 67, 69, 246, 252 and 254 (top to bottom), respectively.
Figure 19 shows the results of an ELISA assay for identifying glycosylation of parent xhCD8v6 (black solid line plus black squares), which was removed after treatment with glycosidase (black dashed line plus black squares). No glycosylation was detected on xhCD8v11 (grey line plus open triangle). Fetuin is shown as a positive control.
Detailed Description
Definition of the definition
As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "molecule" optionally includes a combination of two or more such molecules, and the like.
It should be understood that aspects and embodiments of the present disclosure include, consist of, and consist essentially of the "comprising" aspects and embodiments.
As used herein, the term "about" refers to a common range of error for the individual values that are readily known to those of skill in the art. References herein to "about" a value or parameter include (and describe) embodiments directed to the value or parameter itself.
As used herein, an "immune cell" is a cell of the immune system that responds to organisms or other entities that are considered foreign to the host's immune system. They protect the host from foreign pathogens, organisms and diseases. Immune cells, also known as white blood cells, are involved in innate and adaptive and immune responses against pathogens. The innate immune response occurs immediately after exposure to pathogens without additional priming or learning processes. The adaptive immune process requires an initial priming and subsequent memory generation, which in turn leads to an enhanced reactivity when the same pathogen is subsequently encountered. Innate immune cells include, but are not limited to, monocytes, macrophages, dendritic cells, congenital lymphoid cells (ILCs) including Natural Killer (NK) cells, neutrophils, megakaryocytes, eosinophils, and basophils. Adaptive immune cells include B and T lymphocytes/cells. T cell subsets include, but are not limited to, αβcd4+ T (native cd4+, memory cd4+, effector cd4+, regulatory cd4+) and αβcd8+ T (native cd8+, memory cd8+, effector cd8+). B cell subsets include, but are not limited to, primordial B cells, memory B cells, and plasma cells. NK T cells and tγδ (tγδ) cells exhibit both innate and adaptive lymphocyte properties.
"T cells" or "T lymphocytes" are immune cells that play a critical role in coordinating immune responses in health and disease. There are two major T cell subsets with unique functions and properties: t cells expressing CD8 antigen (CD 8) + T cells) are cytotoxic or killer T cells that can lyse target cells using cytotoxic proteins such as granzymes and perforins; and T cells expressing CD4 antigen (CD 4 + T cells) are capable of modulating, including CD8 + Helper T cells that function as many other immune cell types, such as T cells, B cells, macrophages, etc. Furthermore, CD4 + T cells are further subdivided into several sub-populations such as: t regulatory (Treg) cells capable of suppressing immune responses, and T helper 1 (Th 1), T helper 2 (Th 2) and T helper 17 (Th 17) cells that regulate different types of immune responses by secreting immune regulatory proteins such as cytokines. T cells recognize their targets via αβ T cell receptors that bind to unique antigen-specific motifs, and this recognition mechanism is often required in order to trigger their cytotoxic and cytokine secretion functions. "congenital lymphocytes" may also exhibit CD8 + And CD4 + Characteristics of T cells such as cytotoxic activity or secretion of Th1, th2 and Th17 cytokines. Some of these congenital lymphocyte subpopulations include NK cells, ILC1, ILC2 and ILC3 cells; and congenital-like T cells, such as tγδ cells; NK T cells. In general, these cells can respond rapidly to inflammatory stimuli (such as immunomodulatory cytokines) from infected or injured tissue, but unlike αβt cells, they can respond without the need to recognize antigen-specific patterns.
"cytokines" are forms of immunomodulatory polypeptides that mediate cross-talk between the initiating/primary cells and the target/effector cells. It may act as a soluble form or cell surface associated with binding to a "cytokine receptor" on a target immune cell to activate signaling. As used herein, a "cytokine receptor" is a polypeptide on the cell surface that activates intracellular signaling upon binding to a cytokine on the extracellular cell surface. Cytokines include, but are not limited to, chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors. Cytokines are produced by a variety of cells including immune cells, endothelial cells, fibroblasts, and stromal cells. A given cytokine may be produced by more than one cell type. Cytokines are pleiotropic; because receptors are expressed on multiple immune cell subsets, a single cytokine can activate signaling pathways in multiple cells. However, depending on the cell type, signaling events of cytokines may produce different downstream cellular events such as activation, proliferation, survival, apoptosis, effector function, and secretion of other immunomodulatory proteins.
As used herein, "amino acid" refers to a naturally occurring carboxy alpha-amino acid, including alanine (three letter code: ala, one letter code: a), arginine (arg, R), asparagine (asn, N), aspartic acid (asp, D), cysteine (cys, C), glutamine (gln, Q), glutamic acid (glu, E), glycine (gly, G), histidine (his, H), isoleucine (ile, I), leucine (leu, L), lysine (lys, K), methionine (met, M), phenylalanine (phe, F), proline (pro, P), serine (ser, S), threonine (thr, T), tryptophan (trp, W), tyrosine (tyr, Y), and valine (val, V).
As used herein, "polypeptide" or "protein" refers to a molecule in which monomers (amino acids) are linearly linked to each other via peptide bonds (also referred to as amide bonds). The term "polypeptide" refers to any chain of two or more amino acids and does not refer to a particular length of product. Thus, included within the definition of "polypeptide" are peptides, dipeptides, tripeptides, oligopeptides, "proteins", "amino acid chains" or any other term used to refer to a chain of two or more amino acids, and the term "polypeptide" may be used in place of, or interchangeably with, any of these terms. The term "polypeptide" is also intended to mean that the product of the polypeptide may be derived from natural biological sources or produced by recombinant techniques, but is not necessarily translated from a specified nucleic acid sequence. It can be produced in any manner, including chemical synthesis. Polypeptides generally have a defined three-dimensional structure, but they do not necessarily have such a structure. The polypeptide of the present disclosure may be about 3 or more, 5 or more, 10 or more, 20 or more, 25 or more, 50 or more, 75 or more, 100 or more, 200 or more, 500 or more, 1,000 or more, or 2,000 or more amino acids in size. Polypeptides having a defined three-dimensional structure are referred to as folded, and polypeptides that do not have a defined three-dimensional structure, but can take many different conformations, are referred to as unfolded. The polypeptides may further form multimers, such as dimers, trimers, and higher oligomers, i.e., consisting of more than one polypeptide molecule. Polypeptide molecules forming such dimers, trimers, etc. may be the same or different. Accordingly, the corresponding higher order structures of such multimers are referred to as homo-or heterodimers, homo-or heterotrimers, and the like. The terms "polypeptide" and "protein" also refer to modified polypeptides/proteins in which post-expression modification is effected, including but not limited to glycosylation, acetylation, phosphorylation, amidation, derivatization with known protecting/blocking groups, proteolytic cleavage, or modification with non-naturally occurring amino acids.
As used herein, "residue" means a position in a protein and its associated amino acid identity. For example, leu234 (also referred to as Leu234 or L234) is a residue at position 234 in human antibody IgG 1.
By "wild-type" herein is meant an amino acid sequence or nucleotide sequence found in nature, including dual gene variations. The wild-type protein has an amino acid sequence or nucleotide sequence that has not been modified intentionally.
"substitution" or "mutation" refers to a change in the backbone of a polypeptide in which a naturally occurring amino acid in the wild-type sequence of the polypeptide is replaced by another amino acid that does not occur naturally at the same position in the polypeptide. Preferably, one or more mutations are introduced to modify the affinity of the polypeptide for its receptor, thereby altering its activity such that its affinity and activity become different from the wild-type homologous polypeptide. Mutations may also improve the biophysical properties of the polypeptide. Amino acid mutations can be generated using genetic or chemical methods well known in the art. Genetic methods may include site-directed mutagenesis, PCR, gene synthesis, and the like. It is contemplated that methods of altering amino acid side chain groups by methods other than genetic engineering, such as chemical modification, may also be suitable.
As used herein, "CD8" refers to any natural human CD8. Unless explicitly indicated otherwise or indicated by context, reference to "CD8" refers to CD8aa and/or CD8ab. An exemplary HUMAN CD8B (beta chain of HUMAN CD 8) amino acid sequence is described under UniProt P10966 (cd8b_human). "CD8A" refers to the alpha chain of HUMAN CD8 (e.g., as described under UniProt P01732 (CD8A_HUMAN)). "CD8aa" refers to a homodimer of CD8 a. "CD8ab" refers to a heterodimer of CD8a and CD8 b. "CD8", "CD8a", "CD8b", "CD8aa" and "CD8ab" encompass untreated forms and mature forms resulting from treatment in cells. "CD8", "CD8a", "CD8b", "CD8aa" and "CD8ab" also include, but are not limited to, naturally occurring variants, such as one or more dual genes or splice variants.
As used herein, unless otherwise indicated, "interleukin-2" or "IL-2" refers to any natural human IL-2."IL-2" encompasses untreated IL-2 as "mature IL-2" as a form of IL-2 produced by treatment in a cell. The sequence of "mature IL-2" is depicted in FIG. 1A. An exemplary form of untreated human IL-2 comprises an additional N-terminal amino acid signal peptide linked to mature IL-2."IL-2" also includes, but is not limited to, naturally occurring variants of IL-2, such as one or more dual genes or splice variants. The amino acid sequence of exemplary HUMAN IL-2 is described under UniProt P60568 (IL 2. RTM. HUMAN).
"affinity" or "binding affinity" refers to the molecularSuch as antibodies) to the total amount of non-covalent interactions between the single binding site and its binding partner (e.g., antigen). As used herein, unless otherwise indicated, "binding affinity" refers to an inherent binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). Affinity can generally be determined by dissociation constants (K D ) The dissociation constant is the ratio of dissociation rate constant to association rate constant (kdissociation and kassociation, respectively). Thus, equivalent affinities may comprise different rate constants, as long as the ratio of the rate constants remains the same. Affinity can be measured by common methods known in the art, such as enzyme-linked immunosorbent assays (ELISA), surface Plasmon Resonance (SPR) techniques (e.g., BIAcore), biological Layer Interferometry (BLI) techniques (e.g., octet), and other conventional binding assays (Heeley, endocr Res 28,217-229 (2002).
As used herein, "binding" or "specific binding" refers to the ability of a polypeptide or antigen binding molecule to selectively interact with a receptor of a polypeptide or target antigen, respectively, and this specific interaction may be different from non-targeted or non-desired or non-specific interactions. Examples of specific binding include, but are not limited to, binding of IL-2 cytokines to their specific receptors (e.g., IL-2Rα, IL-2Rβ, and IL-2Rγ) and binding of antigen binding molecules to specific antigens (e.g., CD8 or PD-1).
By "mutant IL-2 polypeptide" is meant a reduced affinity of the IL-2 polypeptide for its receptor, wherein such reduced affinity will result in a reduced biological activity of the mutant. The reduced affinity and thus reduced activity can be obtained by introducing small amino acid mutations or substitutions. Mutant IL-2 polypeptides may also have other modifications to the peptide backbone, including but not limited to amino acid deletions, alignment, cyclization, disulfide bonds, or post-translational modifications of the polypeptide (e.g., glycosylated or altered carbohydrates), chemical or enzymatic modifications of the polypeptide (e.g., attachment of PEG to the polypeptide backbone), addition of peptide tags or labels, or fusion with proteins or protein domains to produce the final construct with desired characteristics (such as reduced IL-2rβγ affinity). The desired activity may also include improved biophysical properties as compared to the wild-type IL-2 polypeptide. Various modifications may be combined to achieve a desired modification of activity, such as reduced affinity or improved biophysical properties. As a non-limiting example, amino acid sequences for consensus N-linked glycosylation can be incorporated into polypeptides to allow glycosylation. Another non-limiting example is that lysine may be incorporated onto the polypeptide to enable pegylation. Preferably, one or more mutations are introduced into the polypeptide to modify its activity.
The terms "antibody" and "immunoglobulin" are used interchangeably and are used in their broadest sense herein and encompass a variety of antibody structures, including, but not limited to, monoclonal antibodies (e.g., full length or intact monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), antibody fragments, and single domain antibodies (as described in greater detail herein), so long as they exhibit the desired antigen-binding activity.
An antibody (immunoglobulin) refers to a protein having a structure substantially similar to that of a native antibody. "protobodies" refer to naturally occurring immunoglobulin molecules having different structures. For example, the IgG class of native immunoglobulin is a hetero-tetrameric glycoprotein of about 150,000 daltons, which is composed of two disulfide-bonded light chains and two heavy chains. From the N-terminal to the C-terminal, each heavy chain has a variable region (VH), also known as a variable heavy chain domain or heavy chain variable domain, followed by three constant domains (CH 1, CH2, and CH 3), also known as heavy chain constant regions. Similarly, from N-terminus to C-terminus, each light chain has a variable region (VL), also known as a variable light chain domain or light chain variable domain, followed by a constant light Chain (CL) domain, also known as a light chain constant region. Subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known and are generally described, for example, in Abbas et al, 2000,Cellular and Mol and Kindt et al, kuby Immunology, 6 th edition, w.h.freeman and co., p 91 (2007). Antibodies (immunoglobulins) fall into different classes depending on the amino acid sequence of the constant domain of the heavy chain. Antibodies exist in five main classes: alpha (IgA), delta (IgD), epsilon (IgE), gamma (IgG) or mu (IgM), some of which may be further divided into subtypes such as gamma 1 (IgG 1), gamma 2 (IgG 2), gamma 3 (IgG 3), gamma 4 (IgG 4), alpha 1 (IgA 1) and alpha 2 (IgA 2). The light chains of immunoglobulins can be categorized into one of two types, called kappa (kappa) and lambda (lambda), based on the amino acid sequence of their constant domains. An immunoglobulin essentially consists of two Fab molecules and one Fc domain linked via an immunoglobulin hinge region.
As used herein, "Fc" or "Fc region" or "Fc domain" refers to the C-terminal region of an antibody heavy chain that contains at least a portion of a constant region. The term includes native sequence Fc regions and variant Fc regions. Fc may refer to the last two constant region immunoglobulin domains (e.g., CH2 and CH 3) of IgA, igD, and IgG; the last three constant region immunoglobulin domains of IgE and IgM; and optionally all or a portion of a flexible hinge at the N-terminus of these domains. For IgA and IgM, the Fc may include the J chain. The IgG Fc region comprises IgG CH2 and IgG CH3 domains, and in some cases, includes a hinge. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also known as the EU index, as described in Kabat et al, sequences of Proteins of Immunological Interest, 5 th edition, public Health Service, national Institutes of Health, bethesda, MD, 1991. The "hinge" region typically extends from an amino acid residue at about position 216 to an amino acid residue at about position 230. The hinge region herein may be a native hinge domain or a variant hinge domain. The "CH2 domain" of a human IgG Fc region typically extends from an amino acid residue at about position 231 to an amino acid residue at about position 340. The CH2 domain herein may be a native sequence CH2 domain or a variant CH2 domain. The "CH3 domain" comprises an extension of the C-terminal residue of the CH2 domain in the Fc region, from an amino acid residue at about position 341 to an amino acid residue at about position 447 of an IgG. The CH3 region herein may be a native sequence CH3 domain or a variant CH3 domain (e.g., a CH3 domain having an introduced "knob" in one strand thereof and a corresponding introduced "cavity" in the other strand thereof; see U.S. patent No. 5,821,333, expressly incorporated herein by reference). Thus, the definition of "Fc domain" includes amino acids 231-447 (CH 2-CH 3) or 216-447 (hinge-CH 2-CH 3) or fragments thereof. An "Fc fragment" herein may contain fewer amino acids from either or both the N-terminus and the C-terminus, but is still capable of forming a dimer with another Fc domain or Fc fragment, as may be detected using standard methods, typically based on size (e.g., non-denaturing chromatography, size exclusion chromatography, etc.). In the present disclosure, a human IgG Fc domain has particular uses and may be an Fc domain from human IgG1, igG2, or IgG 4.
A "variant Fc domain" or "Fc variant" or "variant Fc" contains amino acid modifications (e.g., substitutions, additions, and deletions) as compared to the parent Fc domain. The term also includes naturally occurring dual gene variants of the Fc region of an immunoglobulin. In general, variant Fc domains have at least about 80%, 85%, 90%, 95%, 97%, 98% or 99% identity (using the identity algorithm discussed below, one embodiment utilizes BLAST algorithm as known in the art, using default parameters) to the corresponding parent human IgG Fc domain. Alternatively, a variant Fc domain may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid modifications as compared to the parent Fc domain. For example, the N-terminus or C-terminus of the Fc region of an immunoglobulin may be deleted for one or more amino acids without substantial loss of biological function. In addition, as discussed herein, the variant Fc domain herein is still capable of forming a dimer with another Fc domain, as measured using known techniques as described herein (such as non-denaturing gel electrophoresis).
As used herein, "fcγreceptor," "fcγr," or "fcγr" means any member of the family of proteins that bind to the Fc region of an IgG antibody and are encoded by an fcγr gene. In humans, this family includes, but is not limited to: fcyri (CD 64), including isoforms fcyria, fcyrib, and fcyric; fcγrii (CD 32), including isoforms fcγriia (including isoforms H131 and R131), fcγriib (including fcγriib-1 and fcγriib-2), and fcγriic; and fcyriii (CD 16), including isoforms fcyriiia (including isoforms V158 and F158) and fcyriiib (including isoforms fcyriib-NA 1 and fcyriib-NA 2) (Jefferis et al, 2002,Immunol Lett 82:57-65, incorporated by reference in their entirety) and any undiscovered human fcyr or fcyr isoform or isoform. Fcγr can be from any organism, including but not limited to human, mouse, rat, rabbit, and monkey. Mouse fcγrs include, but are not limited to, fcγri (CD 64), fcγrii (CD 32), fcγriii (CD 16) and fcγriii-2 (CD 16-2), and any undiscovered mouse fcγr or fcγr isoforms or allotypes.
As used herein, "effector function" refers to a biochemical event caused by the interaction of an antibody Fc region with an Fc receptor or ligand, which varies with the antibody isotype. Effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), cytokine secretion, immune complex-mediated antigen uptake by antigen presenting cells, down-regulation of cell surface receptors (e.g., B cell receptors), and B cell activation. "antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a cell-mediated response in which nonspecific cytotoxic cells expressing FcR, such as Natural Killer (NK) cells, neutrophils, and macrophages, recognize antibodies bound on a target cell and subsequently lyse the target cell. ADCC is associated with fcγriiia binding; increased fcγriiia binding results in increased ADCC activity. In order to assess ADCC activity of the relevant molecule, an in vitro ADCC assay, such as the assays described in U.S. Pat. nos. 5,500,362 or 5,821,337, may be performed. As used herein, "ADCP" or "antibody-dependent cell-mediated phagocytosis" means a cell-mediated response in which nonspecific cytotoxic cells expressing fcγr recognize antibodies bound on target cells and subsequently cause phagocytosis of the target cells.
"Fc null" and "Fc null variant" are used interchangeably and are used herein to describe modified Fc with reduced or eliminated effector function. Such Fc-null or Fc-null variants are reduced or eliminated for fcγr and/or complement receptors. Preferably, the effector function of such Fc-null or Fc-null variants is abrogated. Exemplary methods of modification include, but are not limited to, chemical changes, amino acid residue substitutions, insertions, and deletions. Exemplary amino acid positions (numbered based on Eu numbering scheme) of the Fc molecule that incorporate one or more modifications to reduce the effector function of the resulting variant are the following positions: i) IgG1: c220, C226, C229, E233, L234, L235, G237, P238, S239D 265, S267, N297, L328, P331, K322, a327 and P329, ii) IgG2: v234, G237, D265, H268, N297, V309, a330, a331, K322, and iii) IgG4: l235, G237, D265, and E318. Exemplary Fc molecules with reduced effector function include those with one or more of the following substitutions: i) IgG1: N297A, N297Q, N297G, D A/N297A, D265A/N297A, D A/N297Q, C S/C226S/C229S/P238S, S E/L328F, C S/C229S/E233P/L234V/L235A, L F/L235E/P331S, L234A/L235 39234A/L235A/G237A, L A/L235A/G237A/K322A, L A/L235A/G237A/A330S/A331S, L A/L235A/P329G, E P/L234V/L235A/G236del/S239K, E P/L234V/L235A/G236del/S267K, E P/L234V/L235A/G236del/S239K/A327G, E P/L234V/L235A/G236del/S267K/A327G and E233P/L234V/L236A/G236 del L234A/L235A/G237 is deleted; ii) IgG2: A330S/A331S, V A/G237A, V A/G237A/D265A, D265A/A330S/A331S, V A/G237A/D265A/A330S/A331S and H268Q/V309L/A330S/A331S; iii) IgG4: L235A/G237A/E318A, D265A, L A/G237A/D265A and L235A/G237A/D265A/E318A.
As used herein, "epitope" refers to a determinant capable of specific binding to a variable region of an antibody molecule known as a paratope. Epitopes are groupings of molecules such as amino acids or sugar side chains and generally have specific structural features and charge-to-mass ratio features. A single antigen may have more than one epitope. An epitope may comprise amino acid residues that are directly involved in binding and other amino acid residues that are not directly involved in binding, such as amino acid residues that are effectively blocked by an antigen binding peptide (in other words, the amino acid residues are within the footprint of the antigen binding peptide). Epitopes may be conformational or linear. Epitopes typically comprise at least 3 and more often at least 5 or 8-10 amino acids. Antibodies recognizing the same epitope can be validated in a simple immunoassay (e.g., "binning") that shows the ability of one antibody to block the binding of another antibody to a target antigen.
As used herein, "linker" refers to a molecule that connects two polypeptide chains. The linker may be a polypeptide linker or a synthetic chemical linker (see, e.g., protein Engineering,9 (3), 299-305, 1996). The length and sequence of the polypeptide linker is not particularly limited and may be selected by one skilled in the art according to the use. The polypeptide linker comprises one or more amino acids. In some embodiments, the polypeptide linker is a peptide of at least 5 amino acids in length, preferably 5 to 100, more preferably 10 to 50 amino acids in length. In one embodiment, the peptide linkers are G, S, GS, SG, SGG, GGS and GSG (where g=glycine and s=serine). In another embodiment, the peptide linker is (GGGS) xGn (SEQ ID NO: 74) or (GGGGS) xGn (SEQ ID NO: 75) or (GGGGGS) xGn (SEQ ID NO: 76) or S (GGGS) xGn (SEQ ID NO: 386) or S (GGGGS) xGn (SEQ ID NO: 387) or S (GGGGGS) xGn (SEQ ID NO: 388), wherein x = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and n = 0, 1, 2, or 3. Preferably, the linker is (GGGGS) xGn, wherein x=2, 3 or 4, and n=0 (SEQ ID NO: 77); more preferably, the linker is (GGGGS) xGn, wherein x=3 and n=0 (SEQ ID NO: 78). In some embodiments, the linker comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 79) or SGGGGSGGGGSGGGGS (SEQ ID NO: 389). Synthetic chemical linkers include cross-linking agents conventionally used to cross-link peptides, such as N-hydroxysuccinimide (NHS), di-succinimide suberate (DSS), bis (succinimidyl) suberate (BS 3), dithiobis (succinimidyl propionate) (DSP), dithiobis (succinimidyl propionate) (DTSSP), ethylene glycol bis (succinimidyl succinate) (EGS), ethylene glycol bis (sulfosuccinimidyl succinate) (sulfo-EGS), di-succinimidyl tartrate (DST), di-sulfosuccinimidyl tartrate (sulfo-DST), bis [2- (succinimidyloxycarbonyloxy) ethyl ] sulfone (BSOCOES), and bis [2- (succinimidyloxycarbonyloxy) ethyl ] sulfone (sulfo-BSOCOES).
The term "polynucleotide" refers to an isolated nucleic acid molecule or construct, such as messenger RNA (mRNA), virally derived RNA, or plasmid DNA (pDNA), encoding a polypeptide of the present disclosure. Polynucleotides may comprise conventional phosphodiester linkages or non-conventional linkages (e.g., amide linkages such as are found in Peptide Nucleic Acids (PNAs)). The term "nucleic acid molecule" refers to any one or more nucleic acid segments, such as DNA or RNA fragments, present in a polynucleotide. In some aspects, one or more vectors (particularly expression vectors) comprising such nucleic acids are provided. In one aspect, a method for producing a polypeptide of the present disclosure is provided, wherein the method comprises culturing a host cell comprising a nucleic acid encoding the polypeptide under conditions suitable for expression of the polypeptide and recovering the polypeptide from the host cell. "recombinant" means the production of a protein in a foreign host cell using recombinant nucleic acid technology. For the purposes of this disclosure, recombinantly produced proteins expressed in host cells are considered isolated, native or recombinant proteins that have been isolated, fractionated, or partially or substantially purified by any suitable technique are also considered isolated.
"isolated" when used in reference to the various polypeptides disclosed herein means that the polypeptide has been identified and isolated and/or recovered from a cell or cell culture expressing the polypeptide. Typically, the isolated polypeptide will be purified by at least one purification step. The desired purity level is not present; by "purified" or "purified" is meant that the concentration of the target protein in the composition is increased relative to the concentration of the contaminant as compared to the starting material. As used herein, "isolated protein" refers to a target protein that is substantially free of other proteins having different binding specificities.
The term "cancer" refers to a physiological condition in a mammal that is generally characterized by an unregulated and abnormal probability of cell growth and invasion or spread to other parts of the body. Examples of cancers include, but are not limited to, carcinoma, lymphoma, blastoma, endo-tumor, and leukemia. More specific examples of such cancers include lung cancer, small cell lung cancer, non-small cell lung cancer (NSCL), bronchioloalveolar lung cancer, squamous cell carcinoma, lung adenocarcinoma, squamous cell lung cancer, peritoneal carcinoma, head and neck cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, thyroid cancer, uterine cancer, gastrointestinal cancer, ovarian cancer, rectal cancer, anal region cancer, gastric cancer (stomach cancer/cancer), large intestine cancer, breast cancer, endometrial cancer, uterine cancer, fallopian tube cancer, cervical cancer, vaginal cancer, vulval cancer, hodgkin's Disease (Hodgkin's Disease), esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urinary tract cancer, penile carcinoma, prostate cancer, bladder cancer, kidney or urinary canal cancer, renal cell carcinoma, gastrointestinal cancer, bladder cancer, hepatoma, hepatocellular carcinoma, cervical cancer, salivary gland cancer, bile duct cancer, neoplasm (glioma), shaft tumor (glioma), astronoma, brain tumor, astronoma, neuroblastoma, brain tumor, neuroblastoma, glioma, blastoma, including refractory forms of any of the above cancers, or combinations of one or more of the above cancers.
Antibodies and antigen binding domains
Certain aspects of the present disclosure relate to antibodies, antibody fragments, and antigen binding domains that specifically bind human CD8b and/or human CD8ab. Any of the anti-CD 8 antibodies of the disclosure (e.g., specifically binding human CD8b and/or human CD8 ab) can be used for the fusion proteins, methods, and uses disclosed herein.
In some embodiments, an anti-CD 8 antibody of the present disclosure specifically binds human CD8b and/or human CD8ab with an affinity that is at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, or at least 200-fold higher than its binding to human CD8a and/or human CD8aa, e.g., expressed on Natural Killer (NK) cells (e.g., human NK cells). In some embodiments, an anti-CD 8 antibody of the present disclosure specifically binds human CD8b and/or human CD8ab with at least 10-fold higher affinity than it binds human CD8a and/or human CD8aa expressed, for example, on Natural Killer (NK) cells. In some embodiments, the human CD8b and/or human CD8ab is expressed on the surface of a human cell (e.g., a human T cell).
In some embodiments, an anti-CD 8 antibody of the disclosure specifically binds to a cell (e.g., a human T cell) expressing a human CD8ab heterodimer on a surface with an EC50 of less than 1000 nM. In some embodiments, the anti-CD 8 antibodies of the present disclosure specifically bind to human cd8+ T cells.
In some embodiments, the anti-CD 8 antibodies of the present disclosure are human antibodies or antibody fragments. In some embodiments, a human antibody or antibody fragment comprises human CDRs and framework sequences in the variable domain, e.g., isolated from a human or generated using a library comprising human antibody sequences (e.g., CDR sequences). In some embodiments, the anti-CD 8 antibodies of the present disclosure are humanized antibodies or antibody fragments. In some embodiments, a humanized antibody or antibody fragment comprises non-human CDRs (e.g., from a mouse, rabbit, goat, etc.) and a human framework sequence in the variable domain. In some embodiments, the human or humanized antibody further comprises a human Fc region. In some embodiments, the human Fc region further comprises one or more Fc mutations, e.g., as disclosed herein. There are five main classes of intact antibodies: igA, igD, igE, igG and IgM, and several of these classes can be further divided into subclasses (isotypes), such as IgGl, igG2, igG3, igG4, igA, and IgA2. The heavy chain constant domains corresponding to the different classes of antibodies are called α, δ, ε, γ, and μ, respectively. Subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
Various definitions of CDR sequences for antibody variable domains are known in the art. CDR sequences are described herein according to the Kabat definition (see, e.g., kabat et al, sequences of Proteins of Immunological Interest, 5 th edition, NIH publication 91-3242, bethesda MD (1991), volumes 1-3), unless otherwise specified. However, other definitions are known and contemplated for use. For example, in some embodiments, the CDR sequences may be described by the Chothia definition (see, e.g., chothia and Lesk, J.mol.biol.196:901-917 (1987). Depending on the particular CDR definition used, the exact framework sequences may also vary, but as is known in the art, the first framework sequence (FW-1) refers to the sequence from the N-terminus of the VH or VL domain to the start of the CDR-H1/CDR-L1, the second framework sequence (FW-2) refers to the sequence from the end of the CDR-H1/CDR-L1 to the start of the CDR-H2/CDR-L2, the third framework sequence (FW-3) refers to the sequence from the end of the CDR-H2/CDR-L2 to the start of the CDR-H3/CDR-L3, and the fourth framework sequence (FW-4) refers to the sequence from the end of the CDR-H3/CDR-L3 to the C-terminus of the VH or VL domain.
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 1, CDR-H2 comprising amino acid sequence SEQ ID NO. 2 and CDR-H3 comprising amino acid sequence SEQ ID NO. 3; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6. In some embodiments, an anti-CD 8 antibody of the present disclosure comprises 1, 2, or 3 heavy chain CDRs of antibody xhCD8v1 (e.g., as shown in tables 1-3) and/or 1, 2, or 3 light chain CDRs of antibody xhCD8v1 (e.g., as shown in tables 1-3). In some embodiments, the antibody is humanized. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO 58; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from the sequences SEQ ID NO 59.
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 177, CDR-H2 comprising amino acid sequence SEQ ID NO. 178 and CDR-H3 comprising amino acid sequence SEQ ID NO. 179; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182. In some embodiments, an anti-CD 8 antibody of the disclosure comprises 1, 2, or 3 heavy chain CDRs of antibody xhCD8v8 (e.g., as shown in tables 1-3) and/or 1, 2, or 3 light chain CDRs of antibody xhCD8v8 (e.g., as shown in tables 1-3). In some embodiments, the antibody is humanized. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from the sequence SEQ ID NO 185; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from the sequence SEQ ID NO. 186.
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 13, CDR-H2 comprising amino acid sequence SEQ ID NO. 14 and CDR-H3 comprising amino acid sequence SEQ ID NO. 15; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 62, and/or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 63. In some embodiments, an anti-CD 8 antibody of the present disclosure comprises 1, 2, or 3 heavy chain CDRs of antibody xhCD8v2 (e.g., as shown in tables 1-3) and/or 1, 2, or 3 light chain CDRs of antibody xhCD8v2 (e.g., as shown in tables 1-3). In some embodiments, the antibody is humanized. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from the sequence SEQ ID NO. 62; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from the sequence SEQ ID NO. 63.
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 19, CDR-H2 comprising amino acid sequence SEQ ID NO. 20 and CDR-H3 comprising amino acid sequence SEQ ID NO. 21; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 64, and/or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 65. In some embodiments, an anti-CD 8 antibody of the present disclosure comprises 1, 2, or 3 heavy chain CDRs of antibody xhCD8v3 (e.g., as shown in tables 1-3) and/or 1, 2, or 3 light chain CDRs of antibody xhCD8v3 (e.g., as shown in tables 1-3). In some embodiments, the antibody is humanized. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from the sequence SEQ ID NO 64; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from the sequence SEQ ID NO: 65.
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 25, CDR-H2 comprising amino acid sequence SEQ ID NO. 26 and CDR-H3 comprising amino acid sequence SEQ ID NO. 27; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 66, and/or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 67. In some embodiments, an anti-CD 8 antibody of the present disclosure comprises 1, 2, or 3 heavy chain CDRs of antibody xhCD8v4 (e.g., as shown in tables 1-3) and/or 1, 2, or 3 light chain CDRs of antibody xhCD8v4 (e.g., as shown in tables 1-3). In some embodiments, the antibody is humanized. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from the sequence SEQ ID NO 66; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from the sequence SEQ ID NO: 67.
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 31, CDR-H2 comprising amino acid sequence SEQ ID NO. 32 and CDR-H3 comprising amino acid sequence SEQ ID NO. 33; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 68, and/or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 69. In some embodiments, an anti-CD 8 antibody of the present disclosure comprises 1, 2, or 3 heavy chain CDRs of antibody xhCD8v5 (e.g., as shown in tables 1-3) and/or 1, 2, or 3 light chain CDRs of antibody xhCD8v5 (e.g., as shown in tables 1-3). In some embodiments, the antibody is humanized. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO 68; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from the sequences SEQ ID NO 69.
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 37, CDR-H2 comprising amino acid sequence SEQ ID NO. 38 and CDR-H3 comprising amino acid sequence SEQ ID NO. 39; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO. 70, and/or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO. 71. In some embodiments, an anti-CD 8 antibody of the present disclosure comprises 1, 2, or 3 heavy chain CDRs of antibody xhCD8v6 (e.g., as shown in tables 1-3) and/or 1, 2, or 3 light chain CDRs of antibody xhCD8v6 (e.g., as shown in tables 1-3). In some embodiments, the antibody is human. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from the sequence SEQ ID NO 70; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from the sequence SEQ ID NO: 71.
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 43, CDR-H2 comprising amino acid sequence SEQ ID NO. 44 and CDR-H3 comprising amino acid sequence SEQ ID NO. 45; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 72, and/or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 73. In some embodiments, an anti-CD 8 antibody of the present disclosure comprises 1, 2, or 3 heavy chain CDRs of antibody xhCD8v7 (e.g., as shown in tables 1-3) and/or 1, 2, or 3 light chain CDRs of antibody xhCD8v7 (e.g., as shown in tables 1-3). In some embodiments, the antibody is human. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from the sequence SEQ ID NO 72; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from the sequence SEQ ID NO 73.
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising the amino acid sequence X 1 X 2 AIS, wherein X 1 S, K, G, N, R, D, T or G, and wherein X 2 Y, L, H or F (SEQ ID NO: 259); CDR-H2 comprising the amino acid sequence X 1 X 2 X 3 PX 4 X 5 X 6 X 7 X 8 X 9 YX 10 QKFX 11 G, wherein X 1 Is G or H, X 2 Is I or F, X 3 I, N or M, X 4 G, N, H, S, R, I or A, X 5 A, N, H, S, T, F or Y, X 6 A, D or G, X 7 T, E, K, V, Q or A, X 8 Is A or T, X 9 Is N or K, X 10 Is A or N, and X 11 Q or T (SEQ ID NO: 260); and CDR-H3 comprising the amino acid sequence X 1 X 2 X 3 GX 4 X 5 LFX 6 X 7 Wherein X is 1 Is D or A, X 2 A, G, E, R, Y, K, N, Q, L or F, X 3 A, L, P or Y, X 4 Is I or L, X 5 R, A, Q or S, X 6 Is A or D, and X 7 D, E, A or S (SEQ ID NO: 261); and a VL domain comprising: CDR-L1 comprising the amino acid sequence X 1 X 2 SX 3 X 4 IX 5 GX 6 LN, wherein X 1 R or G, X 2 Is A or T, X 3 Q or E, X 4 E, N, T, S, A, K, D, G, R or Q, X 5 Is Y or S, and X 6 A or V (SEQ ID NO: 262); CDR-L2 comprising the amino acid sequence GX 1 X 2 X 3 LX 4 X 5 Wherein X is 1 Is A or S, X 2 T, S, E, Q or D, X 3 N, R, A, E or H, X 4 Q or A, and X 5 Is S or D (SEQ ID NO: 263); and CDR-L3 comprising the amino acid sequence QX 1 X 2 X 3 X 4 X 5 PWT, wherein X 1 S, N, D, Q, A or E, X 2 T, I or S, X 3 Y, L or F, X 4 D, G, T, E, Q, A or Y, and X 5 A, T, R, S, K or Y (SEQ ID NO: 264). In some embodiments, the VH domain further comprises: FW-1 comprising sequence QVQLVQSGAEVKKPGSSVKVSCKASGGTFS (SEQ ID NO: 274), FW-2 comprising sequence WVRQAPGQGLEWMG (SEQ ID NO: 275), FW-3 comprising sequence RVTITADESTSTAYMELSSLRSEDTAV YYCAR (SEQ ID NO: 276) and/or FW-4 comprising sequence WGQGTLVTVSS (SEQ ID NO: 277). In some embodiments, the VL domain further comprises: FW-1 comprising sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 289), FW-2 comprising sequence WYQQKPGKAPKLLIY (SEQ ID NO: 290), FW-3 comprising sequence GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 291) and/or FW-4 comprising sequence FGGGTKVEIK (SEQ ID NO: 292).
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 226 and CDR-H3 comprising amino acid sequence SEQ ID NO. 227; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 245, and/or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 246. In some embodiments, an anti-CD 8 antibody of the disclosure comprises 1, 2, or 3 heavy chain CDRs of antibody xhCD8v9 (e.g., as shown in tables 1-3) and/or 1, 2, or 3 light chain CDRs of antibody xhCD8v9 (e.g., as shown in tables 1-3). In some embodiments, the antibody is humanized. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from the sequence SEQ ID NO 245; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from the sequence SEQ ID NO: 246. In some embodiments, the VH domain further comprises: FW-1 comprising sequence QVQLVQSGAEVKKPGSSVKVSCKASGGTFS (SEQ ID NO: 274), FW-2 comprising sequence WVRQAPGQGLEWMG (SEQ ID NO: 275), FW-3 comprising sequence RVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 276) and/or FW-4 comprising sequence WGQGTLVTVSS (SEQ ID NO: 277). In some embodiments, the VL domain further comprises: FW-1 comprising sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 289), FW-2 comprising sequence WYQQKPGKAPKLLIY (SEQ ID NO: 290), FW-3 comprising sequence GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 291) and/or FW-4 comprising sequence FGGGTKVEIK (SEQ ID NO: 292).
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 232 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 251, and/or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 252. In some embodiments, the VH domain comprises the amino acid sequence SEQ ID NO 251; and the VL domain comprises the amino acid sequence SEQ ID NO. 252. In some embodiments, an anti-CD 8 antibody of the disclosure comprises 1, 2, or 3 heavy chain CDRs of antibody xhCD8v12 (e.g., as shown in tables 1-3) and/or 1, 2, or 3 light chain CDRs of antibody xhCD8v12 (e.g., as shown in tables 1-3). In some embodiments, the antibody is humanized. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO 251; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from sequence SEQ ID NO. 252. In some embodiments, the VH domain further comprises: FW-1 comprising sequence QVQLVQSGAEVKKPGSSVKVSCKASGGTFS (SEQ ID NO: 274), FW-2 comprising sequence WVRQAPGQGLEWMG (SEQ ID NO: 275), FW-3 comprising sequence RVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 276) and/or FW-4 comprising sequence WGQGTLVTVSS (SEQ ID NO: 277). In some embodiments, the VL domain further comprises: FW-1 comprising sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 289), FW-2 comprising sequence WYQQKPGKAPKLLIY (SEQ ID NO: 290), FW-3 comprising sequence GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 291) and/or FW-4 comprising sequence FGGGTKVEIK (SEQ ID NO: 292).
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 232 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 253, and/or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 254. In some embodiments, an anti-CD 8 antibody of the disclosure comprises 1, 2, or 3 heavy chain CDRs of antibody xhCD8v13 (e.g., as shown in tables 1-3) and/or 1, 2, or 3 light chain CDRs of antibody xhCD8v13 (e.g., as shown in tables 1-3). In some embodiments, the antibody is humanized. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO 253; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from the sequence SEQ ID NO: 254. In some embodiments, the VH domain further comprises: FW-1 comprising sequence QVQLVQSGAEVKKPGSSVKVSCKASGGTFS (SEQ ID NO: 274), FW-2 comprising sequence WVRQAPGQGLEWMG (SEQ ID NO: 275), FW-3 comprising sequence RVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 276) and/or FW-4 comprising sequence WGQGTLVTVSS (SEQ ID NO: 277). In some embodiments, the VL domain further comprises: FW-1 comprising sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 289), FW-2 comprising sequence WYQQKPGKAPKLLIY (SEQ ID NO: 290), FW-3 comprising sequence GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 291) and/or FW-4 comprising sequence FGGGTKVEIK (SEQ ID NO: 292).
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising the amino acid sequence X 1 YX 2 MS, wherein X 1 S, D, E, A or Q and X 2 A, G or T (SEQ ID NO: 268); CDR-H2 comprising the amino acid sequence DIX 1 X 2 X 3 GX 4 X 5 TX 6 YADSVKG, wherein X 1 T, N, S, Q, E, H, R or A, X 2 Y, W, F or H, X 3 A, S, Q, E or T, X 4 Is G or E, X 5 Is S or I, and X 6 Is A or G (SEQ ID NO: 269); and CDR-H3 comprising the amino acid sequence X 1 X 2 X 3 YX 4 WX 5 X 6 AX 7 DX 8 Wherein X is 1 Is S or A, X 2 N, H, A, D, L, Q, Y or R, X 3 A, N, S or G, X 4 A, V, R, E or S, X 5 Is D or S, X 6 D, N, Q, E, S, T or L, X 7 L, F or M, and X 8 I, Y or V (SEQ ID NO: 270); and a VL domain comprising: CDR-L1 comprising amino acid sequence RASQSVSSNLA (SEQ ID NO: 40), CDR-L2 comprising amino acid sequence GASSRAT (SEQ ID NO: 41) and CDR-L3 comprising amino acid sequence QQYGSSPPVT (SEQ ID NO: 42). In some embodiments, the VH domain further comprises: FW-1 comprising sequence EVQLVESGG GLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 281), FW-2 comprising sequence WVRQAPGKGLEWVS (SEQ ID NO: 282), FW-3 comprising sequence RF TISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 283) and/or FW-4 comprising sequence WGQGTMVTVSS (SEQ ID NO: 284) or WGQG TLVTVSS (SEQ ID NO: 285). In some embodiments, the VL domain further comprises: FW-1 comprising sequence EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising sequence WYQQKPGQAPRLLIY (SEQ ID NO: 294), FW-3 comprising sequence GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 295) and/or FW-4 comprising sequence FGQGTKVEIK (SEQ ID NO: 296).
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 229, CDR-H2 comprising amino acid sequence SEQ ID NO. 230 and CDR-H3 comprising amino acid sequence SEQ ID NO. 231; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 247, and/or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 248. In some embodiments, an anti-CD 8 antibody of the disclosure comprises 1, 2, or 3 heavy chain CDRs of antibody xhCD8v10 (e.g., as shown in tables 1-3) and/or 1, 2, or 3 light chain CDRs of antibody xhCD8v10 (e.g., as shown in tables 1-3). In some embodiments, the antibody is humanized. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising CDR-H1, CD R-H2 and CDR-H3 from sequence SEQ ID NO 247; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from the sequence SEQ ID NO: 248. In some embodiments, the VH domain further comprises: FW-1 comprising sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 281), FW-2 comprising sequence WVRQAPGKGLEWVS (SEQ ID NO: 282), FW-3 comprising sequence RFTISRDNAKNSLYLQMNSLRAEDT AVYYCAR (SEQ ID NO: 283) and/or FW-4 comprising sequence WGQGTMVT VSS (SEQ ID NO: 284) or WGQGTLVTVSS (SEQ ID NO: 285). In some embodiments, the VL domain further comprises: FW-1 comprising sequence EIVLTQSPGT LSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising sequence WYQQKP GQAPRLLIY (SEQ ID NO: 294), FW-3 comprising sequence GIPDRFSGSGS GTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 295) and/or FW-4 comprising sequence FGQGTKVEIK (SEQ ID NO: 296).
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 229, CDR-H2 comprising amino acid sequence SEQ ID NO. 230 and CDR-H3 comprising amino acid sequence SEQ ID NO. 231; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 249, and/or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 250. In some embodiments, the VH domain comprises the amino acid sequence SEQ ID NO 249; and the VL domain comprises the amino acid sequence SEQ ID NO. 250. In some embodiments, an anti-CD 8 antibody of the disclosure comprises 1, 2, or 3 heavy chain CDRs of antibody xhCD8v11 (e.g., as shown in tables 1-3) and/or 1, 2, or 3 light chain CDRs of antibody xhCD8v11 (e.g., as shown in tables 1-3). In some embodiments, the antibody is humanized. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from the sequence SEQ ID NO 249; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from the sequence SEQ ID NO:250. In some embodiments, the VH domain further comprises: FW-1 comprising sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 281), FW-2 comprising sequence WVRQAPGKGLEWVS (SEQ ID NO: 282), FW-3 comprising sequence RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 283) and/or FW-4 comprising sequence WGQGTMVTVSS (SEQ ID NO: 284) or WGQGTLVTVSS (SEQ ID NO: 285). In some embodiments, the VL domain further comprises: FW-1 comprising sequence EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising sequence WYQQKPGQAPRLLIY (SEQ ID NO: 294), FW-3 comprising sequence GIPDRFSGSGSGTDFTLTISRLEPEDFAVY YC (SEQ ID NO: 295) and/or FW-4 comprising sequence FGQGTKVEIK (SEQ ID NO: 296).
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 229, CDR-H2 comprising amino acid sequence SEQ ID NO. 237 and CDR-H3 comprising amino acid sequence SEQ ID NO. 231; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 255, and/or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 256. In some embodiments, an anti-CD 8 antibody of the present disclosure comprises 1, 2, or 3 heavy chain CDRs of antibody xhCD8v14 (e.g., as shown in tables 1-3) and/or 1, 2, or 3 light chain CDRs of antibody xhCD8v14 (e.g., as shown in tables 1-3). In some embodiments, the antibody is humanized. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising CDR-H1, CD R-H2 and CDR-H3 from sequence SEQ ID NO 255; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from the sequence SEQ ID NO: 256. In some embodiments, the VH domain further comprises: FW-1 comprising sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 281), FW-2 comprising sequence WVRQAPGKGLEWVS (SEQ ID NO: 282), FW-3 comprising sequence RFTISRDNAKNSLYLQMNSLRAEDT AVYYCAR (SEQ ID NO: 283) and/or FW-4 comprising sequence WGQGTMVT VSS (SEQ ID NO: 284) or WGQGTLVTVSS (SEQ ID NO: 285). In some embodiments, the VL domain further comprises: FW-1 comprising sequence EIVLTQSPGT LSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising sequence WYQQKP GQAPRLLIY (SEQ ID NO: 294), FW-3 comprising sequence GIPDRFSGSGS GTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 295) and/or FW-4 comprising sequence FGQGTKVEIK (SEQ ID NO: 296).
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 229, CDR-H2 comprising amino acid sequence SEQ ID NO. 237 and CDR-H3 comprising amino acid sequence SEQ ID NO. 231; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 257, and/or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 258. In some embodiments, an anti-CD 8 antibody of the disclosure comprises 1, 2, or 3 heavy chain CDRs of antibody xhCD8v15 (e.g., as shown in tables 1-3) and/or 1, 2, or 3 light chain CDRs of antibody xhCD8v15 (e.g., as shown in tables 1-3). In some embodiments, the antibody is humanized. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising CDR-H1, CD R-H2 and CDR-H3 from sequence SEQ ID NO 257; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from the sequence SEQ ID NO 258. In some embodiments, the VH domain further comprises: FW-1 comprising sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 281), FW-2 comprising sequence WVRQAPGKGLEWVS (SEQ ID NO: 282), FW-3 comprising sequence RFTISRDNAKNSLYLQMNSLRAEDT AVYYCAR (SEQ ID NO: 283) and/or FW-4 comprising sequence WGQGTMVT VSS (SEQ ID NO: 284) or WGQGTLVTVSS (SEQ ID NO: 285). In some embodiments, the VL domain further comprises: FW-1 comprising sequence EIVLTQSPGT LSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising sequence WYQQKP GQAPRLLIY (SEQ ID NO: 294), FW-3 comprising sequence GIPDRFSGSGS GTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 295) and/or FW-4 comprising sequence FGQGTKVEIK (SEQ ID NO: 296).
In some embodiments, an anti-CD 8 antibody of the disclosure comprises a VH domain and a VL domain, the VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 49, CDR-H2 comprising amino acid sequence SEQ ID NO. 50 and CDR-H3 comprising amino acid sequence SEQ ID NO. 3; the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 51, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 15; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 53, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 21; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 49, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 27; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 54, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 33; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 55, CDR-H2 comprising amino acid sequence SEQ ID NO. 56 and CDR-H3 comprising amino acid sequence SEQ ID NO. 39; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 55, CDR-H2 comprising amino acid sequence SEQ ID NO. 57 and CDR-H3 comprising amino acid sequence SEQ ID NO. 45; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48. In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 183, CDR-H2 comprising amino acid sequence SEQ ID NO. 184 and CDR-H3 comprising amino acid sequence SEQ ID NO. 179; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182.
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising the amino acid sequence GX 1 X 2 FX 3 X 4 X 5 Wherein X is 1 G, Y, S or A, X 2 T, S, G, R, N or H, X 3 S, T, R, H, Y, G or P, X 4 S, K, G, N, R, D, T or G, and X 5 Y, L, H or F (SEQ ID NO: 265); CDR-H2 comprising the amino acid sequence X 1 PX 2 X 3 X 4 X 5 Wherein X is 1 I, N or M, X 2 G, N, H, S, R, I or A, X 3 A, N, H, S, T, F or Y, X 4 A, D or G, and X 5 T, E, K, V, Q or A (SEQ ID NO: 266); and CDR-H3 comprising the amino acid sequence X 1 X 2 X 3 GX 4 X 5 LFX 6 X 7 Wherein X is 1 Is D or A, X 2 A, G, E, R, Y, K, N, Q, L or F, X 3 A, L, P or Y, X 4 Is I or L, X 5 R, A, Q or S, X 6 Is A or D, and X 7 D, E, A or S (SEQ ID NO: 267); and a VL domain comprising: CDR-L1 comprising the amino acid sequence X 1 X 2 SX 3 X 4 IX 5 GX 6 LN, wherein X 1 R or G, X 2 Is A or T, X 3 Q or E, X 4 E, N, T, S, A, K, D, G, R or Q, X 5 Is Y or S, and X 6 A or V (SEQ ID NO: 262); CDR-L2 comprising the amino acid sequence GX 1 X 2 X 3 LX 4 X 5 Wherein X is 1 Is A or S, X 2 T, S, E, Q or D, X 3 N, R, A, E or H, X 4 Q or A, and X 5 S or D (SEQ ID NO: 263); and CDR-L3 comprising the amino acid sequence QX 1 X 2 X 3 X 4 X 5 PWT, wherein X 1 S, N, D, Q, A or E, X 2 T, I or S, X 3 Y, L or F, X 4 D, G, T, E, Q, A or Y, and X 5 For A, T, R, S, K or Y (S)EQ ID NO: 264). In some embodiments, the VH domain further comprises: FW-1 comprising sequence QVQLVQSGAEVKKPGSSVKVSCKAS (SEQ ID NO: 278), FW-2 comprising sequence AISWVRQAPGQGLEWMGGI (SEQ ID NO: 279), FW-3 comprising sequence ANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 280) and/or FW-4 comprising sequence WGQGTLVTVSS (SEQ ID NO: 277). In some embodiments, the VL domain further comprises: FW-1 comprising sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 289), FW-2 comprising sequence WYQQKPGKAPKLLIY (SEQ ID NO: 290), FW-3 comprising sequence GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 291) and/or FW-4 comprising sequence FGGGTKVEIK (SEQ ID NO: 292).
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 239 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228. In some embodiments, the VH domain further comprises: FW-1 comprising sequence QVQLVQSGAEVKKPGSSVKVSCKAS (SEQ ID NO: 278), FW-2 comprising sequence AISWVRQAPGQGLEWMGG I (SEQ ID NO: 279), FW-3 comprising sequence ANYAQKFQGRVTITADEST STAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 280) and/or FW-4 comprising sequence WGQGTLVTVSS (SEQ ID NO: 277). In some embodiments, the VL domain further comprises: FW-1 comprising sequence DIQMTQSPSSLSASVGDRVTIT C (SEQ ID NO: 289), FW-2 comprising sequence WYQQKPGKAPKLLIY (SE Q ID NO: 290), FW-3 comprising sequence GVPSRFSGSGSGTDFTLTISSLQP EDFATYYC (SEQ ID NO: 291) and/or FW-4 comprising sequence FGGGTKVEI K (SEQ ID NO: 292).
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 243 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236. In some embodiments, the VH domain further comprises: FW-1 comprising sequence QVQLVQSGAEVKKPGSSVKVSCKAS (SEQ ID NO: 278), FW-2 comprising sequence AISWVRQAPGQGLEWMGG I (SEQ ID NO: 279), FW-3 comprising sequence ANYAQKFQGRVTITADEST STAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 280) and/or FW-4 comprising sequence WGQGTLVTVSS (SEQ ID NO: 277). In some embodiments, the VL domain further comprises: FW-1 comprising sequence DIQMTQSPSSLSASVGDRVTIT C (SEQ ID NO: 289), FW-2 comprising sequence WYQQKPGKAPKLLIY (SE Q ID NO: 290), FW-3 comprising sequence GVPSRFSGSGSGTDFTLTISSLQP EDFATYYC (SEQ ID NO: 291) and/or FW-4 comprising sequence FGGGTKVEI K (SEQ ID NO: 292).
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 243 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228. In some embodiments, the VH domain further comprises: FW-1 comprising sequence QVQLVQSGAEVKKPGSSVKVSCKAS (SEQ ID NO: 278), FW-2 comprising sequence AISWVRQAPGQGLEWMGG I (SEQ ID NO: 279), FW-3 comprising sequence ANYAQKFQGRVTITADEST STAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 280) and/or FW-4 comprising sequence WGQGTLVTVSS (SEQ ID NO: 277). In some embodiments, the VL domain further comprises: FW-1 comprising sequence DIQMTQSPSSLSASVGDRVTIT C (SEQ ID NO: 289), FW-2 comprising sequence WYQQKPGKAPKLLIY (SE Q ID NO: 290), FW-3 comprising sequence GVPSRFSGSGSGTDFTLTISSLQP EDFATYYC (SEQ ID NO: 291) and/or FW-4 comprising sequence FGGGTKVEI K (SEQ ID NO: 292).
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising the amino acid sequence GFTFX 1 X 2 Y, wherein X 1 S, D, E, Q, S or A and X 2 S, D, E, A or Q (SEQ ID NO: 271); CDR-H2 comprising the amino acid sequence X 1 X 2 X 3 GX 4 X 5 Wherein X is 1 T, N, S, Q, E, H, R or A, X 2 Y, W, F or H, X 3 A, S, Q, E or T, X 4 Is G or E, X 5 S or I (SEQ ID NO: 272); and CDR-H3 comprising the amino acid sequence X 1 X 2 X 3 YX 4 WX 5 X 6 AX 7 DX 8 Wherein X is 1 Is S or A, X 2 N, H, A, D, L, Q, Y or R, X 3 A, N, S or G, X 4 A, V, R, E or S, X 5 Is D or S, X 6 D, N, Q, E, S, T or L, X 7 L, F or M, and X 8 I, Y or V (SEQ ID NO: 273); and a VL domain comprising: CDR-L1 comprising amino acid sequence RASQSVSSNLA (SEQ ID NO: 40), CDR-L2 comprising amino acid sequence GASSRAT (SEQ ID NO: 41) and CDR-L3 comprising amino acid sequence QQYGSSPPVT (SEQ ID NO: 42). In some embodiments, the VH domain further comprises: FW-1 comprising sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 286), FW-2 comprising sequence AMSWVRQAPGKGLEWVSDI (SEQ ID NO: 287), FW-3 comprising sequence TAYADSVKGRFTISRDNAK NSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 288) and/or FW-4 comprising sequence WGQGTMVTVSS (SEQ ID NO: 284) or WGQGTLVTVSS (SEQ ID NO: 285). In some embodiments, the VL domain further comprises: FW-1 comprising sequence EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising sequence WYQQKPGQAPRLLIY (SEQ ID NO: 294), FW-3 comprising sequence GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 295) and/or FW-4 comprising sequence FGQGTKVEIK (SEQ ID NO: 296).
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 240, CDR-H2 comprising amino acid sequence SEQ ID NO. 241 and CDR-H3 comprising amino acid sequence SEQ ID NO. 242; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the VH domain further comprises: FW-1 comprising sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 286), FW-2 comprising sequence AMSWVRQAPGKGLEWVSDI (SEQ ID NO: 287), FW-3 comprising sequence TAYADSVKGRFTISRDNAK NSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 288) and/or FW-4 comprising sequence WGQGTMVTVSS (SEQ ID NO: 284) or WGQGTLVTVSS (SEQ ID NO: 285). In some embodiments, the VL domain further comprises: FW-1 comprising sequence EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising sequence WYQQKPGQAPRLLIY (SEQ ID NO: 294), FW-3 comprising sequence GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 295) and/or FW-4 comprising sequence FGQGTKVEIK (SEQ ID NO: 296).
In some embodiments, an anti-CD 8 antibody of the disclosure comprises: a VH domain comprising: CDR-H1 comprising amino acid sequence SEQ ID NO. 240, CDR-H2 comprising amino acid sequence SEQ ID NO. 244 and CDR-H3 comprising amino acid sequence SEQ ID NO. 242; and a VL domain comprising: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42. In some embodiments, the VH domain further comprises: FW-1 comprising sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 286), FW-2 comprising sequence AMSWVRQAPGKGLEWVSDI (SEQ ID NO: 287), FW-3 comprising sequence TAYADSVKGRFTISRDNAK NSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 288) and/or FW-4 comprising sequence WGQGTMVTVSS (SEQ ID NO: 284) or WGQGTLVTVSS (SEQ ID NO: 285). In some embodiments, the VL domain further comprises: FW-1 comprising sequence EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising sequence WYQQKPGQAPRLLIY (SEQ ID NO: 294), FW-3 comprising sequence GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 295) and/or FW-4 comprising sequence FGQGTKVEIK (SEQ ID NO: 296). In some embodiments, the present disclosure provides an anti-CD 8 antibody comprising: a VH domain comprising CDR-H1, CDR-H2, and CDR-H3 sequences of a monoclonal antibody listed in table 1; and a VL domain comprising CD R-L1, CDR-L2 and CDR-L3 sequences of the monoclonal antibodies listed in Table 1. For example, the anti-CD 8 antibody comprises the six CDRs of antibodies xhCD8V1, xhCD8V1.1, xhCD8V2, xhCD8V3, xhCD8V4, xhCD8V5, xhCD8V6, xhCD8V7, xhCD8V8, xhCD8V9, xhCD8V10, xhCD8V11, xhCD8V12, xhCD8V13, xhCD8V14, xhCD8V15, V9 family, or V11 family shown in table 1. In some embodiments, the present disclosure provides an anti-CD 8 antibody comprising: a VH domain comprising CDR-H1, CDR-H2, and CDR-H3 sequences of a monoclonal antibody listed in table 2; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 sequences of the monoclonal antibodies listed in Table 2. For example, the anti-CD 8 antibody comprises the six CDRs of antibodies xhCD8V1, xhCD8V1.1, xhCD8V2, xhCD8V3, xhCD8V4, xhCD8V5, xhCD8V6, xhCD8V7, xhCD8V8, xhCD8V9, xhCD8V10, xhCD8V11, xhCD8V12, xhCD8V13, xhCD8V14, xhCD8V15, V9 family, or V11 family shown in table 2. In some embodiments, the present disclosure provides a fusion protein comprising an anti-CD 8 antibody comprising: a VH domain comprising CDR-H1, CDR-H2, and CDR-H3 sequences of a monoclonal antibody listed in table 1; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 sequences of the monoclonal antibodies listed in Table 1. For example, the anti-CD 8 antibody of the fusion protein comprises six CD rs of the antibodies xhCD8V1, xhCD8V1.1, xhCD8V2, xhCD8V3, xhCD8V4, xhCD8V5, xhCD8V6, xhCD8V7, xhCD8V8, xhCD8V9, xhCD8V10, xhCD8V11, xhCD8V12, xhCD8V13, xhCD8V14, xhCD8V15, V9 family, or V11 family shown in table 1. In some embodiments, the present disclosure provides a fusion protein comprising an anti-CD 8 antibody comprising: a VH domain comprising CDR-H1, CDR-H2, and CDR-H3 sequences of a monoclonal antibody listed in table 2; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 sequences of the monoclonal antibodies listed in Table 2. For example, the anti-CD 8 antibody of the fusion protein comprises six CDRs of antibodies xhCD8V1, xhCD8V1.1, xhCD8V2, xhCD8V3, xhCD8V4, xhCD8V5, xhCD8V6, xhCD8V7, xhCD8V8, xhCD8V9, xhCD8V10, xhCD8V11, xhCD8V12, xhCD8V13, xhCD8V14, xhCD8V15, V9 family, or V11 family shown in table 2. In some embodiments, the present disclosure provides an anti-CD 8 antibody comprising: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 sequences of the VH domains listed in table 3; and a VL domain comprising CDR-L1, CDR-L2, and CDR-L3 sequences of the VL domains listed in table 3 (in some embodiments, the VH and VL domains are from the same monoclonal antibody listed in table 3). For example, the anti-CD 8 antibody comprises the VH and VL of antibodies xhCD8v1, xhCD8v1.1, xhCD8v2, xhCD8v3, xhCD8v4, xhCD8v5, xhCD8v6, xhCD8v7, xhCD8v8, xhCD8v9, xhCD8v10, xhCD8v11, xhCD8v12, xhCD8v13, xhCD8v14, or xhCD8v15 shown in table 3. In some embodiments, the present disclosure provides a fusion protein comprising an anti-CD 8 antibody comprising: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 sequences of the VH domains listed in table 3; and a VL domain comprising CDR-L1, CDR-L2, and CDR-L3 sequences of the VL domains listed in table 3 (in some embodiments, the VH and VL domains are from the same monoclonal antibody listed in table 3). In some embodiments, the disclosure provides an anti-CD 8 antibody comprising a VH domain sequence and a VL domain sequence of a monoclonal antibody as set forth in table 3. In some embodiments, the disclosure provides a fusion protein comprising an anti-CD 8 antibody comprising a VH domain sequence and a VL domain sequence of a monoclonal antibody as set forth in table 3. For example, the anti-CD 8 antibody of the fusion protein comprises VH and VL of antibodies xhCD8v1, xhCD8v1.1, xhCD8v2, xhCD8v3, xhCD8v4, xhCD8v5, xhCD8v6, xhCD8v7, xhCD8v8, xhCD8v9, xhCD8v10, xhCD8v11, xhCD8v12, xhCD8v13, xhCD8v14, or xhCD8v15 shown in table 3.
TABLE 1 anti-CD 8 antibody CDR (Kabat)
/>
/>
TABLE 2 anti-CD 8 antibody CDR (Chothia)
/>
/>
TABLE 3 variable domain sequences of anti-CD 8 antibodies
/>
/>
/>
Fusion proteins
Further provided herein are fusion proteins comprising any of the anti-CD 8 antibodies or antigen-binding domains or antibody fragments disclosed herein. In some embodiments, the fusion proteins of the present disclosure comprise: a first portion comprising a human or humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab (e.g., any of the anti-CD 8 antibodies described above); and a second portion comprising a cytokine, chemokine or growth factor. In some embodiments, the first moiety is directly fused to the second moiety. In some embodiments, the first moiety is fused to the second moiety via a linker. An exemplary and non-limiting illustration of a fusion protein of the present disclosure is depicted in fig. 7.
Fusion protein forms
In some embodiments, the first portion comprises an antibody (e.g., an anti-CD 8 antibody of the disclosure). In some embodiments, the first portion comprises an antibody fragment (e.g., an anti-CD 8 antibody fragment of the disclosure). In some embodiments, the first portion comprises a single chain antibody or single chain variable fragment (scFv). In some embodiments, the first moiety comprises a VHH antibody. In some embodiments, the first portion comprises one or two antibody heavy chain polypeptides (e.g., of an anti-CD 8 antibody of the disclosure) and one or two antibody light chain polypeptides. In some embodiments, the first portion comprises 3 heavy chain CDRs and/or 3 light chain CDRs of a single anti-CD 8 antibody of the disclosure, e.g., as shown in tables 1-3. In some embodiments, the first portion comprises the VH and/or VL domains of a single anti-CD 8 antibody of the disclosure, e.g., as shown in table 3. In some embodiments, the first portion further comprises one or two human IgG Fc domains. In some embodiments, the one or both human IgG Fc domains are IgG1, igG2, igG3, or IgG4 Fc domains. In some embodiments, the one or both human IgG Fc domains do not have a C-terminal lysine residue. In some embodiments, the one or both human IgG Fc domains comprise amino acid modifications (such as substitutions, deletions, additions, etc.). In some embodiments, the Fc domain modification promotes heterodimer formation (e.g., as shown in table 4). In some embodiments, the one or both Fc domains comprise fcγ null mutations.
In some embodiments, the first portion comprises: two antibody heavy chain polypeptides comprising from N-terminus to C-terminus a structure according to formula [ I ]:
VH-CH 1-hinge-CH 2-CH3 [ I ]
And two antibody light chain polypeptides comprising a structure according to formula [ II ] from N-terminus to C-terminus:
VL-CL [II]
wherein VH is said VH domain, wherein CH1 is an antibody CH1 domain, wherein the hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is said VL domain, and wherein CL is an antibody constant light chain domain. In some embodiments, the N-terminus of the second moiety is fused to the C-terminus of one of the two CH3 domains (see, e.g., form a in fig. 7).
In some embodiments, the first portion comprises: a first antibody heavy chain polypeptide comprising from N-terminus to C-terminus a structure according to formula [ I ]:
VH-CH 1-hinge-CH 2-CH 3I,
an antibody light chain polypeptide comprising a structure according to formula [ II ] from N-terminus to C-terminus:
VL-CL [II]，
and a second antibody heavy chain polypeptide comprising from N-terminus to C-terminus a structure according to formula [ III ]:
hinge-CH 2-CH3 III,
wherein VH is said VH domain, wherein CH1 is an antibody CH1 domain, wherein the hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is said VL domain, and wherein CL is an antibody constant light chain domain. In some embodiments, the N-terminus of the second portion is fused to the C-terminus of the CH3 domain of the second antibody heavy chain polypeptide (see, e.g., form B in fig. 7). In some embodiments, the N-terminus of the second portion is fused to the C-terminus of the CH3 domain of the first antibody heavy chain polypeptide (see, e.g., form D in fig. 7).
In some embodiments, the first portion comprises: a first antibody heavy chain polypeptide comprising from N-terminus to C-terminus a structure according to formula [ I ]:
VH-CH 1-hinge-CH 2-CH 3I,
an antibody light chain polypeptide comprising a structure according to formula [ II ] from N-terminus to C-terminus:
VL-CL [II]，
and a second antibody heavy chain polypeptide comprising from N-terminus to C-terminus a structure according to formula [ III ]:
hinge-CH 2-CH3 III,
wherein VH is said VH domain, wherein CH1 is an antibody CH1 domain, wherein the hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is said VL domain, and wherein CL is an antibody constant light chain domain. In some embodiments, the C-terminus of the second portion is fused to the N-terminus of the hinge domain of the second antibody heavy chain polypeptide (see, e.g., form C in fig. 7).
In some embodiments, an anti-CD 8 antibody of the present disclosure is a multispecific (e.g., bispecific) antibody or antibody fragment. For example, in some embodiments, the multispecific antibody (e.g., bispecific antibody) comprises a first antigen-binding domain that binds to CD8 (e.g., as described above) and a second antigen-binding domain that binds to a target of interest. In some embodiments, bispecific antibodies can be produced by fusing additional binding sites to the heavy or light chain of an immunoglobulin. Examples of additional binding sites include, but are not limited to, variable regions, scFv, fab, VHH, and peptides.
In some embodiments, the recombinant bispecific antibodies disclosed herein can be classified very roughly into two classes, i.e., i) a form resulting from the combination of variable regions alone and ii) a form of combining variable regions with Fc domains. Representative of the first class are tandem scFv (taFv), diabody (Db), DART, single chain diabody (scDb), fab-Fc, tandem Fab, double variable region Fab, and tandem dAb/VHH. The two variable regions may be linked together via covalent bonds or non-covalent interactions.
Non-covalent interactions may involve the use of heterodimerization modules such as leucine zippers, dock-and-lock (dock-and-lock) methods using regulatory subunits of cAMP-dependent Protein Kinase (PKA), and the anchor domain or knob CH3 domain of the A Kinase Anchor Protein (AKAP) (U.S. Pat. No. 5,731,168; U.S. Pat. No. 7,695,936; ridgway et al, prot Eng 9,617-621 (1996) and Carter, J Immunol Meth 248,7-15 (2001)) to pair variable regions.
In some embodiments, bispecific antibodies are produced on a native immunoglobulin architecture that contains two pairs of heavy and light chain combinations, each pair having a different binding specificity. Homodimerization of the two heavy chains in IgG is mediated by CH3 interactions. To promote heterodimer formation, genetic modifications were introduced into two separate CH3 regions. These heterodimerization mutations typically involve steric repulsion, charge-steering interactions, or interchain disulfide bond formation. Exemplary and non-limiting Fc modifications that promote heterodimerization include the following:
Table 4. Exemplary Fc modifications that promote heterodimerization.
/>
/>
In some embodiments, bispecific antibodies can be produced by post-production assembly of half antibodies, thereby solving the heavy and light chain mismatch problem. These antibodies typically contain modifications that favor heterodimerization of the half-antibodies. Exemplary systems include, but are not limited to, pestle, igG1 (EEE-RRR), igG2 (EEE-RRRRRRR) (Strop et al J Mol Biol (2012)) and DuoBody (F405L-K409R), listed in Table 5. In such cases, the half antibodies are produced individually in separate cell lines and purified. The purified antibodies are then subjected to light reduction to obtain half antibodies, which are subsequently assembled into bispecific antibodies. The heterodimeric bispecific antibody is then purified from the mixture using conventional purification methods.
In some embodiments, bispecific antibody production strategies that do not rely on preferential chain pairing may also be employed. These strategies typically involve introducing genetic modifications on the antibody in such a way that the heterodimer will have biochemical or biophysical properties that differ from those of the homodimer; thus, the assembled or expressed heterodimer can be selectively purified from the homodimer. One example is the introduction of H435R/Y436F in the IgG1 CH3 domain to eliminate Fc binding to protein A resin and subsequent co-expression of H435R/Y436F variants with wild-type Fc. The resulting homodimeric antibodies containing two copies of H435R/Y436F failed to bind to the protein A column, whereas a heterodimeric antibody containing one copy of the H435R/Y436F mutation would have a reduced protein A affinity (Tustin et al Mabs 2016) compared to the strong interaction of the homodimeric wild-type antibody. Other examples include kappa/lambda antibodies (Fischer et al Nature Communication 2015) and different charge introduction on the respective chains (E357Q, S267K or N208D/Q295E/N384D/Q418E/N421D) (US 2018/0142040A 1; strop et al J Mol Biol (2012)).
In some embodiments, bispecific antibodies can be produced by fusing additional binding sites to the heavy or light chain of an immunoglobulin. Examples of additional binding sites include, but are not limited to, variable regions, scFv, fab, VHH, and peptides.
Fusion protein Fc region
In some embodiments, an antibody or fusion protein of the disclosure comprises an Fc region. In some embodiments, the Fc region comprises one or more mutations that reduce or eliminate fcγr binding and/or effector function. In some embodiments, the Fc region (e.g., igG1 Fc region) comprises substitutions at one or more of the following positions: c220, C226, C229, E233, L234, L235, G237, P238, S239, D265, S267, N297, L328, P331, K322, a327 and P329. In some embodiments, the Fc region (e.g., igG2 Fc region) comprises substitutions at one or more of the following positions: v234, G237, D265, H268, N297, V309, a330, a331, K322. In some embodiments, the Fc region (e.g., igG4 Fc region) comprises substitutions at one or more of the following positions: l235, G237, D265, and E318. In some embodiments, the Fc region (e.g., igG1 Fc region) comprises one or more of the following mutations or sets of mutations: N297A, N297Q, N297G, D A/N297A, D265A/N297A, D A/N297Q, C S/C226S/C229S/P238S, S E/L328F, C S/C229S/E233P/L234V/L235A, L F/L235E/P331S, L234A/L235 39234A/L235A/G237A, L A/L235A/G237A/K322A, L A/L235A/G237A/A330S/A331S, L A/L235A/P329G, E P/L234V/L235A/G236del/S239K, E P/L234V/L235A/G236del/S267K, E P/L234V/L235A/G236del/S239K/A327G, E P/L234V/L235A/G236del/S267K/A327G and E233P/L234V/L236A/G236 del L234A/L235A/G237 is absent. In some embodiments, the Fc region (e.g., igG2 Fc region) comprises one or more of the following mutations or sets of mutations: A330S/A331S, V A/G237A, V A/G237A/D265A, D265A/A330S/A331S, V A/G237A/D265A/A330S/A331S and H268Q/V309L/A330S/A331S. In some embodiments, the Fc region (e.g., igG4 Fc region) comprises one or more of the following mutations or sets of mutations: L235A/G237A/E318A, D265A, L A/G237A/D265A and L235A/G237A/D265A/E318A. In some embodiments, the Fc region comprises one, two, three, or all of the following mutations: L234A, L235A, G a and K322A, numbered according to EU index. In some embodiments, the Fc region comprises one, two, or all of the following mutations: L234A, L a and G237A, numbered according to EU index.
In some embodiments, the first and second Fc domains of a fusion protein contain one or more of the following Fc mutations that reduce effector function according to EU numbering: L234A, L235A, G a and K322A. In some embodiments, the first and second Fc domains of a fusion protein contain the following Fc mutations that reduce effector function according to EU numbering: L234A, L a and G237A. In some embodiments, the first and second Fc domains of a fusion protein contain the following Fc mutations that reduce effector function according to EU numbering: L234A, L235A, G a and K322A. In some embodiments, the first and second Fc domains of a fusion protein contain the following amino acid substitutions that promote heterodimer formation: Y349C/T366W (pestle) and S354C, T366S, L368A and Y407V (mortar).
In some embodiments, the heterodimeric mutation and/or mutation that modifies fcγ receptor binding results in decreased Fc stability. Thus, additional one or more mutations are added to the Fc region to increase its stability. For example, one or more disulfide pairs (such as a287C and L306C, V259C and L306C, R292C and V302C, and V323C and I332C) are introduced into the Fc region. Another example is the introduction of S228P to IgG 4-based bispecific antibodies to stabilize the hinge disulfide bond. Additional examples include the introduction of K338I, A339K and K340S mutations to enhance Fc stability and aggregation resistance (Gao et al 2019Mol Pharm.2019;16:3647).
Fusion protein cytokines
In some embodiments, the second moiety induces activation of cd8+ T cells. In some embodiments, the second moiety comprises a polypeptide that induces signaling via IL2rβγ. For example, in some embodiments, the second portion comprises an IL-15 polypeptide (e.g., a human IL-15 polypeptide or derivative thereof) or a neoleukin. In some embodiments, the second portion comprises an IL-21 polypeptide (e.g., a human IL-21 polypeptide or derivative thereof).
In some embodiments, the second portion comprises an IL-2 polypeptide (e.g., a human IL-2 polypeptide or derivative thereof).
In some embodiments, the mutant IL-2 polypeptide has a binding affinity for IL-2Rα that is 50% or more reduced compared to the binding affinity for IL-2Rα of a wild-type IL-2 polypeptide comprising sequence SEQ ID: 81. In some embodiments, the mutant IL-2 polypeptide has a binding affinity for IL-2Rβ that is reduced by 50% or more compared to the binding affinity for IL-2Rβ of a wild-type IL-2 polypeptide comprising sequence SEQ ID: 81. In some embodiments, the mutant IL-2 polypeptide has a binding affinity for IL-2 Rgamma that is reduced by 50% or more compared to the binding affinity for IL-2 Rgamma of a wild-type IL-2 polypeptide comprising sequence SEQ ID: 81. Differences in binding affinity of wild-type and disclosed mutant polypeptides to IL-2rα and IL-2rβ can be measured, for example, in standard Surface Plasmon Resonance (SPR) assays that measure affinity for protein-protein interactions familiar to those skilled in the art. The difference in binding affinity of wild-type and the disclosed mutant polypeptides to IL-2rγ cannot be reliably measured by SPR analysis because the affinity of wild-type IL-2 polypeptides to IL-2rγ is extremely low. Alternatively, its reduced IL-2 Rgamma affinity can be inferred by performing an in vitro assay that measures pSTAT5 and compares the activity of IL-2 polypeptides in the presence and absence of IL-2 Rgamma affinity-reducing substitutions on IL-2R expressing cells. Exemplary sequences for IL-2Rα, IL-2Rβ and IL-2Rγ are provided below.
IL-2Rα：
IL-2Rβ：
IL-2Rγ：
In some embodiments, the IL-2 polypeptide is a mutant IL-2 polypeptide comprising one or more mutations relative to a human IL-2 polypeptide, which human IL-2 polypeptide comprises sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 81). In some embodiments, the mutant IL-2 polypeptides of the disclosure have one or more, two or more, or three or more affinity-reducing amino acid substitutions relative to a wild-type mature IL-2 polypeptide having, for example, the amino acid sequence SEQ ID NO. 81. In some embodiments, one or more, two or more, or three or more substituted residues are selected from the group consisting of: q11, H16, L18, L19, D20, D84, S87, Q22, R38, F42, K43, Y45, E62, P65, E68, V69, L72, D84, S87, N88, V91, I92, T123, Q126, S127, I129, and S130. Reduced affinity for IL-2 ra can be obtained by substituting one or more of the following residues in the sequence of the wild-type mature IL-2 polypeptide: r38, F42, K43, Y45, E62, P65, E68, V69 and L72. Reduced affinity for IL-2rβ can be obtained by substitution of one or more of the following residues: e15, H16, L19, D20, D84, S87, N88, V91 and I92. Reduced affinity for IL-2rγ can be obtained by substituting one or more of the following residues in the sequence of the wild-type mature IL-2 polypeptide: q11, L18, Q22, T123, Q126, S127, I129, and S130.
In some embodiments, the mutant IL-2 polypeptide comprises an F42A or F42K amino acid substitution relative to the wild-type mature IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises an F42A or F42K amino acid substitution and an R38A, R38D, R E, E Q, E68A, E68Q, E K or E68R amino acid substitution relative to the wild-type mature IL-2 amino acid sequence. For example, in some embodiments, a mutant IL-2 polypeptide comprises the following amino acid substitutions relative to the wild-type mature IL-2 amino acid sequence, e.g., as set forth in SEQ ID NO: 81: F42A; R38A and F42A; R38D and F42A; R38E and F42A; F42A and E62Q; F42A and E68A; F42A and E68Q; F42A and E68K; F42A and E68R; or R38A and F42K. In some embodiments, the mutant IL-2 polypeptide comprises R38E and F42A amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38D and F42A amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises F42A and E62Q amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38A and F42K amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38D and F42A amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38A and F42K amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises F42A and E62Q amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises the following amino acid substitutions relative to the wild-type IL-2 amino acid sequence: h16 16 16 20 23 23 84 84 84 84 84 84 84 84 84 84 88 88 88 88 88 88 91 91 91 92 95 95 123 123 123 123 123 123 123 126 126 127 127 127K or S127Q. In some embodiments, the mutant IL-2 polypeptide comprises the following amino acid substitutions relative to the wild-type mature IL-2 amino acid sequence: F42A; R38A and F42A; R38D and F42A; R38E and F42A; F42A and E62Q; F42A and E68A; F42A and E68Q; F42A and E68K; F42A and E68R; or R38A and F42K; and comprises the following amino acid substitutions relative to the wild-type mature IL-2 amino acid sequence as set forth, for example, in SEQ ID NO. 81: h16 16 16 20 23 23 84 84 84 84 84 84 84 84 84 84 88 88 88 88 88 88 91 91 91 92 95 95 123 123 123 123 123 123 123 126 126 127 127 127K or S127Q. For example, in some embodiments, the mutant IL-2 polypeptide comprises R38E, F A and H16E amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F A and H16D amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F A and D84K amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F A and D84R amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F A and N88S amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F A and N88A amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F A and N88G amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F A and N88R amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F A and N88T amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F A and N88D amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F A and V91E amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F A and Q126S amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence of SEQ ID NO. 81 having one of the following sets of amino acid substitutions (relative to sequence SEQ ID NO. 81): R38E and F42A; R38D and F42A; F42A and E62Q; R38A and F42K; R38E, F a and N88S; R38E, F a and N88A; R38E, F a and N88G; R38E, F a and N88R; R38E, F a and N88T; R38E, F a and N88D; R38E, F a and V91E; R38E, F a and D84H; R38E, F a and D84K; R38E, F a and D84R; H16D, R E and F42A; H16E, R E and F42A; R38E, F a and Q126S; R38D, F a and N88S; R38D, F a and N88A; R38D, F a and N88G; R38D, F a and N88R; R38D, F a and N88T; R38D, F a and N88D; R38D, F a and V91E; R38D, F a and D84H; R38D, F a and D84K; R38D, F a and D84R; H16D, R D and F42A; H16E, R D and F42A; R38D, F a and Q126S; R38A, F K and N88S; R38A, F K and N88A; R38A, F K and N88G; R38A, F K and N88R; R38A, F K and N88T; R38A, F K and N88D; R38A, F K and V91E; R38A, F K and D84H; R38A, F K and D84K; R38A, F K and D84R; H16D, R a and F42K; H16E, R a and F42K; R38A, F K and Q126S; F42A, E Q and N88S; F42A, E Q and N88A; F42A, E Q and N88G; F42A, E Q and N88R; F42A, E Q and N88T; F42A, E Q and N88D; f42A, E Q and V91E; F42A, E Q and D84H; F42A, E Q and D84K; F42A, E Q and D84R; H16D, F a and E62Q; H16E, F a and E62Q; F42A, E Q and Q126S; R38E, F a and C125A; R38D, F a and C125A; F42A, E Q and C125A; R38A, F K and C125A; R38E, F42A, N S and C125A; R38E, F42A, N a and C125A; R38E, F42A, N G and C125A; R38E, F42A, N R and C125A; R38E, F42A, N T and C125A; R38E, F42A, N D and C125A; R38E, F, 42, A, V E and C125A; R38E, F42A, D H and C125A; R38E, F42A, D K and C125A; R38E, F42A, D R and C125A; H16D, R E, F a and C125A; H16E, R E, F a and C125A; R38E, F42A, C a and Q126S; R38D, F42A, N S and C125A; R38D, F42A, N a and C125A; R38D, F42A, N G and C125A; R38D, F42A, N R and C125A; R38D, F42A, N T and C125A; R38D, F42A, N D and C125A; R38D, F, 42, A, V E and C125A; R38D, F42A, D H and C125A; R38D, F42A, D K and C125A; R38D, F42A, D R and C125A; H16D, R D, F a and C125A; H16E, R D, F a and C125A; R38D, F42A, C a and Q126S; R38A, F42K, N S and C125A; R38A, F42K, N a and C125A; R38A, F42K, N G and C125A; R38A, F42K, N R and C125A; R38A, F42K, N T and C125A; R38A, F42K, N D and C125A; R38A, F, 42, K, V E and C125A; R38A, F42K, D H and C125A; R38A, F42K, D K and C125A; R38A, F42K, D R and C125A; H16D, R A, F K and C125A; H16E, R A, F K and C125A; R38A, F42K, C a and Q126S; F42A, E62Q, N S and C125A; F42A, E62Q, N a and C125A; F42A, E62Q, N G and C125A; F42A, E62Q, N88R and C125A; F42A, E62Q, N T and C125A; F42A, E62Q, N88D and C125A; F42A, E62Q, V E and C125A; F42A, E Q and D84H and C125A; F42A, E Q and D84K and C125A; F42A, E Q and D84R and C125A; H16D, F a and E62Q and C125A; H16E, F, 42, A, E Q and C125A; F42A, E62Q, C a and Q126S; F42A, N S and C125A; F42A, N a and C125A; F42A, N G and C125A; F42A, N R and C125A; F42A, N T and C125A; F42A, N D and C125A; F42A, V91E and C125A; F42A, D H and C125A; F42A, D K and C125A; F42A, D R and C125A; H16D, F a and C125A; H16E, F a and C125A; and F42A, C125A and Q126S. In some embodiments, the IL-2 polypeptide comprises the sequence of SEQ ID NO:81 having one, two, three, four, or five amino acid substitutions relative to SEQ ID NO:81, and wherein the one, two, three, four, or five substitutions comprise a substitution at a position of SEQ ID NO:81 selected from the group consisting of: q11, H16, L18, L19, D20, Q22, R38, F42, K43, Y45, E62, P65, E68, V69, L72, D84, S87, N88, V91, I92, T123, Q126, S127, I129, and S130. In some embodiments, the IL-2 polypeptide comprises the sequence of SEQ ID NO:81 having one of the following sets of amino acid substitutions (relative to sequence SEQ ID NO: 81): R38E and F42A; R38D and F42A; F42A and E62Q; R38A and F42K; R38E, F a and N88S; R38E, F a and N88A; R38E, F a and N88G; R38E, F a and N88R; R38E, F a and N88T; R38E, F a and N88D; R38E, F a and V91E; R38E, F a and D84H; R38E, F a and D84K; R38E, F a and D84R; H16D, R E and F42A; H16E, R E and F42A; R38E, F a and Q126S; R38D, F a and N88S; R38D, F a and N88A; R38D, F a and N88G; R38D, F a and N88R; R38D, F a and N88T; R38D, F a and N88D; R38D, F a and V91E; R38D, F a and D84H; R38D, F a and D84K; R38D, F a and D84R; H16D, R D and F42A; H16E, R D and F42A; R38D, F a and Q126S; R38A, F K and N88S; R38A, F K and N88A; R38A, F K and N88G; R38A, F K and N88R; R38A, F K and N88T; R38A, F K and N88D; R38A, F K and V91E; R38A, F K and D84H; R38A, F K and D84K; R38A, F K and D84R; H16D, R a and F42K; H16E, R a and F42K; R38A, F K and Q126S; F42A, E Q and N88S; F42A, E Q and N88A; F42A, E Q and N88G; F42A, E Q and N88R; F42A, E Q and N88T; F42A, E Q and N88D; f42A, E Q and V91E; F42A, E Q and D84H; F42A, E Q and D84K; and F42A, E Q and D84R.
In some embodiments, the IL-2 polypeptide comprises the sequence of SEQ ID NO:81 having another amino acid substitution at position C125 relative to SEQ ID NO: 81. In some embodiments, the IL-2 polypeptide comprises the sequence of SEQ ID NO:81 of one of the following sets of amino acid substitutions (relative to sequence SEQ ID NO: 81): R38E, F a and C125A; R38D, F a and C125A; F42A, E Q and C125A; R38A, F K and C125A; R38E, F42A, N S and C125A; R38E, F42A, N a and C125A; R38E, F42A, N G and C125A; R38E, F42A, N R and C125A; R38E, F42A, N D and C125A; R38E, F42A, N T and C125A; R38E, F, 42, A, V E and C125A; R38E, F42A, D H and C125A; R38E, F42A, D K and C125A; R38E, F42A, D R and C125A; H16D, R E, F a and C125A; H16E, R E, F a and C125A; R38E, F42A, C a and Q126S; R38D, F42A, N S and C125A; R38D, F42A, N a and C125A; R38D, F42A, N G and C125A; R38D, F42A, N R and C125A; R38D, F42A, N T and C125A; R38D, F42A, N D and C125A; R38D, F, 42, A, V E and C125A; R38D, F42A, D H and C125A; R38D, F42A, D K and C125A; R38D, F42A, D R and C125A; H16D, R D, F a and C125A; H16E, R D, F a and C125A; R38D, F42A, C a and Q126S; R38A, F42K, N S and C125A; R38A, F42K, N G and C125A; R38A, F42K, N R and C125A; R38A, F42K, N T and C125A; R38A, F42K, N D and C125A; R38A, F42K, N a and C125A; R38A, F, 42, K, V E and C125A; R38A, F42K, D H and C125A; R38A, F42K, D K and C125A; R38A, F42K, D R and C125A; H16D, R A, F K and C125A; H16E, R A, F K and C125A; R38A, F42K, C a and Q126S; F42A, E62Q, N S and C125A; F42A, E62Q, N a and C125A; F42A, E62Q, N G and C125A; F42A, E62Q, N88R and C125A; F42A, E62Q, N T and C125A; F42A, E62Q, N88D and C125A; F42A, E62Q, V E and C125A; F42A, E Q and D84H and C125A; F42A, E Q and D84K and C125A; F42A, E Q and D84R and C125A; H16D, F a and E62Q and C125A; H16E, F, 42, A, E Q and C125A; F42A, E62Q, C a and Q126S; F42A, N S and C125A; F42A, N a and C125A; F42A, N G and C125A; F42A, N R and C125A; F42A, N T and C125A; F42A, N D and C125A; F42A, V91E and C125A; F42A, D H and C125A; F42A, D K and C125A; F42A, D R and C125A; H16D, F a and C125A; H16E, F a and C125A; and F42A, C125A and Q126S.
In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFY MPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISAINV IVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 80). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFY MPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINV IVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 85). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFY
MPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT(SEQ ID
NO: 86). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 87). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 88). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 89). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 90). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 91). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 92). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 93). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 94). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCSSIISTLT (SEQ ID NO: 95). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 96). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 97). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 98). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 99). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 100). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 101). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCSSIISTLT (SEQ ID NO: 102). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 103). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 104). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 105). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 106). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 107). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 108). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCSSIISTLT (SEQ ID NO: 109). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 110). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 111). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 112). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 113). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 114). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 115). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCSSIISTLT (SEQ ID NO: 116). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 117). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 118). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 119). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 120). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 121). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 122). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 123). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 124). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 125). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 126). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFASSIISTLT (SEQ ID NO: 127). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 128). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 129). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 130). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 131). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 132). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 133). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFASSIISTLT (SEQ ID NO: 134). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 135). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 136). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 137). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 138). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 139). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 140). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFASSIISTLT (SEQ ID NO: 141). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 142). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 143). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 144). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 145). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 146). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 147). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFASSIISTLT (SEQ ID NO: 148). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 149). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 150). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 151). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 152). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 153). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 154). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFASSIISTLT (SEQ ID NO: 155). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 190). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRKLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 191). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 192). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 193). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRKLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 194). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 195). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 196). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRKLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 197). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 198). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 199). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRKLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 200). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 201). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 202). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRKLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 203). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 204). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 205). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRKLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 206). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 207). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 208). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRKLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 209). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 210). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 211). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRKLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 212). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 213). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 214). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRKLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 215). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 216). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 297). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 354). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 355). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 356). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 357). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 358). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 359). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 360). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 361). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 362). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 363). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 364). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 365). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 366). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 367). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 368). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 369). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 370). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 371). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 372). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 373). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 374). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 375). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 376). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 377). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 378). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 379). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 380). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 381). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 382). In some embodiments, the mutant IL-2 polypeptide comprises amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFY MPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISDINV IVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 383). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequences of the IL-2 polypeptides listed in Table 7.
TABLE 7 exemplary IL-2 polypeptide sequences
/>
In some embodiments, the mutant IL-2 polypeptides of the present disclosure also contain other modifications that provide additional advantages such as improved biophysical properties, including, but not limited to, mutations and deletions. Improved biophysical properties include, but are not limited to, improved thermal stability, aggregation propensity, acid reversibility, viscosity, and yield in mammalian or bacterial or yeast cells. For example, residue C125 may be substituted with a neutral amino acid such as serine, alanine, threonine, or valine; and the N-terminal A1 residue may be deleted, both of which are described in us patent No. 4,518,584. Mutant IL-2 polypeptides may also include mutations at residue M104, such as M104A, as described in U.S. patent No. 5,206,344. Thus, in certain embodiments, a mutant IL-2 polypeptide of the present disclosure comprises the amino acid substitution C125A. In other embodiments, one, two, or three N-terminal residues are deleted.
Fusion protein linker
In some embodiments, the fusion proteins of the present disclosure comprise a linker. In some embodiments, the linker is a chemical linker (e.g., as disclosed in Protein Engineering,9 (3), 299-305, 1996). Synthetic chemical linkers include cross-linking agents conventionally used to cross-link peptides, such as N-hydroxysuccinimide (NHS), di-succinimide suberate (DSS), bis (succinimidyl) suberate (BS 3), dithiobis (succinimidyl propionate) (DSP), dithiobis (succinimidyl propionate) (DTSSP), ethylene glycol bis (succinimidyl succinate) (EGS), ethylene glycol bis (sulfosuccinimidyl succinate) (sulfo-EGS), di-succinimidyl tartrate (DST), di-sulfosuccinimidyl tartrate (sulfo-DST), bis [2- (succinimidyloxycarbonyloxy) ethyl ] sulfone (BSOCOES), and bis [2- (succinimidyloxycarbonyloxy) ethyl ] sulfone (sulfo-BSOCOES).
In some embodiments, the linker is an amino acid-based or peptide-based linker. In some embodiments, the polypeptide linker is a peptide of at least 5 amino acids in length, preferably 5 to 100, more preferably 10 to 50 amino acids in length. In one embodiment, the peptide linkers are G, S, GS, SG, SGG, GGS and GSG (where g=glycine and s=serine). In some embodiments, the linker comprises the sequence (GGGS) xGn (SEQ ID NO: 74), (GGGGS) xGn (SEQ ID NO: 75), (GGGGGS) xGn (SEQ ID NO: 76), S (GGGS) xGn (SEQ ID NO: 386), S (GGGGS) xGn (SEQ ID NO: 387), or S (GGGGGS) xGn (SEQ ID NO: 388), wherein x = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and wherein n = 0, 1, 2, or 3. In some embodiments, the linker comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 79) or SGGGGSGGGGSGGGGS (SEQ ID NO: 389).
Fusion protein Properties
In some embodiments, the fusion protein induces activation of cells expressing human CD8ab heterodimer with at least 2-fold, at least 5-fold, or at least 10-fold greater potency than activation of cells expressing human CD8aa homodimer. In some embodiments, the fusion protein induces activation of cd8+ T cells with at least 2-fold, at least 5-fold, or at least 10-fold greater potency than activation of NK cells. In some embodiments, the activation efficacy is measured by EC50 as assessed by cell proliferation. Exemplary assays are described further below.
The preferential activity of a targeted IL-2 fusion protein comprising a mutant IL-2 polypeptide on antigen-expressing cells was demonstrated in assays containing antigen-expressing cells that also express IL-2rβγ or IL-2rαβγ and antigen-not. One such assay is an in vitro assay that measures the expression of the STAT5 (pSTAT 5) phosphorylation and/or proliferation marker Ki-67 in human immune cells, such as human peripheral blood and/or tumor-infiltrating immune cells, following exposure to IL-2 polypeptides. In one form of the assay, the activity of the targeted IL-2 fusion protein is measured on antigen-expressing and antigen-non-expressing cells to confirm the selectivity of antigen-expressing cells. In another form of analysis, the activity of a targeted IL-2 fusion protein comprising a mutant IL-2 polypeptide on cells expressing an antigen is compared to the activity of a non-targeted IL-2 fusion protein comprising the same mutant IL-2 polypeptide and a control antibody that does not recognize any antigen on cells expressing the antigen to confirm the extent of salvage of the mutant IL-2 polypeptide in signaling when fused to an antigen binding molecule.
In some embodiments, the fusion proteins of the present disclosure containing a CD8b antigen binding molecule activate cd8b+ IL-2rβ+ cells at least 10-fold, at least 50-fold, or at least 100-fold more than activate cd8b-IL-2rβ+ cells. In some embodiments, the fusion protein activates cd8b+ IL-2rβ+ cells 50-fold, 100-fold or 200-fold more than a fusion molecule comprising the IL-2 mutant polypeptide and a control antibody that does not bind to any antigen expressed on the cells. The activation of the cells by the IL-2 fusion protein is determined by measuring the expression of pSTAT5 or the cell proliferation marker Ki67 in the cells after treatment with the IL-2 fusion protein.
In some embodiments, the fusion proteins of the present disclosure exhibit one or more of the following: binds human CD8 and does not block CD8 interaction with MHC class I; and activates cd8+ T cells at least 10-fold, 25-fold, 50-fold, 100-fold, 250-fold, 500-fold or 1000-fold more potent than, for example, NK cells. In some embodiments, the anti-CD 8 antibodies or fusion proteins of the present disclosure can be analyzed for blocking CD8 interaction with MHC class I, for example, by analyzing the activation status of cd8+ T cells in the presence or absence of the anti-CD 8 antibodies or fusion proteins (e.g., after antigen stimulation). In some embodiments, activation of cd8+ T cells and/or NK cells can be measured, for example, by analysis of proliferation of one or more markers (e.g., ki 67) (e.g., the proportion of treated cells expressing one or more markers), IL-2rβ/γ downstream signaling, and/or STAT5 downstream signaling.
Exemplary fusion proteins
In some embodiments, the fusion proteins of the present disclosure comprise one, two, or all three polypeptides shown in table 5 for a single fusion protein. In some embodiments, the fusion proteins of the present disclosure comprise two light chains of a single fusion protein in table 5, a heavy chain comprising an IL-2 fusion, and a heavy chain not comprising an IL-2 fusion. As is known in the art, the C-terminal lysine of some antibody heavy chain materials can be cleaved in a portion of the molecule. Thus, in some embodiments, the fusion proteins of the present disclosure comprise two light chains of a single fusion protein in table 5, a heavy chain comprising an IL-2 fusion, and a heavy chain not comprising an IL-2 fusion, wherein the heavy chain not comprising an IL-2 fusion comprises the sequences SEQ ID nos. 158, 161, 164, 167, 170, 173, 176, 189, 300, 304, 308, 312, 326, 320, 324, 328, 332, 336, 340, 344, 348, or 352 of the respective fusion proteins. In some embodiments, the fusion proteins of the present disclosure comprise two light chains of a single fusion protein in Table 5, a heavy chain comprising an IL-2 fusion, and a heavy chain not comprising an IL-2 fusion, wherein the heavy chain not comprising an IL-2 fusion comprises the sequence SEQ ID No. 217-224, 301, 305, 309, 313, 317, 321, 325, 329, 333, 337, 341, 345, 349, or 353 of the respective fusion protein. In some embodiments, the disclosure provides a plurality of fusion proteins of the disclosure (e.g., as a mixture), wherein each fusion protein in the plurality comprises two light chains of a single fusion protein in table 5, a heavy chain comprising an IL-2 fusion, and a heavy chain not comprising an IL-2 fusion, wherein the heavy chain not comprising an IL-2 fusion comprises the sequence of the respective fusion protein SEQ ID No:158, 161, 164, 167, 170, 173, 176, 189, 300, 304, 308, 312, 326, 320, 324, 328, 332, 336, 340, 344, 348, or 352, or the sequence of the respective fusion protein SEQ ID No:217-224, 301, 305, 309, 313, 317, 321, 325, 329, 333, 337, 341, 345, 349, or 353, or the plurality comprises a fusion substance (e.g., the sequence of the respective fusion protein SEQ ID No:158, 161, 164, 167, 170, 173, 176, 300, 304, 308, 312, 326, 320, 324, 328, 332, 340, 321, or 352, and the sequence of the respective fusion protein SEQ ID No:217-224, 301, 305, 329, or 353, or the plurality comprises a cleavage substance (e.g., the respective fusion protein).
For example, in some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 156, a heavy chain comprising amino acid sequence SEQ ID NO. 157, and a heavy chain comprising amino acid sequence SEQ ID NO. 158. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 159, a heavy chain comprising the amino acid sequence SEQ ID NO. 160, and a heavy chain comprising the amino acid sequence SEQ ID NO. 161. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 162, a heavy chain comprising the amino acid sequence SEQ ID NO. 163, and a heavy chain comprising the amino acid sequence SEQ ID NO. 164. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 165, a heavy chain comprising the amino acid sequence SEQ ID NO. 166, and a heavy chain comprising the amino acid sequence SEQ ID NO. 167. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 168, a heavy chain comprising the amino acid sequence SEQ ID NO. 169, and a heavy chain comprising the amino acid sequence SEQ ID NO. 170. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 171, a heavy chain comprising the amino acid sequence SEQ ID NO. 172, and a heavy chain comprising the amino acid sequence SEQ ID NO. 173. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO:174, a heavy chain comprising amino acid sequence SEQ ID NO:175, and a heavy chain comprising amino acid sequence SEQ ID NO: 176. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 187, a heavy chain comprising the amino acid sequence SEQ ID NO. 188, and a heavy chain comprising the amino acid sequence SEQ ID NO. 189. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 298, a heavy chain comprising the amino acid sequence SEQ ID NO. 299, and a heavy chain comprising the amino acid sequence SEQ ID NO. 300. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 302, a heavy chain comprising amino acid sequence SEQ ID NO. 303, and a heavy chain comprising amino acid sequence SEQ ID NO. 304. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 306, a heavy chain comprising amino acid sequence SEQ ID NO. 307, and a heavy chain comprising amino acid sequence SEQ ID NO. 308. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 310, a heavy chain comprising amino acid sequence SEQ ID NO. 311, and a heavy chain comprising amino acid sequence SEQ ID NO. 312. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 314, a heavy chain comprising amino acid sequence SEQ ID NO. 315, and a heavy chain comprising amino acid sequence SEQ ID NO. 316. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 318, a heavy chain comprising the amino acid sequence SEQ ID NO. 319, and a heavy chain comprising the amino acid sequence SEQ ID NO. 320. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 322, a heavy chain comprising the amino acid sequence SEQ ID NO. 323, and a heavy chain comprising the amino acid sequence SEQ ID NO. 324. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO:326, a heavy chain comprising the amino acid sequence SEQ ID NO:327, and a heavy chain comprising the amino acid sequence SEQ ID NO: 328. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 334, a heavy chain comprising the amino acid sequence SEQ ID NO. 335, and a heavy chain comprising the amino acid sequence SEQ ID NO. 336. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 338, a heavy chain comprising the amino acid sequence SEQ ID NO. 339, and a heavy chain comprising the amino acid sequence SEQ ID NO. 340. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 342, a heavy chain comprising the amino acid sequence SEQ ID NO. 343, and a heavy chain comprising the amino acid sequence SEQ ID NO. 344. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 346, a heavy chain comprising the amino acid sequence SEQ ID NO. 347, and a heavy chain comprising the amino acid sequence SEQ ID NO. 348. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 350, a heavy chain comprising the amino acid sequence SEQ ID NO. 351, and a heavy chain comprising the amino acid sequence SEQ ID NO. 352.
In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 156, a heavy chain comprising the amino acid sequence SEQ ID NO. 157, and a heavy chain comprising the amino acid sequence SEQ ID NO. 217. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 159, a heavy chain comprising the amino acid sequence SEQ ID NO. 160, and a heavy chain comprising the amino acid sequence SEQ ID NO. 218. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 162, a heavy chain comprising the amino acid sequence SEQ ID NO. 163, and a heavy chain comprising the amino acid sequence SEQ ID NO. 219. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 165, a heavy chain comprising the amino acid sequence SEQ ID NO. 166, and a heavy chain comprising the amino acid sequence SEQ ID NO. 220. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 168, a heavy chain comprising the amino acid sequence SEQ ID NO. 169, and a heavy chain comprising the amino acid sequence SEQ ID NO. 221. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 171, a heavy chain comprising the amino acid sequence SEQ ID NO. 172, and a heavy chain comprising the amino acid sequence SEQ ID NO. 222. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 174, a heavy chain comprising the amino acid sequence SEQ ID NO. 175, and a heavy chain comprising the amino acid sequence SEQ ID NO. 223. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 187, a heavy chain comprising the amino acid sequence SEQ ID NO. 188, and a heavy chain comprising the amino acid sequence SEQ ID NO. 224. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 298, a heavy chain comprising the amino acid sequence SEQ ID NO. 299, and a heavy chain comprising the amino acid sequence SEQ ID NO. 301. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 302, a heavy chain comprising amino acid sequence SEQ ID NO. 303, and a heavy chain comprising amino acid sequence SEQ ID NO. 305. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 306, a heavy chain comprising amino acid sequence SEQ ID NO. 307, and a heavy chain comprising amino acid sequence SEQ ID NO. 309. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 310, a heavy chain comprising amino acid sequence SEQ ID NO. 311, and a heavy chain comprising amino acid sequence SEQ ID NO. 313. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 314, a heavy chain comprising amino acid sequence SEQ ID NO. 315, and a heavy chain comprising amino acid sequence SEQ ID NO. 317. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 318, a heavy chain comprising amino acid sequence SEQ ID NO. 319, and a heavy chain comprising amino acid sequence SEQ ID NO. 321. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 322, a heavy chain comprising the amino acid sequence SEQ ID NO. 323, and a heavy chain comprising the amino acid sequence SEQ ID NO. 325. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 326, a heavy chain comprising the amino acid sequence SEQ ID NO. 327, and a heavy chain comprising the amino acid sequence SEQ ID NO. 329. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 330, a heavy chain comprising amino acid sequence SEQ ID NO. 331, and a heavy chain comprising amino acid sequence SEQ ID NO. 333. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 334, a heavy chain comprising the amino acid sequence SEQ ID NO. 335, and a heavy chain comprising the amino acid sequence SEQ ID NO. 337. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 338, a heavy chain comprising the amino acid sequence SEQ ID NO. 339, and a heavy chain comprising the amino acid sequence SEQ ID NO. 341. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 342, a heavy chain comprising the amino acid sequence SEQ ID NO. 343, and a heavy chain comprising the amino acid sequence SEQ ID NO. 345. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence SEQ ID NO. 346, a heavy chain comprising the amino acid sequence SEQ ID NO. 347, and a heavy chain comprising the amino acid sequence SEQ ID NO. 349. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising amino acid sequence SEQ ID NO. 350, a heavy chain comprising amino acid sequence SEQ ID NO. 351, and a heavy chain comprising amino acid sequence SEQ ID NO. 353.
In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO:156, a heavy chain comprising amino acid sequence SEQ ID NO:157, and a heavy chain comprising amino acid sequence SEQ ID NO:158 or 217. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO. 159, a heavy chain comprising amino acid sequence SEQ ID NO. 160, and a heavy chain comprising amino acid sequence SEQ ID NO. 161 or 218. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO:162, a heavy chain comprising amino acid sequence SEQ ID NO:163, and a heavy chain comprising amino acid sequence SEQ ID NO:164 or 219. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO:165, a heavy chain comprising amino acid sequence SEQ ID NO:166, and a heavy chain comprising amino acid sequence SEQ ID NO:167 or 220. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO:168, a heavy chain comprising amino acid sequence SEQ ID NO:169, and a heavy chain comprising amino acid sequence SEQ ID NO:170 or 221. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO:171, a heavy chain comprising amino acid sequence SEQ ID NO:172, and a heavy chain comprising amino acid sequence SEQ ID NO:173 or 222. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO:174, a heavy chain comprising amino acid sequence SEQ ID NO:175, and a heavy chain comprising amino acid sequence SEQ ID NO:176 or 223. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising the amino acid sequence of SEQ ID NO. 187, a heavy chain comprising the amino acid sequence of SEQ ID NO. 188, and a heavy chain comprising the amino acid sequence of SEQ ID NO. 189 or 224. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO. 298, a heavy chain comprising amino acid sequence SEQ ID NO. 299, and a heavy chain comprising amino acid sequence SEQ ID NO. 300 or 301. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO:302, a heavy chain comprising amino acid sequence SEQ ID NO:303, and a heavy chain comprising amino acid sequence SEQ ID NO:304 or 305. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO:306, a heavy chain comprising amino acid sequence SEQ ID NO:307, and a heavy chain comprising amino acid sequence SEQ ID NO:308 or 309. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO:310, a heavy chain comprising amino acid sequence SEQ ID NO:311, and a heavy chain comprising amino acid sequence SEQ ID NO:312 or 313. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO. 314, a heavy chain comprising amino acid sequence SEQ ID NO. 315, and a heavy chain comprising amino acid sequence SEQ ID NO. 316 or 317. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO:318, a heavy chain comprising amino acid sequence SEQ ID NO:319, and a heavy chain comprising amino acid sequence SEQ ID NO:320 or 321. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO:322, a heavy chain comprising amino acid sequence SEQ ID NO:323, and a heavy chain comprising amino acid sequence SEQ ID NO:324 or 325. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO:326, a heavy chain comprising amino acid sequence SEQ ID NO:327, and a heavy chain comprising amino acid sequence SEQ ID NO:328 or 329. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO:330, a heavy chain comprising amino acid sequence SEQ ID NO:331, and a heavy chain comprising amino acid sequence SEQ ID NO:332 or 333. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO:334, a heavy chain comprising amino acid sequence SEQ ID NO:335, and a heavy chain comprising amino acid sequence SEQ ID NO:336 or 337. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO. 338, a heavy chain comprising amino acid sequence SEQ ID NO. 339, and a heavy chain comprising amino acid sequence SEQ ID NO. 340 or 341. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO:342, a heavy chain comprising amino acid sequence SEQ ID NO:343, and a heavy chain comprising amino acid sequence SEQ ID NO:344 or 345. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO. 346, a heavy chain comprising amino acid sequence SEQ ID NO. 347, and a heavy chain comprising amino acid sequence SEQ ID NO. 348 or 349. In some embodiments, the present disclosure provides a mixture of fusion protein materials, wherein each material comprises one or two light chains comprising amino acid sequence SEQ ID NO:350, a heavy chain comprising amino acid sequence SEQ ID NO:351, and a heavy chain comprising amino acid sequence SEQ ID NO:352 or 353.
In some embodiments, the disclosure provides a fusion protein comprising two heavy chain sequences and two light chain sequences of a single fusion protein listed in table 5, wherein one of the heavy chain sequences contains an IL2 fusion and the other heavy chain sequence does not contain an IL2 fusion, and wherein the two light chain sequences are identical. In some embodiments, the heavy chain sequence that does not contain an IL2 fusion comprises a lysine at the C-terminus. In some embodiments, the fusion protein has form a shown in fig. 7. For example, in some embodiments, the fusion protein comprises four polypeptide chains, wherein: (1) The first polypeptide chain comprises the amino acid sequence SEQ ID NO. 334, the second polypeptide chain comprises the amino acid sequence SEQ ID NO. 335, the third polypeptide chain comprises the amino acid sequence SEQ ID NO. 336, and the fourth polypeptide chain comprises the amino acid sequence SEQ ID NO. 334; (2) The first polypeptide chain comprises the amino acid sequence SEQ ID NO. 334, the second polypeptide chain comprises the amino acid sequence SEQ ID NO. 335, the third polypeptide chain comprises the amino acid sequence SEQ ID NO. 337, and the fourth polypeptide chain comprises the amino acid sequence SEQ ID NO. 334; (3) The first polypeptide chain comprises the amino acid sequence SEQ ID NO. 338, the second polypeptide chain comprises the amino acid sequence SEQ ID NO. 339, the third polypeptide chain comprises the amino acid sequence SEQ ID NO. 340, and the fourth polypeptide chain comprises the amino acid sequence SEQ ID NO. 338; or (4) the first polypeptide chain comprises the amino acid sequence SEQ ID NO. 338, the second polypeptide chain comprises the amino acid sequence SEQ ID NO. 339, the third polypeptide chain comprises the amino acid sequence SEQ ID NO. 341, and the fourth polypeptide chain comprises the amino acid sequence SEQ ID NO. 338.
TABLE 5 anti-CD 8 IL2 fusion protein sequences
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
Production of antibodies and fusion proteins
Further provided herein are polynucleotides (e.g., isolated polynucleotides) encoding any of the antibodies, antibody fragments, and fusion proteins described herein. Further provided herein are vectors (e.g., expression vectors) encoding any of the antibodies, antibody fragments, and fusion proteins described herein.
Further provided herein are host cells (e.g., isolated host cells or host cell lines) comprising any of the polynucleotides or vectors described herein.
Further provided herein are methods of producing any of the antibodies, antibody fragments, and fusion proteins described herein. In some embodiments, the methods comprise culturing a host cell of the present disclosure under conditions suitable for production of the antibody, antibody fragment, or fusion protein. In some embodiments, the method further comprises recovering the antibody, antibody fragment, or fusion protein.
Antibodies, antibody fragments, and fusion proteins can be produced using, for example, recombinant methods as exemplified below. In some embodiments, the nucleic acid encoding the antibody/fusion protein may be isolated and inserted into a replicable vector for further cloning or expression. The DNA encoding the antibody/fusion protein can be readily isolated and sequenced using conventional procedures (e.g., via oligonucleotide probes capable of binding specifically to genes encoding the heavy and light chains of the antibody/fragment). Many vectors are known in the art; the carrier component generally includes, but is not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. Host cells suitable for cloning or expressing the DNA in the vector herein are prokaryotes, yeast or higher eukaryote cells. When recombinant techniques are used, the antibody/fusion protein may be produced in the cell, in the periplasmic space or directly secreted into the culture medium. If the antibodies/fragments are produced intracellularly, then the particulate fragments, i.e., host cells or dissolved fragments, are removed, e.g., by centrifugation or ultrafiltration. When the antibody/fusion protein is secreted into the culture medium, the supernatant from such an expression system is typically first concentrated using a commercially available protein concentration filter.
Pharmaceutical composition
In some embodiments, the fusion proteins of the present disclosure are part of a pharmaceutical composition, e.g., comprising the fusion protein and one or more pharmaceutically acceptable carriers. Pharmaceutical compositions and formulations as described herein may be prepared in the form of lyophilized formulations or aqueous solutions by mixing an active ingredient (such as a fusion protein) of the desired purity with one or more optionally present pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences, 16 th edition, osol, a. Code (1980)). Pharmaceutically acceptable carriers are generally non-toxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; a preservative; a low molecular weight (less than about 10 residues) polypeptide; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt forming counter ions such as sodium; metal complexes (e.g., zn-protein complexes); and/or nonionic surfactants such as polyethylene glycol (PEG). In some embodiments, the fusion proteins of the present disclosure are lyophilized.
Methods and kits
Certain aspects of the present disclosure relate to methods of treating cancer or chronic infection. In some embodiments, the method comprises administering to the patient an effective amount of the fusion protein or antibody, or a pharmaceutical composition comprising the fusion protein or antibody and a pharmaceutically acceptable carrier. In some embodiments, the patient in need of such treatment has been previously diagnosed with cancer.
In some embodiments, the fusion protein or composition is administered in combination with a T cell therapy, a cancer vaccine, a chemotherapeutic agent, or an Immune Checkpoint Inhibitor (ICI). In some embodiments, the chemotherapeutic agent is a kinase inhibitor, an antimetabolite, a cytotoxin or cytostatic agent, an antihormonal agent, a platinum-based chemotherapeutic agent, a methyltransferase inhibitor, an antibody, or an anticancer peptide. In some embodiments, the immune checkpoint inhibitor targets PD-L1, PD-1, CTLA-4, CEACAM, LAIR1, CD160, 2B4, CD80, CD86, CD276, VTCN1, HVEM, KIR, A AR, MHC class I, MHC class II, GALS, adenosine, TGFR, OX40, CD137, CD40, CD47, TREM1, TREM2, HLA-G, CCR4, CCR8, CD39, CD73, IDO, CSF1R, TIM-3, BTLA, VISTA, LAG-3, TIGIT, IDO, MICA/B, LILRB4, SIGLEC-15, or arginase, including but not limited to PD-1 inhibitors (e.g., anti-PD-1 antibodies), PD-L1 inhibitors (e.g., anti-PD-L1 antibodies), or CTLA-4 inhibitors (e.g., anti-CTLA-4 antibodies).
Examples of anti-PD-1 antibodies include, but are not limited to, palbociclizumab (pembrolizumab), nivolumab (nivolumab), sibirizumab (cemiplimab), certolizumab (zimbellizumab) (Arcus), salesman Sang Lishan anti (sasanlimab) (Pfizer), JTX-4014, stadazumab (spitalizumab) (PDR 001; novartis), carilizumab (camrelizumab) (SHR 1210; jiangsu HengRui Medicine), xindi Li Shan anti (sintil limab) (IBI 308; innovant and elily), tirelizumab (tisdilizumab) (BGB-A317), terrap Li Shan anti (toripalimab) (JS), polyslimab (dostarl 285) (TSR-042, WBP-012), INCMGA 12 (MGA 012), and MGA 224-AMP (0680). Examples of anti-PD-L1 antibodies include, but are not limited to, alemtuzumab (atezolizumab), avistuzumab (avelumab), dewaruzumab (durvalum ab), KN035, and CK-301 (Checkpoint Therapeutics). Examples of PD-L1 inhibitors (not antibody-based) include, but are not limited to, AUNP12, CA-170, and BMS-986189. Examples of anti-CTLA-4 antibodies include, but are not limited to, ipilimumab (ipilimumab), tizetimumab (tremeliumab), BMS-986218, BMS-986249, BMS-986288, HBM4003, ONC-392, KN044, ADG116, ADU-1604, AGEN1181, AGEN1884, MK-1308, and REGN4659.
Examples of T cell therapies include, but are not limited to, cd4+ or cd8+ T cell based therapies, adoptive T cell therapies, chimeric Antigen Receptor (CAR) based T cell therapies, tumor Infiltrating Lymphocyte (TIL) based therapies, autologous T cell therapies, allogeneic T cell therapies, and therapies containing T cells carrying a transduced TCR. Exemplary cancer vaccines include, but are not limited to, dendritic cell vaccines, vaccines comprising one or more polynucleotides encoding one or more cancer antigens, and vaccines comprising one or more cancer antigen peptides.
Certain aspects of the present disclosure relate to methods of expanding T cells ex vivo, for example. In some embodiments, the methods comprise contacting one or more T cells, e.g., ex vivo, with an effective amount of an antibody or fusion protein of the disclosure. In some embodiments, the one or more T cells are Tumor Infiltrating Lymphocytes (TILs). In some embodiments, the method further comprises isolating tumor-infiltrating lymphocytes (TILs) from the tumor or tumor sample.
Certain aspects of the present disclosure relate to kits or articles of manufacture comprising any of the antibodies, antibody fragments, or fusion proteins disclosed herein. In some embodiments, the article comprises a container and a label or package insert on or attached to the container. In some embodiments, the kit or article of manufacture further comprises instructions for using the antibody or fusion protein according to any of the methods disclosed herein, e.g., to treat cancer or chronic infection, or to expand T cells ex vivo, for example.
Suitable containers include, for example, bottles, vials, syringes, and the like. The container may be formed of various materials, such as glass or plastic. The container contains a composition that is effective for treating the condition and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is an antibody or fusion protein as described herein. The label or package insert indicates that the composition is for treating a particular disorder. The label or package insert will also contain instructions for administering the antibody or fusion protein composition to an individual. Articles of manufacture and kits comprising the combination therapies described herein are also contemplated.
Package inserts refer to instructions that typically include information about indications, use, dosages, administration, contraindications and/or warnings regarding use of such therapeutic products in commercial therapeutic product packages.
In addition, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution, and dextrose solution. It may also include other materials from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.
Examples
Example 1: production and characterization of antibodies that bind to human CD8ab
Materials and methods
Recombinant DNA technology
Techniques involving manipulation of recombinant DNA are previously described in Sambrook et al, molecular cloning: A laboratory manual; cold Spring Harbor Laboratory Press, cold Spring Harbor, n.y., 1989. All reagents were used according to the manufacturer's instructions. The DNA sequence was determined by double strand sequencing.
Gene synthesis
The desired gene segments were generated by PCR using appropriate templates or synthesized from Genewiz (South Plainfield, NJ), integrated DNA Technologies (Coralville, IA) or GeneScript (Piscataway, NJ) with synthetic oligonucleotides. Using GibsonMethods or use restriction digests followed by ligation to clone gene segments into expression vectors. DNA was purified from the transformed bacteria and the concentration was determined by UV-visible spectroscopy. DNA sequencing was used to confirm the DNA sequence of the subcloned gene fragments.
Isolation of antibodies
Humanized or in vitro phage display systems using mouse antibodies produce antibodies that bind to CD8 antigen.
With respect to humanization, the Complementarity Determining Regions (CDRs) of the mouse residues are grafted into a selected human framework that exhibits close sequence similarity and good stability to the parental mouse framework. The resulting CDR-grafted antibody is further humanized to remove any unnecessary non-human mutations.
With respect to the in vitro display method, the non-immunized human single chain Fv phage library produced from primary B cells was panned 5 to 6 rounds to isolate antibodies to CD8 antigen. After panning, individual phage clones that exhibited specific binding to the target antigen compared to non-specific antigen in ELISA were identified. The DNA fragments of the heavy and light chain V domains of the specific binders were then cloned and sequenced. Parental clones of xhCD8v6 and xhCD8v7 were isolated from a human antibody phage library. The xhCD8v1 is a mouse monoclonal antibody against CD8b, and xhCD8v1.1 is a humanized form of xCD8v 1.
In vitro affinity maturation of human antibodies
Affinity maturation libraries are generated by shuffling the parental cloned light chains against light chains isolated from healthy donor primary B cells or by mutating selected CDR residues. The resulting library is displayed as scFv on phage or yeast surface. Three to five rounds of screening were performed, with decreasing soluble CD8 antigen concentration. The selected clones obtained were then cloned and sequenced. The xhCD8v6 and xhCD8v7 clones were generated by affinity maturation. xhCD8v2, xhCD8v3, xhCD8v4 and xhCD8v5 are affinity matured antibodies derived from xhCD8v 1.1.
Cloning of antibody constructs
General information about the nucleotide sequences of human immunoglobulin light and heavy chains is provided in: from Lefranc et althe international ImMunoGeneTics information/>25years on.Nucleic Acids Res.2015, month 1; 43->(the international ImMunoGeneTics information/>) Is a kind of medium. The DNA fragments of the heavy and light chain V domains were inserted in frame into mammalian expression vectors containing human IgG1 and CK.
Antibody preparation
DNA sequence verification constructs containing antibody heavy and light chains were transfected into Expi 293 cells using Polyethylenimine (PEI). After 5 days of incubation, the supernatant was collected and incubated with protein a resin for >2h at room temperature. Next, the resin was used multiple times with PBS and then the antibody was eluted from the resin with 20mM sodium citrate (pH 3.6). The eluted fractions were pooled and further purified by size exclusion chromatography (Superdex 200,GE Healthcare) in PBS.
Determination of binding affinity to CD8ab antigen by Surface Plasmon Resonance (SPR)
Recombinant human CD8ab protein was produced. Recombinant CD8ab contained the extracellular domain of CD8a fused to an acidic leucine zipper and 8 x histidine tag and CD8b fused to a basic leucine zipper and Strep-tag II, expressed in secreted form in HEK293 cells and purified by IMAC, size exclusion and streptavidin affinity column chromatography. Affinity of antibodies to CD8 at 37 ℃ was determined by surface plasmon resonance using Biacore T200 (cytova). Antibodies were first captured on the surface of anti-hIgG-Fc CM5 or CM4 prepared using the human antibody capture kit (Cytiva). Soluble CD8ab antigen diluted in HBS-ep+ buffer at four or more concentrations spanning 0.1 x to 10 xkd was allowed to flow over the surface captured anti-CD 8 mAb for 1-2 minutes. Dissociation was monitored for 5-10 min and the anti-hIgG-Fc surface was regenerated with 3M MgCl2, after which mAb was captured again in each subsequent cycle. Binding data was analyzed by Biacore T200 evaluation software version 3.2 using a 1:1 binding model.
Results
Table 1 shows the binding kinetics of isolated anti-CD 8ab antibodies (xhCD 8v1 through xhCD8v 7) to recombinant human CD8ab proteins as determined by surface plasmon resonance.
Table 1.
As depicted in table 1, isolated CD8ab antibodies had an affinity range ranging from 0.35nM to 137 nM.
As depicted in fig. 1A-1C, three types of antibodies (CD 8ab antibodies) that bind to CD8ab antigen can be identified: 1) Antibodies that bind to CD8a antigen alone but not CD8b antigen (fig. 1A), which target epitopes present on CD8a molecules; 2) Antibodies that weakly bound or did not bind to CD8a antigen alone and CD8B antigen alone (fig. 1B), which bound to an epitope between CD8a and CD8B on CD8ab heterodimers; 3) Antibodies that bind to the CD8b antigen alone, but not to the CD8a antigen alone (fig. 1C), which target an epitope on the CD8b molecule.
The binding specificity of the antibodies was determined by ELISA. PBS containing 2. Mu.g/mL recombinant CD8ab, CD8a (Sino biological), CD8b (Sino biological) and ovalbumin (Sigma) or Erb2 (human epidermal growth factor receptor 2) (Sino biological) was spread onto a maxisorp culture dish overnight at 4 ℃. Ovalbumin or Erb2 was used as negative control. The plates were then blocked with casein blocking solution (Thermo Scientific) at room temperature for 1h. After blocking, the plates were washed with wash buffer (PBS/0.05% Tween-20). Next, a dilution of 30nM to 0.0009nM of antibody in PBS/0.5% BSA/0.05% Tween-20 was added to the culture dish and incubated for 1-2h at room temperature. After incubation, the incubation plates were washed and incubated with PBS/0.5% BSA/0.05% Tween-20 containing anti-human IgG (Fc-specific) -HRP conjugate or anti-mouse IgG (Fc-specific) -HRP conjugate (Jackson Immunoresearch) for 1h. Binding was detected by adding TMB substrate (SeraCare) to the culture dish followed by 0.1M HCl stop solution. Using The Discover microplate reader (Promega) reads the binding absorbance.
Figure 2A shows two examples of antibodies that bind to CD8a epitopes: xhCD8a1 (clone OKT8, invitrogen) and xhCD8a2 (clone SK1, bioleged), both of which bind to CD8a alone and not CD8b alone. anti-CD 8ab antibodies xhCD8v6 and xhCD8v7 both bound the epitope between CD8a and CD8B and did not bind CD8a alone and CD8B alone (fig. 2B). The mouse monoclonal antibodies xhCD8v1 and humanized variants thereof xhCD8v2 to xhCD8v5, xhCD8v9, xhCD8v12 and xhCD8v13 all bind CD8b alone, but not CD8 alone, thus binding to an epitope on the CD8b molecule (fig. 2C).
As depicted in fig. 3A-3C, the binding epitope of the CD8ab antibody determines its specificity for cd8+ T cells relative to cd8+ NK cells. Certain immune cells (such as NK cells) express only CD8aa homodimers and will be recognized by the antibodies depicted in fig. 3A. T cells typically express both CD8aa homodimers and CD8ab heterodimers and will be recognized by all three types of antibodies depicted in fig. 3A-3C. However, the antibodies depicted in fig. 3B and 3C will bind only to cd8+ T cells and not to cd8+ NK cells, and thus are suitable for distinguishing between these two cell types.
The binding of CD8ab antibodies to cells was determined by flow cytometry. Freshly isolated PBMCs were incubated with CD8ab antibodies for 2 hours at 4 ℃. Cells were then stained with antibodies to the surface markers CD3 (UCHT 1), CD4 (RPA-T4), CD8a (SK 1), CD56 (HCD 56) and anti-human Fc antibody (HP 6017). The binding of the hFc-containing CD8ab antibodies was measured using an anti-human Fc antibody. The stained cells were washed and analyzed by flow cytometry, and the Mean Fluorescence Intensity (MFI) stained with anti-hFc was used to indicate binding.
As depicted in fig. 4 and 5, the xhCD8a1 antibody that recognizes an epitope on CD8a binds both cd8+ T cells and cd8+ NK cells. A CD8ab antibody that recognizes a CD8ab epitope or a CD8b epitope selectively binds to cd8+ T cells relative to cd8+ NK cells.
Subsequently, the anti-CD 8 antibody xhCD8v1 was humanized and affinity matured. Unexpectedly, binding to cd8+ T cells was lost when xhCD8v1 was grafted onto the human framework to produce xhCD8v1.1 (fig. 6).
Affinity maturation of xhCD8v1.1 resulted in several new variants xhCD8v2, xhCD8v3, xhCD8v4 and xhCD8v5 with increased binding to cd8+ T cells.
Example 2: fusion proteins targeting the CD8ab heterodimer but not the CD8aa homodimer selectively activate human CD8+ T cells over CD8+ NK cells
Materials and methods
Cloning of fusion constructs
Antibody constructs were cloned as described in example 1. The IL-2 portion of the construct was cloned in frame with the heavy chain using a (G4S) 3 15 mer linker between the C-terminus of the IgG heavy chain and the N-terminus of IL-2. The C-terminal lysine residue of the IgG heavy chain was eliminated after fusion of the IL-2 moiety. To generate a construct with a single IL-2 gene fused to an intact IgG, two heavy chain plasmids need to be constructed and transfected to undergo heterodimerization promoted by a knob-to-socket modification in the IgG CH3 domain. The "mortar" heavy chain linked to the IL-2 moiety carries the Y349C, T366S, L368A and Y407V mutations in the CH3 domain, while the unfused "mortar" heavy chain carries the S354C and T366W mutations in the CH3 domain (EU numbering). To eliminate fcγr binding/effector functions and prevent FcR coactivation, the following mutations were introduced into the CH2 domain of each IgG heavy chain: L234A/L235A/G237A (EU numbering). Expression of the antibody-IL-2 fusion construct is driven by the CMV promoter and transcription is terminated by a synthetic polyA signal sequence located downstream of the coding sequence.
Preparation of fusion proteins containing IL-2 polypeptides
Constructs encoding fusion proteins containing IL-2 polypeptides as used in the examples were generated by co-transfection of exponentially growing Expi293 cells with mammalian expression vectors using Polyethylenimine (PEI). The supernatant was collected after 4-5 days of culture. The IL-2 fusion construct was first purified by affinity chromatography using a protein A matrix. Protein a columns were equilibrated and washed in Phosphate Buffered Saline (PBS). The fusion construct was eluted with 20mM sodium citrate, 50mM sodium chloride (pH 3.6). The eluted fractions were pooled and dialyzed into 10mM MES, 25mM sodium chloride (pH 6). The protein was further purified using ion exchange chromatography (Mono-S, GE Healthcare) to purify the heterodimer relative to the homodimer. After loading the protein, the column was washed with 10mM MES 25mM sodium chloride (pH 6). The protein was then eluted with an increasing gradient of sodium chloride from 25mM to 500mM in 10mM MES pH 6 buffer. The main eluent peaks corresponding to the heterodimers were collected and concentrated. The purified protein was then purified by size exclusion chromatography (Superdex 200,GE Healthcare) in PBS.
The protein concentration of the purified IL-2 fusion construct was determined by measuring the Optical Density (OD) at 280nm using the molar extinction coefficient calculated based on the amino acid sequence. In the presence and absence of a reducing agent (5 mM 1, 4-dithiothreitol) and with Coomassie blue (SimpleBlue) TM SafeStain, invitrogen) staining, analysis of fusion constructs by SDS-PAGEPurity, integrity and monomer status of (c). According to the manufacturer's instructionsPre-cast gel system (Invitrogen) (4-20% Tris-glycine gel or 3-12% bis-Tris). Superdex 200 10/300GL analytical size exclusion column (GE Healthcare) was used to analyze the aggregate content of immunoconjugate samples.
pSTAT5 and Ki-67 assays to measure activation of IL-2 fusion proteins
The activity of IL-2 fusion proteins was determined in an assay that measures phosphorylation of STAT5 using human PBMC. PBMC were isolated from blood of healthy donors using Ficoll-Paque Plus (GE Healthcare), and erythrocytes were lysed using ACK lysis buffer (Gibco) according to manufacturer's instructions. Typically at 20X 10 6 Individual cells/ml PBMCs were resuspended in serum-free RPMI1640 medium and aliquoted into 96-well U-bottom culture plates (50 μl/well). IL-2 fusion proteins and control proteins (such as recombinant human IL-2 and control fusion proteins) were diluted to the desired concentration and added to wells (50. Mu.l added as 2X stimulus). Incubation is typically carried out at 37 ℃ for 30min, after which incubation is terminated with 100 μl of pre-warmed 8% pfa (final 4%) at room temperature for 10min. Cells were washed 3× with wash buffer (2% fbs/PBS). Cells were infiltrated in pre-cooled Phosflow Perm buffer III (BD Biosciences) according to the manufacturer's protocol and stored overnight at-20 ℃. The next day, cells were washed 3× with wash buffer and stained with antibodies to the following at 4 ℃ for 30-45min: CD3 (UCHT 1, BD Biosciences), CD8 alpha (SK 1, bioleged; RPA-T8, bioleged), CD4 (RPA-T4, bioleged) and CD25 (M-A251, bioleged), perforin (clone δG9, BD Biosciences), foxp3 (clone 319D, bioleged), pSTAT5[ pY 694) ](clone 47,BD Biosciences). The cells were then analyzed on a flow cytometer. The data are expressed as percent pSTAT5 positive, and in some cases as pSTAT5 Mean Fluorescence Intensity (MFI), and are introduced into GraphPad Prism.
To further measure IL-2 fusion protein-induced cellular changes downstream of pSTAT5, such as proliferation, flow-through fines were usedThe intracellular proliferation marker Ki-67 expression was detected by a cytometry analysis. Briefly, PBMC were isolated as described above and at 1X 10 6 Individual cells/ml were resuspended in RPMI1640 (10% fbs) supplemented with serum for 4 to 6 days or in serum-free AIM V medium (Gibco). Cells were inoculated into 96-well U-bottom culture plates (150. Mu.l/well) and incubated with 150. Mu.l IL-2 fusion protein for five days at 37 ℃. The last day, cell surface staining was first performed by adding antibodies to: CD3 (UCHT 1, BD Biosciences), CD 8. Alpha. (SK 1, bioleged), CD4 (RPA-T4, bioleged), CD56 (HCD 56, bioleged), and CD25 (M-A251, bioleged). Cells were washed 3× with wash buffer and intracellular staining was performed using Foxp 3/transcription factor staining buffer set (Thermo Fisher Scientific) according to the manufacturer's protocol. Briefly, 1 XFix/Perm buffer was added to cells in the dark at 4℃for 45min. Cells were washed 3 x with 1 xperm wash buffer and stained with antibodies to intracellular markers Ki-67 (B56, BD Biosciences) and Foxp3 (319 d, biolegend) in the dark at 4 ℃ for 45min. The cells were then washed 3 x with Perm wash buffer and analyzed on a flow cytometer.
Results
Fusion proteins comprising the CD8ab antibodies and IL-2 polypeptides of the present disclosure were prepared in one of four forms (forms A, B, C and D shown in fig. 7).
Fusion proteins comprising CD8ab antibodies targeting CD8A activate IL-2rβγ signaling on both cd8+ T cells and cd8+ NK cells (fig. 8A). Fusion proteins comprising CD8ab antibodies targeting an epitope between CD8a and CD8B preferentially activate IL-2rβγ signaling on cd8+ T cells relative to cd8+ NK cells (fig. 8B). Fusion proteins comprising CD8ab antibodies targeting CD8b preferentially activate IL-2rβγ signaling on cd8+ T cells relative to cd8+ NK cells (fig. 8C).
Because a greater proportion of NK cells can express CD8, fusion proteins comprising CD8ab antibodies that do not bind to the CD8a epitope also preferentially activate CD8+ T cells relative to total NK cells. In FIG. 9, the selectivity of different fusion proteins for human CD8+ T cells and NK cells was determined by measuring Ki-67 expression as described in example 1. Fusion proteins comprising a control antibody and a previously disclosed IL-2 variant (IL 2 v) preferentially activate NK cells over cd8+ T cells. Fusion proteins comprising a CD8ab antibody targeting CD8a (xhCD 8a 1) and the IL-2 mutant polypeptide IL2m1 preferentially activate cd8+ T cells over NK cells, but only with a preference of about 10 x. Fusion proteins comprising CD8ab antibody targeting CD8b (xhCD 8v 1) and IL-2 mutant polypeptide IL2m1 gave a stronger preference (> 1000×) for activating cd8+ T cells.
In additional embodiments shown in fig. 10A-10C, other CD8ab antibodies targeting an epitope between CD8a and CD8B, such as xhCD8v6 (fig. 10A) and xhCD8v7 (fig. 10B), or CD8ab antibodies targeting an epitope of CD8B alone, such as xhCD8v2 to xhCD8v5 (fig. 10A and 10C), show a stronger preference over NK cell activation of Ki-67 proliferation markers on cd8+ T cells. For each of the tested fusion proteins comprising CD8ab antibodies, the preference for CD 8T cells over NK cells was >100× in the form of a reading using Ki-67 analysis.
As shown in FIGS. 11A-11D, similar preference for CD8+ T cells over NK cells was also confirmed using pSTAT5 assay. STAT5 activation was measured in different lymphocyte subsets from one human PBMC donor. The fusion protein Ctrl-IL2v indifferently activates cd8+ T cells, NK cells, treg cells and T effector (cd4+foxp3-) cells, whereas the fusion protein comprising a CD8ab antibody and a mutant IL-2 polypeptide of the present disclosure has a selective activation of cd8+ T cells of at least 100× relative to NK cells.
After incubation of hPBMC from another donor with a fusion protein comprising the same xhCD8v1 antibody and one of the following IL-2 polypeptides, ki67 activation of cd8+ T cells and NK cells was tested: IL2m1, IL2m2, IL2m3, IL2m4 or IL2m5. The IL-2 polypeptide sequences are shown in Table 7. As depicted in fig. 12, all five fusion proteins achieved cd8+ T cell activation (EC 50 About 0.01 nM), in preference to NK cells, per EC of NK cells 50 The following classification was carried out: IL2m3, IL2m4<IL2m1、IL2m2<IL2m5。
FIG. 13A shows a fusion protein pair CD8+ T cells and one of the following IL-2 polypeptides containing the same xhCD8v1 antibody as compared to Ctrl Ab-IL2v (dashed line)STAT5 activation of NK cells: IL2m1, IL2m2, IL2m6, IL2m7, IL2m8, IL2m9 or IL2m10 (solid line). All fusion proteins comprising xhCD8v1 were expressed in EC lower than Ctrl Ab-IL2v 50 And the following EC 50 Graded activation of cd8+ T cells: IL2m6<IL2m7<IL2m1、IL2m8<IL2m2<IL2m9, IL2m10. All fusion proteins comprising xhCD8v1 were expressed in EC higher than Ctrl Ab-IL2v 50 Activating NK cells. STAT5 activated EC of NK cells in addition to xhCD8v1-IL2m6 and xhCD8v1-IL2m7 50 >100nM. FIG. 13B shows STAT5 activation of CD8+ T cells and NK cells by fusion proteins containing either the xhCD8v11 or xhCD8v12 antibodies and one of the following IL-2 polypeptides compared to Ctrl Ab-IL2 v: IL2m11, IL2m12 or IL2m13. All fusion proteins comprising xhCD8v11 or xhCD8v12 activate cd8+ T cells with EC50 lower than NK cells and the following EC50 classification: IL2m12, IL2m11<IL2m13. All fusion proteins comprising the xhCD8v11 or xhCD8v12 antibodies activate NK cells with EC50 higher than Ctrl Ab-IL2 v. STAT5 activated EC50 of NK cells >100nM。
Example 3: effect of fusion protein forms on CD8+ T cell activation
FIG. 14A depicts the effect of fusion protein forms on preferential CD8+ T cell activation. Activation of cd8+ T cells (solid line) and NK cells (dashed line) by 3 different forms of xhCD8v1-IL2m1 (left panel) and xhCD8v6-IL2m1 (right panel) as indicated in the legend of fig. 14A (A, B, C, see fig. 7) are shown. Although all three forms preferentially activated cd8+ T cells over NK cells, form a has the greatest preference over forms B and C. This suggests that form a is optimal for fusion proteins containing CD8ab antibodies targeting an epitope between CD8a and CD8b or CD8b alone.
FIG. 14B depicts the effect of fusion protein forms on preferential CD8+ T cell activation. All four forms (A, B, C and D) of xhCD8v6-IL2m1 shown in fig. 7 were evaluated for their ability to bind and induce Ki 67. Form a shows about 5-fold higher cell binding affinity than the other forms; this is likely due to the affinity driven binding enhancement of form a. Unexpectedly, form a (solid black line) showed a greater degree of Ki67 induction than fold change of binding, about 20-fold to 40-fold compared to forms B, C and D (dashed gray line). The results herein indicate that form a can preferentially and disproportionately induce a greater degree of Ki-67 activation than other forms. FIG. 14C depicts the results of fusion molecules of forms A and D assessed for binding to CD8+ T cells and induction of Ki67 in CD8+ T cells with respect to multiple xhCD8 binders fused to IL2m1 and IL2m 4. Due to the avidity enhancement mediated by bivalent binding, form a shows about a 10-fold decrease in binding EC50 relative to form D in all fusions. Unexpectedly, form a showed about 200-fold to over 1,000-fold increase in potency of proliferation biomarker Ki-67 activation relative to form D over the 10-fold increase observed for binding. Thus, the results herein confirm that form a is more excellent at inducing downstream proliferation and is therefore a preferred form of fusion protein containing a CD8ab antibody targeting an epitope between CD8a and CD8B (fig. 8B) or a CD8B epitope (fig. 8C).
FIG. 15 depicts preferential Ki67 activation of CD 8T cells (filled squares) by xCD8v8-IL2m1 fusion proteins containing the CD8ab antibody xCD8v8 10-fold over NK cells (filled triangles).
Example 4: the fusion proteins of the present disclosure selectively activate and enrich cd8+ T cells in TIL from human cancer patients
The single cell suspension containing TIL was isolated from tumor biopsies taken from renal cell carcinoma patients using a human tumor dissociation kit (Miltenyi) according to the manufacturer's protocol. The single cell suspension was resuspended in complete RPMI medium and 1X 10 with the indicated fusion protein 5 Individual cells/well were seeded for a total of 300 μl/well. Five days later, the cultures were analyzed for expression of Ki-67 in various subpopulations and the total cell count per well was determined by flow cytometry.
The ability of rhIL-2, ctrl Ab-IL2v and xhCD8v1-IL2m1 to activate Ki-67 in CD8+ T cells and NK cells in single cell suspensions isolated from renal cell carcinoma was determined (FIG. 16A). The results show that xhCD8v1-IL2m1 activated Ki-67 in CD8+ T cells more strongly than rhIL-2 and Ctrl-IL2v, but did not activate Ki-67 in NK cells. In addition, cd8+ T cell counts preferentially increased over NK cells and cd4+ T cell counts (fig. 16B).
Extending from these findings, one application of fusion proteins containing targeted CD8ab antibodies is to enhance selective cd8+ T cell expansion in TIL isolated from cancer patients for reinjection into the patients for treatment.
Another application is the use of fusion proteins comprising CD8ab antibodies in combination with TIL therapy or other T cell therapies (particularly MHC class I restricted T cell-containing TCR-T cell therapies).
Example 5: testing for additional CD8 antibodies targeting CD8ab heterodimers that selectively activate human CD8+ T cells relative to CD8+ NK cells
Additional CD8ab antibodies xhCD8v9-v15 were produced and tested for binding to recombinant CD8ab as described in example 1. These antibodies are designed in improved forms (e.g., v 2-based v9, v12 and v13, and v 6-based v10, v11, v14 and v 15), which (1) reduce the number of potential amino acid trends (e.g., putative N-linked glycosylation, deamination or acid cleavage sites), potentially improving manufacturability; and (2) reduces the number of amino acid mismatches with the human germline, potentially reducing immunogenicity in vivo (fig. 18A). As noted above, binding to cd8+ T cells was unexpectedly lost when the anti-CD 8 antibody xhCD8v1 was grafted onto the human framework to produce xhCD8v1.1 (as depicted in fig. 18B) (fig. 6). Additional substitutions were required to restore binding in the case of humanized antibodies, and were introduced to reduce potential liabilities and/or human germline mismatches (fig. 18C and 18D).
As shown in table 6, all additional antibodies xhCD8v9-v15 showed high affinity binding to CD8 ab.
Table 6. Biosensor data for novel CD8ab antibody binding.
ka(1/Ms) kd(1/s) K D (M) K D (nM)
xhCD8v8 - - 2.36E-07* 236.0*
xhCD8v9 2.25E+05 2.73E-02 1.21E-07 121.0
xhCD8v10 1.06E+05 3.86E-03 3.64E-08 36.4
xhCD8v11 9.55E+04 3.61E-03 3.78E-08 37.8
xhCD8v12 2.59E+05 2.71E-02 1.05E-07 105.0
xhCD8v13 3.68E+05 3.01E-02 8.18E-08 81.8
xhCD8v14 1.62E+05 8.55E-03 5.29E-08 52.9
xhCD8v15 1.86E+05 1.75E-02 9.43E-08 94.3
* Determination by steady state fitting
These antibodies were also tested for their ability to selectively activate human cd8+ T cells relative to cd8+ NK cells as described in example 2 above, in the form of fusion proteins containing form a (as shown in fig. 7) of the mutant IL-2 polypeptides (IL 2m1 or IL2m 4). As shown in fig. 17A-17E, these antibodies were able to promote selective activation of human cd8+ T cells relative to cd8+ NK cells when used in the context of fusion proteins comprising mutant IL-2 polypeptides.
Example 6: evaluation of Heat stability of xhCD8v2 related family clones
Materials and methods
Forced degradation analysis
To assess molecular stability and aggregation propensity, purified antibodies at a concentration of 1mg/mL in PBS were pressurized at a temperature of 4 ℃ to 64 ℃ for 24 hours. The samples were filtered and analyzed by analytical size exclusion chromatography on Superdex 200 5/150GL (Cytiva). The percent monomer and monomer area were calculated using OpenLab ChemStation (Agilent Technologies). Experiments were performed in duplicate.
Measurement of thermal stability
To determine the thermal stability profile, intrinsic Differential Scanning Fluorescence (DSF) and Static Light Scattering (SLS) were measured on a unc instrument (Unchained labs). Purified antibody at a concentration of 1mg/mL in PBS was subjected to a thermal ramp of 25℃to 95℃at a rate of 1℃per minute. UV spectra were recorded for DSF and SLS was recorded at 266 nm. Samples were run in quadruplicate. The melting temperature (Tm) and aggregation temperature (Tagg) were analyzed and calculated by unclle analysis software V3.2 (Unchained labs).
Results
Thermal stability improvement of xhCD8v9, xhCD8v12 and xhCD8v13 compared to the parent xhCD8v2
The parent antibodies xhCD8v2 and derivatives thereof xhCD8v9, xhCD8v12 and xhCD8v13 were subjected to forced degradation and thermal stability analysis. The result of the forced degradation analysis is the recovery of the monomers depicted as different antibodies (ratio of monomer area at 64 ℃ to 4 ℃) shown in table 7. The xhCD8v9, xhCD8v12 and xhCD8v13 antibodies had higher% recovery compared to the parent antibody xhCD8v 2. The thermostability measurements shown in table 7 reveal that the xhCD8v9, xhCD8v12 and xhCD8v13 antibodies have higher Tm and Tagg values than the parent antibody xhCD8v 2. Taken together, these results demonstrate that the xhCD8v9, xhCD8v12 and xhCD8v13 molecules have improved thermostability relative to the parent antibody xhCD8v2 and thus, xhCD8v9, xhCD8v12 and xhCD8v13 are more desirable as therapeutic agents.
TABLE 7 results of forced degradation and thermal stability analysis
Example 7: evaluation of glycan occupancy of parental xhCD8v6 and derivatives thereof
Materials and methods
Deglycosylation of antibodies
To remove N-linked and O-linked glycosylation, 10. Mu.g of antibody was mixed with 1. Mu.l of 10 XGlycoBuffer 2 (New England Biolabs), 1. Mu.l of protein deglycosylation mixture II (New England Biolabs), and water was added to 10. Mu.l. The reaction was incubated overnight at room temperature.
ELISA for glycosylation detection of P3F4 related molecules
The presence of N-linked glycosylation was determined by ELISA. Briefly, 25. Mu.L of protein at 0.5 to 10. Mu.g/mL was plated onto 384 well Nunc MaxiSorp plates (Thermo Fisher Scientific) and incubated for 1 hour at 37 ℃. Proteins were removed and the plates were washed with PBS+0.05% Tween-20 (PBST). The wells were filled with a carbohydrate-free blocking solution (Vector Labs) and incubated for 30min at room temperature. The blocking solution was removed and the wells were washed with PBST. 25. Mu.L of PBS containing 5. Mu.g/mL biotinylated wheat germ agglutinin (Vector Labs) bound to the glycoconjugate was added and incubated for 30min at room temperature. It was then removed and the culture dish was washed again with PBST. mu.L of detection reagent VECTASTAIN Elite ABC-HRP reagent peroxidase R.T.U. (Vector Labs) was added and allowed to incubate at room temperature for 30min. The reagent was removed and the wells were washed with PBST. Wells were developed using 25 μl L KPL SureBlue TMB microwell substrate (SeraCare) for 5-7min and quenched with 25 μl 0.1M HCl. Absorbance at 450nm was recorded on a SpectraMax iD5 plate reader (Molecular Devices). Glycoprotein fetuin containing sialylated N-linked and O-linked glycans was used as a positive control. All experiments were performed with n=8.
Results
Removal of the N-linked glycosylation site on xhCD8v6 improves homogeneity
xCD8v6 has a putative N-linked glycosylation motif in the CDR-H2 region. This putative N-linked glycosylation motif in the derivatives of xhCD8v6 (i.e., xhCD8v10, xhCD8v11, xhCD8v14 and xhCD8v 15) was removed. The presence of variable amounts of glycans in the CDR regions reduces the homogeneity of the final product and may affect binding capacity. To detect the presence of glycans, an ELISA using wheat germ lectin (WGA) conjugated to N-acetylglucosamine was performed. Fab of the parents xhCD8v6 and xhCD8v11, which served as negative controls, were analyzed to examine only the variable domains. Fetuin was used as a positive control. As shown in figure 19, WGA binding of the parent xhCD8v6, but not xhCD8v11, was detected. After treatment with the deglycosidase, WGA did not bind to deglycosylated xhCD8v6, confirming the presence of glycans on xhCD8v 6. The results herein show that xhCD8v10, xhCD8v11, xhCD8v14 and xhCD8v15, which do not have a putative N-linked glycosylation motif, are better and more homogeneous therapeutics than the parent xCD8v 6.
Sequence listing
<110> subunit biotherapy Co Ltd
<120> fusion comprising CD8 antigen binding molecules that modulate immune cell function
<130> 18284-20004.40
<140> not yet allocated
<141> along with the submission
<150> US 63/190,669
<151> 2021-05-19
<150> US 63/121,663
<151> 2020-12-04
<150> US 63/105,162
<151> 2020-10-23
<160> 389
<170> FastSEQ for Windows Version 4.0
<210> 1
<211> 5
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 1
Lys Tyr Thr Met His
1 5
<210> 2
<211> 17
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 2
His Phe Asn Pro Asn Asn Asp Glu Thr Lys Tyr Asn Gln Lys Phe Thr
1 5 10 15
Gly
<210> 3
<211> 10
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 3
Asp Gly Leu Gly Leu Arg Leu Phe Ala Asp
1 5 10
<210> 4
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 4
Gly Ala Ser Glu Asn Ile Tyr Gly Ala Leu Asn
1 5 10
<210> 5
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 5
Gly Ala Thr Asn Leu Ala Asp
1 5
<210> 6
<211> 9
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 6
Gln Asn Ile Leu Asp Thr Pro Trp Thr
1 5
<210> 7
<211> 5
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 7
Lys Tyr Ala Ile Ser
1 5
<210> 8
<211> 17
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 8
His Phe Asn Pro Asn Asn Asp Glu Thr Lys Tyr Asn Gln Lys Phe Gln
1 5 10 15
Gly
<210> 9
<211> 10
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 9
Asp Gly Leu Gly Leu Arg Leu Phe Ala Asp
1 5 10
<210> 10
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 10
Arg Ala Ser Glu Asn Ile Tyr Gly Ala Leu Asn
1 5 10
<210> 11
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 11
Gly Ala Thr Asn Leu Ala Asp
1 5
<210> 12
<211> 9
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 12
Gln Asn Ile Leu Asp Thr Pro Trp Thr
1 5
<210> 13
<211> 5
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 13
Asn Phe Ala Ile Ser
1 5
<210> 14
<211> 17
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 14
Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 15
<211> 10
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 15
Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp
1 5 10
<210> 16
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 16
Arg Ala Ser Gln Glu Ile Tyr Gly Ala Leu Asn
1 5 10
<210> 17
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 17
Gly Ala Thr Asn Leu Gln Ser
1 5
<210> 18
<211> 9
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 18
Gln Asp Ile Tyr Asp Ala Pro Trp Thr
1 5
<210> 19
<211> 5
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 19
Lys Phe Ala Ile Ser
1 5
<210> 20
<211> 17
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 20
Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 21
<211> 10
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 21
Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp
1 5 10
<210> 22
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 22
Arg Ala Ser Gln Glu Ile Tyr Gly Ala Leu Asn
1 5 10
<210> 23
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 23
Gly Ala Thr Asn Leu Gln Ser
1 5
<210> 24
<211> 9
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 24
Gln Asp Ile Tyr Asp Ala Pro Trp Thr
1 5
<210> 25
<211> 5
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 25
Lys Tyr Ala Ile Ser
1 5
<210> 26
<211> 17
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 26
Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 27
<211> 10
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 27
Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp
1 5 10
<210> 28
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 28
Arg Ala Ser Gln Lys Ile Tyr Gly Ala Leu Asn
1 5 10
<210> 29
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 29
Gly Ala Thr Asn Leu Gln Ser
1 5
<210> 30
<211> 9
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 30
Gln Asn Thr Tyr Asp Thr Pro Trp Thr
1 5
<210> 31
<211> 5
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 31
Gly His Ala Ile Ser
1 5
<210> 32
<211> 17
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 32
Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 33
<211> 10
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 33
Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp
1 5 10
<210> 34
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 34
Arg Ala Ser Gln Lys Ile Tyr Gly Ala Leu Asn
1 5 10
<210> 35
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 35
Gly Ala Thr Asn Leu Gln Ser
1 5
<210> 36
<211> 9
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 36
Gln Asn Thr Tyr Asp Thr Pro Trp Thr
1 5
<210> 37
<211> 5
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 37
Asp Tyr Gly Met Ser
1 5
<210> 38
<211> 17
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 38
Asp Ile Asn Trp Ser Gly Glu Ile Thr Ala Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 39
<211> 12
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 39
Ser Asn Ser Tyr Arg Trp Asp Asp Ala Leu Asp Ile
1 5 10
<210> 40
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 40
Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala
1 5 10
<210> 41
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 41
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 42
<211> 10
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 42
Gln Gln Tyr Gly Ser Ser Pro Pro Val Thr
1 5 10
<210> 43
<211> 5
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 43
Asp Tyr Ala Met His
1 5
<210> 44
<211> 17
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 44
Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 45
<211> 13
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 45
Asp Arg Ile Gly Trp Tyr Asp Tyr Asp Ala Phe Asp Ile
1 5 10
<210> 46
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 46
Arg Ala Ser His Ser Val Gly Ser Asn Leu Ala
1 5 10
<210> 47
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 47
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 48
<211> 9
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 48
Gln Gln Arg Ser Asn Trp Pro Pro Thr
1 5
<210> 49
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 49
Gly Tyr Thr Phe Thr Lys Tyr
1 5
<210> 50
<211> 6
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 50
Asn Pro Asn Asn Asp Glu
1 5
<210> 51
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 51
Gly Tyr Arg Phe His Asn Phe
1 5
<210> 52
<211> 6
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 52
Ile Pro Gly His Ala Lys
1 5
<210> 53
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 53
Gly Ser Arg Phe Tyr Lys Phe
1 5
<210> 54
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 54
Gly Ser Gly Phe Arg Gly His
1 5
<210> 55
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 55
Gly Phe Thr Phe Asp Asp Tyr
1 5
<210> 56
<211> 6
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 56
Asn Trp Ser Gly Glu Ile
1 5
<210> 57
<211> 6
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 57
Ser Tyr Asp Gly Ser Asn
1 5
<210> 58
<211> 119
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 58
Gln Val His Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Lys Tyr
20 25 30
Thr Met His Trp Val Lys Gln Gly His Glu Glu Ser Leu Glu Trp Ile
35 40 45
Gly His Phe Asn Pro Asn Asn Asp Glu Thr Lys Tyr Asn Gln Lys Phe
50 55 60
Thr Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Asp Asp Ser Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Leu Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Ile Thr Val Ser Ala
115
<210> 59
<211> 107
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 59
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Arg Lys Gln Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Phe Gly Ala Thr Asn Leu Ala Asp Gly Val Ser Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Asp Arg Gln Tyr Ser Leu Lys Ile Ser Ser Leu His Pro
65 70 75 80
Asp Asp Val Ala Thr Tyr Tyr Cys Gln Asn Ile Leu Asp Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 60
<211> 119
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 60
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Lys Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly His Phe Asn Pro Asn Asn Asp Glu Thr Lys Tyr Asn Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Leu Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 61
<211> 107
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 61
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Ile Leu Asp Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 62
<211> 119
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 62
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Arg Phe His Asn Phe
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 63
<211> 107
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 63
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asp Ile Tyr Asp Ala Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 64
<211> 119
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 64
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Arg Phe Tyr Lys Phe
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 65
<211> 107
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 65
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asp Ile Tyr Asp Ala Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 66
<211> 119
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 66
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Lys Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 67
<211> 107
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 67
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Thr Tyr Asp Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 68
<211> 119
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 68
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Gly Phe Arg Gly His
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 69
<211> 107
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 69
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Thr Tyr Asp Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 70
<211> 121
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 70
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ala Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Asn Trp Ser Gly Glu Ile Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ser Tyr Arg Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 71
<211> 108
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 71
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 72
<211> 122
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 72
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Ile Gly Trp Tyr Asp Tyr Asp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 73
<211> 107
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 73
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Gly Ala Thr Leu Ser Cys Arg Ala Ser His Ser Val Gly Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 74
<211> 5
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> (1)..(4)
<223> may be 1, 2, 3, 4, 5, 6, 7, 8, 9,
10. 11 or 12 repeats
<220>
<221> variant
<222> 5
<223> may be present in 0, 1, 2 or 3 repeats
<400> 74
Gly Gly Gly Ser Gly
1 5
<210> 75
<211> 6
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> (1)..(5)
<223> may be 1, 2, 3, 4, 5, 6, 7, 8, 9,
10. 11 or 12 repeats
<220>
<221> variant
<222> 6
<223> may be present in 0, 1, 2 or 3 repeats
<400> 75
Gly Gly Gly Gly Ser Gly
1 5
<210> 76
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> (1)..(6)
<223> may be 1, 2, 3, 4, 5, 6, 7, 8, 9,
10. 11 or 12 repeats
<220>
<221> variant
<222> 7
<223> may be present in 0, 1, 2 or 3 repeats
<400> 76
Gly Gly Gly Gly Gly Ser Gly
1 5
<210> 77
<211> 6
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> (1)..(5)
<223> may be present in 2, 3 or 4 repetitions
<220>
<221> variant
<222> 6
<223> can exist in 0 repetitions
<400> 77
Gly Gly Gly Gly Ser Gly
1 5
<210> 78
<211> 6
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> (1)..(5)
<223> can exist in 3 repetitions
<220>
<221> variant
<222> 6
<223> can exist in 0 repetitions
<400> 78
Gly Gly Gly Gly Ser Gly
1 5
<210> 79
<211> 15
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 79
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 80
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 80
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 81
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 81
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 82
<211> 272
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 82
Met Asp Ser Tyr Leu Leu Met Trp Gly Leu Leu Thr Phe Ile Met Val
1 5 10 15
Pro Gly Cys Gln Ala Glu Leu Cys Asp Asp Asp Pro Pro Glu Ile Pro
20 25 30
His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr Met Leu Asn
35 40 45
Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly Ser Leu Tyr
50 55 60
Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp Asn Gln Cys
65 70 75 80
Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln Val Thr Pro
85 90 95
Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met Gln Ser Pro
100 105 110
Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys Arg Glu Pro
115 120 125
Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His Phe Val Val
130 135 140
Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg Ala Leu His
145 150 155 160
Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly Lys Thr Arg
165 170 175
Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu Thr Ser Gln
180 185 190
Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly Arg Pro Glu
195 200 205
Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln Ile Gln Thr
210 215 220
Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr Glu Tyr Gln
225 230 235 240
Val Ala Val Ala Gly Cys Val Phe Leu Leu Ile Ser Val Leu Leu Leu
245 250 255
Ser Gly Leu Thr Trp Gln Arg Arg Gln Arg Lys Ser Arg Arg Thr Ile
260 265 270
<210> 83
<211> 551
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 83
Met Ala Ala Pro Ala Leu Ser Trp Arg Leu Pro Leu Leu Ile Leu Leu
1 5 10 15
Leu Pro Leu Ala Thr Ser Trp Ala Ser Ala Ala Val Asn Gly Thr Ser
20 25 30
Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala Asn Ile Ser Cys Val Trp
35 40 45
Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser Cys Gln Val His Ala Trp
50 55 60
Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys Glu Leu Leu Pro Val Ser
65 70 75 80
Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu Gly Ala Pro Asp Ser Gln
85 90 95
Lys Leu Thr Thr Val Asp Ile Val Thr Leu Arg Val Leu Cys Arg Glu
100 105 110
Gly Val Arg Trp Arg Val Met Ala Ile Gln Asp Phe Lys Pro Phe Glu
115 120 125
Asn Leu Arg Leu Met Ala Pro Ile Ser Leu Gln Val Val His Val Glu
130 135 140
Thr His Arg Cys Asn Ile Ser Trp Glu Ile Ser Gln Ala Ser His Tyr
145 150 155 160
Phe Glu Arg His Leu Glu Phe Glu Ala Arg Thr Leu Ser Pro Gly His
165 170 175
Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu Lys Gln Lys Gln Glu Trp
180 185 190
Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr Gln Tyr Glu Phe Gln Val
195 200 205
Arg Val Lys Pro Leu Gln Gly Glu Phe Thr Thr Trp Ser Pro Trp Ser
210 215 220
Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala Ala Leu Gly Lys Asp Thr
225 230 235 240
Ile Pro Trp Leu Gly His Leu Leu Val Gly Leu Ser Gly Ala Phe Gly
245 250 255
Phe Ile Ile Leu Val Tyr Leu Leu Ile Asn Cys Arg Asn Thr Gly Pro
260 265 270
Trp Leu Lys Lys Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe
275 280 285
Phe Ser Gln Leu Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu
290 295 300
Ser Ser Pro Phe Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro
305 310 315 320
Glu Ile Ser Pro Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu
325 330 335
Leu Leu Gln Gln Asp Lys Val Pro Glu Pro Ala Ser Leu Ser Ser Asn
340 345 350
His Ser Leu Thr Ser Cys Phe Thr Asn Gln Gly Tyr Phe Phe Phe His
355 360 365
Leu Pro Asp Ala Leu Glu Ile Glu Ala Cys Gln Val Tyr Phe Thr Tyr
370 375 380
Asp Pro Tyr Ser Glu Glu Asp Pro Asp Glu Gly Val Ala Gly Ala Pro
385 390 395 400
Thr Gly Ser Ser Pro Gln Pro Leu Gln Pro Leu Ser Gly Glu Asp Asp
405 410 415
Ala Tyr Cys Thr Phe Pro Ser Arg Asp Asp Leu Leu Leu Phe Ser Pro
420 425 430
Ser Leu Leu Gly Gly Pro Ser Pro Pro Ser Thr Ala Pro Gly Gly Ser
435 440 445
Gly Ala Gly Glu Glu Arg Met Pro Pro Ser Leu Gln Glu Arg Val Pro
450 455 460
Arg Asp Trp Asp Pro Gln Pro Leu Gly Pro Pro Thr Pro Gly Val Pro
465 470 475 480
Asp Leu Val Asp Phe Gln Pro Pro Pro Glu Leu Val Leu Arg Glu Ala
485 490 495
Gly Glu Glu Val Pro Asp Ala Gly Pro Arg Glu Gly Val Ser Phe Pro
500 505 510
Trp Ser Arg Pro Pro Gly Gln Gly Glu Phe Arg Ala Leu Asn Ala Arg
515 520 525
Leu Pro Leu Asn Thr Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly
530 535 540
Gln Asp Pro Thr His Leu Val
545 550
<210> 84
<211> 369
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 84
Met Leu Lys Pro Ser Leu Pro Phe Thr Ser Leu Leu Phe Leu Gln Leu
1 5 10 15
Pro Leu Leu Gly Val Gly Leu Asn Thr Thr Ile Leu Thr Pro Asn Gly
20 25 30
Asn Glu Asp Thr Thr Ala Asp Phe Phe Leu Thr Thr Met Pro Thr Asp
35 40 45
Ser Leu Ser Val Ser Thr Leu Pro Leu Pro Glu Val Gln Cys Phe Val
50 55 60
Phe Asn Val Glu Tyr Met Asn Cys Thr Trp Asn Ser Ser Ser Glu Pro
65 70 75 80
Gln Pro Thr Asn Leu Thr Leu His Tyr Trp Tyr Lys Asn Ser Asp Asn
85 90 95
Asp Lys Val Gln Lys Cys Ser His Tyr Leu Phe Ser Glu Glu Ile Thr
100 105 110
Ser Gly Cys Gln Leu Gln Lys Lys Glu Ile His Leu Tyr Gln Thr Phe
115 120 125
Val Val Gln Leu Gln Asp Pro Arg Glu Pro Arg Arg Gln Ala Thr Gln
130 135 140
Met Leu Lys Leu Gln Asn Leu Val Ile Pro Trp Ala Pro Glu Asn Leu
145 150 155 160
Thr Leu His Lys Leu Ser Glu Ser Gln Leu Glu Leu Asn Trp Asn Asn
165 170 175
Arg Phe Leu Asn His Cys Leu Glu His Leu Val Gln Tyr Arg Thr Asp
180 185 190
Trp Asp His Ser Trp Thr Glu Gln Ser Val Asp Tyr Arg His Lys Phe
195 200 205
Ser Leu Pro Ser Val Asp Gly Gln Lys Arg Tyr Thr Phe Arg Val Arg
210 215 220
Ser Arg Phe Asn Pro Leu Cys Gly Ser Ala Gln His Trp Ser Glu Trp
225 230 235 240
Ser His Pro Ile His Trp Gly Ser Asn Thr Ser Lys Glu Asn Pro Phe
245 250 255
Leu Phe Ala Leu Glu Ala Val Val Ile Ser Val Gly Ser Met Gly Leu
260 265 270
Ile Ile Ser Leu Leu Cys Val Tyr Phe Trp Leu Glu Arg Thr Met Pro
275 280 285
Arg Ile Pro Thr Leu Lys Asn Leu Glu Asp Leu Val Thr Glu Tyr His
290 295 300
Gly Asn Phe Ser Ala Trp Ser Gly Val Ser Lys Gly Leu Ala Glu Ser
305 310 315 320
Leu Gln Pro Asp Tyr Ser Glu Arg Leu Cys Leu Val Ser Glu Ile Pro
325 330 335
Pro Lys Gly Gly Ala Leu Gly Glu Gly Pro Gly Ala Ser Pro Cys Asn
340 345 350
Gln His Ser Pro Tyr Trp Ala Pro Pro Cys Tyr Thr Leu Lys Pro Glu
355 360 365
Thr
<210> 85
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 85
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 86
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 86
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 87
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 87
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 88
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 88
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 89
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 89
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ser Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 90
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 90
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 91
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 91
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Glu Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 92
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 92
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg His Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 93
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 93
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Asp
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 94
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 94
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Glu
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 95
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 95
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Ser Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 96
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 96
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ser Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 97
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 97
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 98
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 98
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Glu Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 99
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 99
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg His Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 100
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 100
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Asp
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 101
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 101
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Glu
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 102
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 102
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Ser Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 103
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 103
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ser Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 104
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 104
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 105
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 105
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Glu Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 106
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 106
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg His Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 107
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 107
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Asp
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 108
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 108
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Glu
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 109
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 109
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Ser Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 110
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 110
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ser Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 111
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 111
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 112
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 112
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Glu Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 113
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 113
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg His Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 114
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 114
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Asp
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 115
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 115
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Glu
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 116
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 116
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Ser Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 117
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 117
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 118
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 118
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 119
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 119
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 120
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 120
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 121
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 121
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ser Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 122
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 122
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 123
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 123
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Glu Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 124
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 124
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg His Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 125
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 125
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Asp
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 126
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 126
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Glu
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 127
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 127
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Ser Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 128
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 128
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ser Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 129
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 129
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 130
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 130
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Glu Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 131
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 131
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg His Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 132
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 132
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Asp
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 133
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 133
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Glu
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 134
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 134
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Ser Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 135
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 135
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ser Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 136
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 136
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 137
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 137
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Glu Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 138
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 138
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg His Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 139
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 139
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Asp
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 140
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 140
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Glu
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 141
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 141
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Ser Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 142
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 142
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ser Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 143
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 143
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 144
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 144
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Glu Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 145
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 145
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg His Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 146
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 146
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Asp
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 147
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 147
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Glu
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 148
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 148
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Ser Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 149
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 149
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ser Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 150
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 150
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 151
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 151
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Glu Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 152
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 152
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg His Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 153
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 153
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Asp
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 154
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 154
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Glu
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 155
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 155
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Ser Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 156
<211> 214
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 156
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Arg Lys Gln Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Phe Gly Ala Thr Asn Leu Ala Asp Gly Val Ser Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Asp Arg Gln Tyr Ser Leu Lys Ile Ser Ser Leu His Pro
65 70 75 80
Asp Asp Val Ala Thr Tyr Tyr Cys Gln Asn Ile Leu Asp Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 157
<211> 597
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 157
Gln Val His Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Lys Tyr
20 25 30
Thr Met His Trp Val Lys Gln Gly His Glu Glu Ser Leu Glu Trp Ile
35 40 45
Gly His Phe Asn Pro Asn Asn Asp Glu Thr Lys Tyr Asn Gln Lys Phe
50 55 60
Thr Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Asp Asp Ser Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Leu Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
465 470 475 480
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
485 490 495
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
500 505 510
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
515 520 525
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
530 535 540
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
545 550 555 560
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
565 570 575
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
580 585 590
Ile Ser Thr Leu Thr
595
<210> 158
<211> 448
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 158
Gln Val His Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Lys Tyr
20 25 30
Thr Met His Trp Val Lys Gln Gly His Glu Glu Ser Leu Glu Trp Ile
35 40 45
Gly His Phe Asn Pro Asn Asn Asp Glu Thr Lys Tyr Asn Gln Lys Phe
50 55 60
Thr Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Asp Asp Ser Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Leu Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 159
<211> 214
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 159
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asp Ile Tyr Asp Ala Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 160
<211> 597
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 160
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Arg Phe His Asn Phe
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
465 470 475 480
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
485 490 495
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
500 505 510
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
515 520 525
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
530 535 540
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
545 550 555 560
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
565 570 575
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
580 585 590
Ile Ser Thr Leu Thr
595
<210> 161
<211> 448
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 161
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Arg Phe His Asn Phe
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 162
<211> 214
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 162
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asp Ile Tyr Asp Ala Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 163
<211> 597
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 163
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Arg Phe Tyr Lys Phe
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
465 470 475 480
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
485 490 495
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
500 505 510
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
515 520 525
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
530 535 540
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
545 550 555 560
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
565 570 575
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
580 585 590
Ile Ser Thr Leu Thr
595
<210> 164
<211> 448
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 164
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Arg Phe Tyr Lys Phe
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 165
<211> 214
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 165
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Thr Tyr Asp Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 166
<211> 597
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 166
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Lys Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
465 470 475 480
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
485 490 495
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
500 505 510
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
515 520 525
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
530 535 540
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
545 550 555 560
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
565 570 575
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
580 585 590
Ile Ser Thr Leu Thr
595
<210> 167
<211> 448
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 167
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Lys Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 168
<211> 214
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 168
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Lys Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Thr Tyr Asp Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 169
<211> 597
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 169
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Gly Phe Arg Gly His
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
465 470 475 480
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
485 490 495
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
500 505 510
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
515 520 525
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
530 535 540
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
545 550 555 560
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
565 570 575
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
580 585 590
Ile Ser Thr Leu Thr
595
<210> 170
<211> 448
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 170
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Gly Phe Arg Gly His
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 171
<211> 215
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 171
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 172
<211> 599
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 172
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ala Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Asn Trp Ser Gly Glu Ile Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ser Tyr Arg Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu
465 470 475 480
Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn
485 490 495
Tyr Lys Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met
500 505 510
Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu
515 520 525
Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe
530 535 540
His Leu Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu
545 550 555 560
Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu
565 570 575
Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln
580 585 590
Ser Ile Ile Ser Thr Leu Thr
595
<210> 173
<211> 450
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 173
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ala Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Asn Trp Ser Gly Glu Ile Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ser Tyr Arg Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 174
<211> 214
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 174
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Gly Ala Thr Leu Ser Cys Arg Ala Ser His Ser Val Gly Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 175
<211> 600
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 175
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Ile Gly Trp Tyr Asp Tyr Asp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
225 230 235 240
Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
450 455 460
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
465 470 475 480
Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
485 490 495
Asn Tyr Lys Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr
500 505 510
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
515 520 525
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
530 535 540
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val
545 550 555 560
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
565 570 575
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala
580 585 590
Gln Ser Ile Ile Ser Thr Leu Thr
595 600
<210> 176
<211> 451
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 176
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Ile Gly Trp Tyr Asp Tyr Asp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
225 230 235 240
Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly
450
<210> 177
<211> 5
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 177
Ser Tyr Trp Met Asn
1 5
<210> 178
<211> 17
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 178
Gln Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe Lys
1 5 10 15
Gly
<210> 179
<211> 13
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 179
Ser Gly Ala Ala Phe Ser Ser Tyr Tyr Ala Met Asp Tyr
1 5 10
<210> 180
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 180
Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala
1 5 10
<210> 181
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 181
Ala Ala Thr Asn Leu Ala Asp
1 5
<210> 182
<211> 9
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 182
Gln His Phe Trp Gly Thr Pro Trp Thr
1 5
<210> 183
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 183
Gly Tyr Ala Phe Ser Ser Tyr
1 5
<210> 184
<211> 6
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 184
Tyr Pro Gly Asp Gly Asp
1 5
<210> 185
<211> 122
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 185
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Ser Gly Ala Ala Phe Ser Ser Tyr Tyr Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 186
<211> 107
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 186
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Val Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
35 40 45
Tyr Ala Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Asn Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 187
<211> 214
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 187
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Val Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
35 40 45
Tyr Ala Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Asn Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 188
<211> 600
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 188
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Ser Gly Ala Ala Phe Ser Ser Tyr Tyr Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
225 230 235 240
Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
450 455 460
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
465 470 475 480
Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
485 490 495
Asn Tyr Lys Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr
500 505 510
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
515 520 525
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
530 535 540
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val
545 550 555 560
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
565 570 575
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala
580 585 590
Gln Ser Ile Ile Ser Thr Leu Thr
595 600
<210> 189
<211> 451
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 189
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Ser Gly Ala Ala Phe Ser Ser Tyr Tyr Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
225 230 235 240
Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly
450
<210> 190
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 190
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Gly Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 191
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 191
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Lys Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 192
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 192
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Arg Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 193
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 193
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Gly Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 194
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 194
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Lys Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 195
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 195
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Arg Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 196
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 196
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Gly Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 197
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 197
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Lys Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 198
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 198
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Arg Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 199
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 199
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Gly Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 200
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 200
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Lys Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 201
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 201
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Arg Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 202
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 202
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Gly Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 203
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 203
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Lys Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 204
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 204
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Arg Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 205
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 205
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Gly Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 206
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 206
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Lys Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 207
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 207
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Arg Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 208
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 208
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Gly Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 209
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 209
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Lys Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 210
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 210
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Arg Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 211
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 211
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Gly Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 212
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 212
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Lys Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 213
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 213
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Arg Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 214
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 214
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Gly Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 215
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 215
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Lys Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 216
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 216
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Arg Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 217
<211> 449
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 217
Gln Val His Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Lys Tyr
20 25 30
Thr Met His Trp Val Lys Gln Gly His Glu Glu Ser Leu Glu Trp Ile
35 40 45
Gly His Phe Asn Pro Asn Asn Asp Glu Thr Lys Tyr Asn Gln Lys Phe
50 55 60
Thr Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Asp Asp Ser Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Leu Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 218
<211> 449
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 218
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Arg Phe His Asn Phe
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 219
<211> 449
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 219
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Arg Phe Tyr Lys Phe
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 220
<211> 449
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 220
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Lys Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 221
<211> 449
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 221
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Ser Gly Phe Arg Gly His
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly His Ala Lys Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Leu Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 222
<211> 451
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 222
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ala Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Asn Trp Ser Gly Glu Ile Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ser Tyr Arg Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 223
<211> 452
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 223
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Ile Gly Trp Tyr Asp Tyr Asp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
225 230 235 240
Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210> 224
<211> 452
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 224
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Ser Gly Ala Ala Phe Ser Ser Tyr Tyr Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
225 230 235 240
Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210> 225
<211> 5
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 225
Ser Tyr Ala Ile Ser
1 5
<210> 226
<211> 17
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 226
Gly Ile Ile Pro Gly Ala Ala Thr Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 227
<211> 10
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 227
Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp
1 5 10
<210> 228
<211> 9
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 228
Gln Ser Thr Tyr Asp Ala Pro Trp Thr
1 5
<210> 229
<211> 5
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 229
Ser Tyr Ala Met Ser
1 5
<210> 230
<211> 17
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 230
Asp Ile Thr Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 231
<211> 12
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 231
Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile
1 5 10
<210> 232
<211> 17
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 232
Gly Ile Ile Pro Gly Tyr Ala Thr Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 233
<211> 10
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 233
Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp
1 5 10
<210> 234
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 234
Arg Ala Ser Gln Ser Ile Tyr Gly Ala Leu Asn
1 5 10
<210> 235
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 235
Gly Ala Ser Asn Leu Gln Ser
1 5
<210> 236
<211> 9
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 236
Gln Ser Thr Tyr Thr Ala Pro Trp Thr
1 5
<210> 237
<211> 17
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 237
Asp Ile Ser Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 238
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 238
Gly Gly Thr Phe Ser Ser Tyr
1 5
<210> 239
<211> 6
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 239
Ile Pro Gly Ala Ala Thr
1 5
<210> 240
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 240
Gly Phe Thr Phe Ser Ser Tyr
1 5
<210> 241
<211> 6
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 241
Thr Tyr Ala Gly Gly Ser
1 5
<210> 242
<211> 12
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 242
Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile
1 5 10
<210> 243
<211> 6
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 243
Ile Pro Gly Tyr Ala Thr
1 5
<210> 244
<211> 6
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 244
Ser Tyr Ala Gly Gly Ser
1 5
<210> 245
<211> 119
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 245
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Ala Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 246
<211> 107
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 246
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Asp Ala Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 247
<211> 121
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 247
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Thr Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 248
<211> 108
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 248
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 249
<211> 121
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 249
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Thr Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 250
<211> 108
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 250
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 251
<211> 119
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 251
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Tyr Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 252
<211> 107
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 252
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Thr Ala Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 253
<211> 119
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 253
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Tyr Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 254
<211> 107
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 254
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Asp Ala Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 255
<211> 121
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 255
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Ser Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 256
<211> 108
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 256
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 257
<211> 121
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 257
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Ser Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 258
<211> 108
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 258
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 259
<211> 5
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> 1
<223> xaa= S, K, G, N, R, D, T or G
<220>
<221> variant
<222> 2
<223> xaa= Y, L, H or F
<400> 259
Xaa Xaa Ala Ile Ser
1 5
<210> 260
<211> 17
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> 1
<223> xaa=g or H
<220>
<221> variant
<222> 2
<223> xaa=i or F
<220>
<221> variant
<222> 3
<223> xaa= I, N or M
<220>
<221> variant
<222> 5
<223> xaa= G, N, H, S, R, I or a
<220>
<221> variant
<222> 6
<223> xaa= A, N, H, S, T, F or Y
<220>
<221> variant
<222> 7
<223> xaa= A, D or G
<220>
<221> variant
<222> 8
<223> xaa= T, E, K, V, Q or a
<220>
<221> variant
<222> 9
<223> Xaa=A or T
<220>
<221> variant
<222> 10
<223> xaa=n or K
<220>
<221> variant
<222> 12
<223> Xaa=A or N
<220>
<221> variant
<222> 16
<223> xaa=q or T
<400> 260
Xaa Xaa Xaa Pro Xaa Xaa Xaa Xaa Xaa Xaa Tyr Xaa Gln Lys Phe Xaa
1 5 10 15
Gly
<210> 261
<211> 10
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> 1
<223> xaa=d or a
<220>
<221> variant
<222> 2
<223> xaa= A, G, E, R, Y, K, N, Q, L or F
<220>
<221> variant
<222> 3
<223> xaa= A, L, P or Y
<220>
<221> variant
<222> 5
<223> Xaa=I or L
<220>
<221> variant
<222> 6
<223> Xaa= R, A, Q or S
<220>
<221> variant
<222> 9
<223> xaa=a or D
<220>
<221> variant
<222> 10
<223> Xaa= D, E, A or S
<400> 261
Xaa Xaa Xaa Gly Xaa Xaa Leu Phe Xaa Xaa
1 5 10
<210> 262
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> 1
<223> Xaa=R or G
<220>
<221> variant
<222> 2
<223> Xaa=A or T
<220>
<221> variant
<222> 4
<223> Xaa=Q or E
<220>
<221> variant
<222> 5
<223> Xaa= E, N, T, S, A, K, D, G, R or Q
<220>
<221> variant
<222> 7
<223> Xaa=Y or S
<220>
<221> variant
<222> 9
<223> Xaa=A or V
<400> 262
Xaa Xaa Ser Xaa Xaa Ile Xaa Gly Xaa Leu Asn
1 5 10
<210> 263
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> 2
<223> Xaa=A or S
<220>
<221> variant
<222> 3
<223> xaa= T, S, E, Q or D
<220>
<221> variant
<222> 4
<223> xaa= N, R, A, E or H
<220>
<221> variant
<222> 6
<223> xaa=q or a
<220>
<221> variant
<222> 7
<223> Xaa=S or D
<400> 263
Gly Xaa Xaa Xaa Leu Xaa Xaa
1 5
<210> 264
<211> 9
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> 2
<223> xaa= S, N, D, Q, A or E
<220>
<221> variant
<222> 3
<223> Xaa= T, I or S
<220>
<221> variant
<222> 4
<223> xaa= Y, L or F
<220>
<221> variant
<222> 5
<223> xaa= D, G, T, E, Q, A or Y
<220>
<221> variant
<222> 6
<223> xaa= A, T, R, S, K or Y
<400> 264
Gln Xaa Xaa Xaa Xaa Xaa Pro Trp Thr
1 5
<210> 265
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> 2
<223> xaa= G, Y, S or a
<220>
<221> variant
<222> 3
<223> xaa= T, S, G, R, N or H
<220>
<221> variant
<222> 5
<223> xaa= S, T, R, H, Y, G or P
<220>
<221> variant
<222> 6
<223> xaa= S, K, G, N, R, D, T or G
<220>
<221> variant
<222> 7
<223> xaa= Y, L, H or F
<400> 265
Gly Xaa Xaa Phe Xaa Xaa Xaa
1 5
<210> 266
<211> 6
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> 1
<223> xaa= I, N or M
<220>
<221> variant
<222> 3
<223> xaa= G, N, H, S, R, I or a
<220>
<221> variant
<222> 4
<223> xaa= A, N, H, S, T, F or Y
<220>
<221> variant
<222> 5
<223> xaa= A, D or G
<220>
<221> variant
<222> 6
<223> xaa= T, E, K, V, Q or a
<400> 266
Xaa Pro Xaa Xaa Xaa Xaa
1 5
<210> 267
<211> 10
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> 1
<223> xaa=d or a
<220>
<221> variant
<222> 2
<223> xaa= A, G, E, R, Y, K, N, Q, L or F
<220>
<221> variant
<222> 3
<223> xaa= A, L, P or Y
<220>
<221> variant
<222> 5
<223> Xaa=I or L
<220>
<221> variant
<222> 6
<223> Xaa= R, A, Q or S
<220>
<221> variant
<222> 9
<223> xaa=a or D
<220>
<221> variant
<222> 10
<223> Xaa= D, E, A or S
<400> 267
Xaa Xaa Xaa Gly Xaa Xaa Leu Phe Xaa Xaa
1 5 10
<210> 268
<211> 5
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> 1
<223> Xaa= S, D, E, A or Q
<220>
<221> variant
<222> 3
<223> xaa= A, G or T
<400> 268
Xaa Tyr Xaa Met Ser
1 5
<210> 269
<211> 17
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> 3
<223> xaa= T, N, S, Q, E, H, R or a
<220>
<221> variant
<222> 4
<223> xaa= Y, W, F or H
<220>
<221> variant
<222> 5
<223> xaa= A, S, Q, E or T
<220>
<221> variant
<222> 7
<223> xaa=g or E
<220>
<221> variant
<222> 8
<223> Xaa=S or I
<220>
<221> variant
<222> 10
<223> Xaa=A or G
<400> 269
Asp Ile Xaa Xaa Xaa Gly Xaa Xaa Thr Xaa Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 270
<211> 12
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> 1
<223> Xaa=S or A
<220>
<221> variant
<222> 2
<223> xaa= N, H, A, D, L, Q, Y or R
<220>
<221> variant
<222> 3
<223> xaa= A, N, S or G
<220>
<221> variant
<222> 5
<223> Xaa= A, V, R, E or S
<220>
<221> variant
<222> 7
<223> Xaa=D or S
<220>
<221> variant
<222> 8
<223> xaa= D, N, Q, E, S, T or L
<220>
<221> variant
<222> 10
<223> xaa= L, F or M
<220>
<221> variant
<222> 12
<223> xaa= I, Y or V
<400> 270
Xaa Xaa Xaa Tyr Xaa Trp Xaa Xaa Ala Xaa Asp Xaa
1 5 10
<210> 271
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> 5
<223> xaa= S, D, E, Q, S or a
<220>
<221> variant
<222> 6
<223> Xaa= S, D, E, A or Q
<400> 271
Gly Phe Thr Phe Xaa Xaa Tyr
1 5
<210> 272
<211> 6
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> 1
<223> xaa= T, N, S, Q, E, H, R or a
<220>
<221> variant
<222> 2
<223> xaa= Y, W, F or H
<220>
<221> variant
<222> 3
<223> xaa= A, S, Q, E or T
<220>
<221> variant
<222> 5
<223> xaa=g or E
<220>
<221> variant
<222> 6
<223> Xaa=S or I
<400> 272
Xaa Xaa Xaa Gly Xaa Xaa
1 5
<210> 273
<211> 12
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> 1
<223> Xaa=S or A
<220>
<221> variant
<222> 2
<223> xaa= N, H, A, D, L, Q, Y or R
<220>
<221> variant
<222> 3
<223> xaa= A, N, S or G
<220>
<221> variant
<222> 5
<223> Xaa= A, V, R, E or S
<220>
<221> variant
<222> 7
<223> Xaa=D or S
<220>
<221> variant
<222> 8
<223> xaa= D, N, Q, E, S, T or L
<220>
<221> variant
<222> 10
<223> xaa= L, F or M
<220>
<221> variant
<222> 12
<223> xaa= I, Y or V
<400> 273
Xaa Xaa Xaa Tyr Xaa Trp Xaa Xaa Ala Xaa Asp Xaa
1 5 10
<210> 274
<211> 30
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 274
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser
20 25 30
<210> 275
<211> 14
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 275
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 276
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 276
Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 277
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 277
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 278
<211> 25
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 278
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser
20 25
<210> 279
<211> 19
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 279
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
1 5 10 15
Gly Gly Ile
<210> 280
<211> 41
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 280
Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp
1 5 10 15
Glu Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu
20 25 30
Asp Thr Ala Val Tyr Tyr Cys Ala Arg
35 40
<210> 281
<211> 30
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 281
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
20 25 30
<210> 282
<211> 14
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 282
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
1 5 10
<210> 283
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 283
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 284
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 284
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
1 5 10
<210> 285
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 285
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 286
<211> 25
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 286
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 287
<211> 19
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 287
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
1 5 10 15
Ser Asp Ile
<210> 288
<211> 41
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 288
Thr Ala Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
1 5 10 15
Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
20 25 30
Asp Thr Ala Val Tyr Tyr Cys Ala Arg
35 40
<210> 289
<211> 23
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 289
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys
20
<210> 290
<211> 15
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 290
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 291
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 291
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
20 25 30
<210> 292
<211> 10
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 292
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 293
<211> 23
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 293
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys
20
<210> 294
<211> 15
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 294
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
1 5 10 15
<210> 295
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 295
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
20 25 30
<210> 296
<211> 10
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 296
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 297
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 297
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Glu
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 298
<211> 214
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 298
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Asp Ala Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 299
<211> 597
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 299
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Ala Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
465 470 475 480
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
485 490 495
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
500 505 510
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
515 520 525
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
530 535 540
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
545 550 555 560
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
565 570 575
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
580 585 590
Ile Ser Thr Leu Thr
595
<210> 300
<211> 448
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 300
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Ala Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 301
<211> 449
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 301
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Ala Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 302
<211> 215
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 302
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 303
<211> 599
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 303
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Thr Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu
465 470 475 480
Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn
485 490 495
Tyr Lys Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met
500 505 510
Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu
515 520 525
Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe
530 535 540
His Leu Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu
545 550 555 560
Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu
565 570 575
Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln
580 585 590
Ser Ile Ile Ser Thr Leu Thr
595
<210> 304
<211> 450
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 304
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Thr Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 305
<211> 451
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 305
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Thr Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 306
<211> 215
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 306
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 307
<211> 599
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 307
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Thr Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu
465 470 475 480
Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn
485 490 495
Tyr Lys Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met
500 505 510
Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu
515 520 525
Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe
530 535 540
His Leu Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu
545 550 555 560
Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu
565 570 575
Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln
580 585 590
Ser Ile Ile Ser Thr Leu Thr
595
<210> 308
<211> 450
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 308
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Thr Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 309
<211> 451
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 309
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Thr Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 310
<211> 214
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 310
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Thr Ala Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 311
<211> 597
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 311
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Tyr Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
465 470 475 480
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
485 490 495
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
500 505 510
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
515 520 525
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
530 535 540
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
545 550 555 560
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
565 570 575
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
580 585 590
Ile Ser Thr Leu Thr
595
<210> 312
<211> 448
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 312
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Tyr Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 313
<211> 449
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 313
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Tyr Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 314
<211> 214
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 314
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Asp Ala Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 315
<211> 597
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 315
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Tyr Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
465 470 475 480
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
485 490 495
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
500 505 510
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
515 520 525
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
530 535 540
Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu
545 550 555 560
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
565 570 575
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
580 585 590
Ile Ser Thr Leu Thr
595
<210> 316
<211> 448
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 316
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Tyr Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 317
<211> 449
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 317
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Tyr Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 318
<211> 215
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 318
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 319
<211> 599
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 319
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Ser Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu
465 470 475 480
Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn
485 490 495
Tyr Lys Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met
500 505 510
Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu
515 520 525
Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe
530 535 540
His Leu Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu
545 550 555 560
Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu
565 570 575
Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln
580 585 590
Ser Ile Ile Ser Thr Leu Thr
595
<210> 320
<211> 450
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 320
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Ser Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 321
<211> 451
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 321
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Ser Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 322
<211> 215
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 322
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 323
<211> 599
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 323
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Ser Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu
465 470 475 480
Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn
485 490 495
Tyr Lys Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met
500 505 510
Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu
515 520 525
Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe
530 535 540
His Leu Arg Pro Arg Asp Leu Ile Ser Ala Ile Asn Val Ile Val Leu
545 550 555 560
Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu
565 570 575
Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln
580 585 590
Ser Ile Ile Ser Thr Leu Thr
595
<210> 324
<211> 450
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 324
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Ser Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 325
<211> 451
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 325
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Ser Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 326
<211> 214
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 326
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Asp Ala Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 327
<211> 597
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 327
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Ala Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Glu
465 470 475 480
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
485 490 495
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
500 505 510
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
515 520 525
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
530 535 540
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
545 550 555 560
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
565 570 575
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
580 585 590
Ile Ser Thr Leu Thr
595
<210> 328
<211> 448
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 328
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Ala Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 329
<211> 449
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 329
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Ala Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 330
<211> 215
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 330
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 331
<211> 599
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 331
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Thr Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu
465 470 475 480
Glu Glu Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn
485 490 495
Tyr Lys Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met
500 505 510
Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu
515 520 525
Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe
530 535 540
His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu
545 550 555 560
Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu
565 570 575
Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln
580 585 590
Ser Ile Ile Ser Thr Leu Thr
595
<210> 332
<211> 450
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 332
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Thr Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 333
<211> 451
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 333
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Thr Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 334
<211> 215
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 334
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 335
<211> 599
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 335
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Thr Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu
465 470 475 480
Glu Glu Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn
485 490 495
Tyr Lys Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met
500 505 510
Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu
515 520 525
Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe
530 535 540
His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu
545 550 555 560
Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu
565 570 575
Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln
580 585 590
Ser Ile Ile Ser Thr Leu Thr
595
<210> 336
<211> 450
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 336
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Thr Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 337
<211> 451
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 337
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Thr Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 338
<211> 214
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 338
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Thr Ala Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 339
<211> 597
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 339
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Tyr Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Glu
465 470 475 480
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
485 490 495
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
500 505 510
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
515 520 525
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
530 535 540
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
545 550 555 560
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
565 570 575
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
580 585 590
Ile Ser Thr Leu Thr
595
<210> 340
<211> 448
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 340
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Tyr Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 341
<211> 449
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 341
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Tyr Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 342
<211> 214
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 342
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Asp Ala Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 343
<211> 597
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 343
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Tyr Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Glu
465 470 475 480
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
485 490 495
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
500 505 510
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
515 520 525
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
530 535 540
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
545 550 555 560
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
565 570 575
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
580 585 590
Ile Ser Thr Leu Thr
595
<210> 344
<211> 448
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 344
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Tyr Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 345
<211> 449
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 345
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Gly Tyr Ala Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Ala Gly Ile Arg Leu Phe Ala Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 346
<211> 215
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 346
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 347
<211> 599
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 347
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Ser Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu
465 470 475 480
Glu Glu Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn
485 490 495
Tyr Lys Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met
500 505 510
Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu
515 520 525
Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe
530 535 540
His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu
545 550 555 560
Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu
565 570 575
Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln
580 585 590
Ser Ile Ile Ser Thr Leu Thr
595
<210> 348
<211> 450
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 348
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Ser Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 349
<211> 451
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 349
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Ser Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 350
<211> 215
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 350
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 351
<211> 599
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 351
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Ser Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu
465 470 475 480
Glu Glu Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn
485 490 495
Tyr Lys Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met
500 505 510
Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu
515 520 525
Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe
530 535 540
His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu
545 550 555 560
Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu
565 570 575
Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln
580 585 590
Ser Ile Ile Ser Thr Leu Thr
595
<210> 352
<211> 450
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 352
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Ser Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 353
<211> 451
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 353
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Ser Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Ala Tyr Ala Trp Asp Asp Ala Leu Asp Ile Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 354
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 354
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asp Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 355
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 355
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Thr Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 356
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 356
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 357
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 357
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 358
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 358
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Thr Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 359
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 359
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asp Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 360
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 360
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 361
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 361
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Thr Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 362
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 362
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asp Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 363
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 363
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 364
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 364
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Thr Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 365
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 365
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asp Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 366
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 366
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 367
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 367
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Thr Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 368
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 368
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asp Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 369
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 369
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 370
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 370
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Thr Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 371
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 371
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Glu Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asp Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 372
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 372
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 373
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 373
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Thr Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 374
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 374
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Asp Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asp Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 375
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 375
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 376
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 376
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Thr Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 377
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 377
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Lys Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asp Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 378
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 378
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 379
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 379
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Thr Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 380
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 380
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Gln Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asp Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 381
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 381
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 382
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 382
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Thr Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 383
<211> 133
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 383
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asp Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 384
<211> 98
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 384
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg
<210> 385
<211> 95
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 385
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro
85 90 95
<210> 386
<211> 6
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> (2)..(5)
<223> may be 1, 2, 3, 4, 5, 6, 7, 8, 9,
10. 11 or 12 repeats
<220>
<221> variant
<222> 6
<223> may be present in 0, 1, 2 or 3 repeats
<400> 386
Ser Gly Gly Gly Ser Gly
1 5
<210> 387
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> (2)..(6)
<223> may be 1, 2, 3, 4, 5, 6, 7, 8, 9,
10. 11 or 12 repeats
<220>
<221> variant
<222> 7
<223> may be present in 0, 1, 2 or 3 repeats
<400> 387
Ser Gly Gly Gly Gly Ser Gly
1 5
<210> 388
<211> 8
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<220>
<221> variant
<222> (2)..(7)
<223> may be 1, 2, 3, 4, 5, 6, 7, 8, 9,
10. 11 or 12 repeats
<220>
<221> variant
<222> 8
<223> may be present in 0, 1, 2 or 3 repeats
<400> 388
Ser Gly Gly Gly Gly Gly Ser Gly
1 5
<210> 389
<211> 16
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> synthetic construct
<400> 389
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15

Claims (110)

1. A human or humanized antibody or antigen binding fragment thereof, wherein said antibody or fragment specifically binds human CD8b and/or human CD8ab with at least 10-fold higher affinity than it binds human CD8a and/or human CD8 aa.
2. The antibody or fragment of claim 1, wherein the antibody or fragment binds to a cell expressing human CD8ab heterodimer on a surface with an EC50 of less than 1000 nM.
3. The antibody or fragment of claim 1 or claim 2, wherein the antibody or fragment binds to a human cd8+ T cell.
4. A humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 13, CDR-H2 comprising amino acid sequence SEQ ID NO. 14 and CDR-H3 comprising amino acid sequence SEQ ID NO. 15; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18.
5. A humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 51, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 15; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18.
6. The antibody or fragment of claim 4 or claim 5, wherein the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 62, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 63.
7. A humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 19, CDR-H2 comprising amino acid sequence SEQ ID NO. 20 and CDR-H3 comprising amino acid sequence SEQ ID NO. 21; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24.
8. A humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 53, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 21; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24.
9. The antibody or fragment of claim 7 or claim 8, wherein the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 64, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 65.
10. A humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 25, CDR-H2 comprising amino acid sequence SEQ ID NO. 26 and CDR-H3 comprising amino acid sequence SEQ ID NO. 27; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30.
11. A humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 49, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 27; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30.
12. The antibody or fragment of claim 10 or claim 11, wherein the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 66, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 67.
13. A humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 31, CDR-H2 comprising amino acid sequence SEQ ID NO. 32 and CDR-H3 comprising amino acid sequence SEQ ID NO. 33; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36.
14. A humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 54, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 33; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36.
15. The antibody or fragment of claim 13 or claim 14, wherein the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 68, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 69.
16. A human antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 37, CDR-H2 comprising amino acid sequence SEQ ID NO. 38 and CDR-H3 comprising amino acid sequence SEQ ID NO. 39; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42.
17. A human antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 55, CDR-H2 comprising amino acid sequence SEQ ID NO. 56 and CDR-H3 comprising amino acid sequence SEQ ID NO. 39; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42.
18. The antibody or fragment of claim 16 or claim 17, wherein the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 70, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 71.
19. A human antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 43, CDR-H2 comprising amino acid sequence SEQ ID NO. 44 and CDR-H3 comprising amino acid sequence SEQ ID NO. 45; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48.
20. A human antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 55, CDR-H2 comprising amino acid sequence SEQ ID NO. 57 and CDR-H3 comprising amino acid sequence SEQ ID NO. 45; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48.
21. The antibody or fragment of claim 19 or claim 20, wherein the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 72, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 73.
22. A humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 1, CDR-H2 comprising amino acid sequence SEQ ID NO. 2 and CDR-H3 comprising amino acid sequence SEQ ID NO. 3; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6.
23. A humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 49, CDR-H2 comprising amino acid sequence SEQ ID NO. 50 and CDR-H3 comprising amino acid sequence SEQ ID NO. 3; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6.
24. A humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 177, CDR-H2 comprising amino acid sequence SEQ ID NO. 178 and CDR-H3 comprising amino acid sequence SEQ ID NO. 179; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182.
25. A humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain; wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 183, CDR-H2 comprising amino acid sequence SEQ ID NO. 184 and CDR-H3 comprising amino acid sequence SEQ ID NO. 179; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182.
26. A humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain;
wherein the VH domain comprises:
CDR-H1 comprising the amino acid sequence X 1 X 2 AIS, wherein X 1 S, K, G, N, R, D, T or G, and wherein X 2 Y, L, H or F (SEQ ID NO: 259),
CDR-H2 comprising the amino acid sequence X 1 X 2 X 3 PX 4 X 5 X 6 X 7 X 8 X 9 YX 10 QKFX 11 G, wherein X 1 Is G or H, X 2 Is I or F, X 3 I, N or M, X 4 G, N, H, S, R, I or A, X 5 A, N, H, S, T, F or Y, X 6 A, D or G, X 7 T, E, K, V, Q or A, X 8 Is A or T, X 9 Is N or K, X 10 Is A or N, and X 11 Q or T (SEQ ID NO: 260), and
CDR-H3 comprising the amino acid sequence X 1 X 2 X 3 GX 4 X 5 LFX 6 X 7 Which is provided withMiddle X 1 Is D or A, X 2 A, G, E, R, Y, K, N, Q, L or F, X 3 A, L, P or Y, X 4 Is I or L, X 5 R, A, Q or S, X 6 Is A or D, and X 7 D, E, A or S (SEQ ID NO: 261); and is also provided with
Wherein the VL domain comprises:
CDR-L1 comprising the amino acid sequence X 1 X 2 SX 3 X 4 IX 5 GX 6 LN, wherein X 1 R or G, X 2 Is A or T, X 3 Q or E, X 4 E, N, T, S, A, K, D, G, R or Q, X 5 Is Y or S, and X 6 A or V (SEQ ID NO: 262),
CDR-L2 comprising the amino acid sequence GX 1 X 2 X 3 LX 4 X 5 Wherein X is 1 Is A or S, X 2 T, S, E, Q or D, X 3 N, R, A, E or H, X 4 Q or A, and X 5 S or D (SEQ ID NO: 263), and
CDR-L3 comprising the amino acid sequence QX 1 X 2 X 3 X 4 X 5 PWT, wherein X 1 S, N, D, Q, A or E, X 2 T, I or S, X 3 Y, L or F, X 4 D, G, T, E, Q, A or Y, and X 5 A, T, R, S, K or Y (SEQ ID NO: 264).
27. The antibody of claim 26, wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 226 and CDR-H3 comprising amino acid sequence SEQ ID NO. 227; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228.
28. The antibody of claim 26, wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 232 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236.
29. The antibody of claim 26, wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 232 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228.
30. The antibody of any one of claims 26-29, wherein the VH domain further comprises: FW-1 comprising sequence QVQLVQSGAEVKKPGSSVKVSCKASGGTFS (SEQ ID NO: 274), FW-2 comprising sequence WVRQAPGQGLEWMG (SEQ ID NO: 275), FW-3 comprising sequence RVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 276) and FW-4 comprising sequence WGQGTLVTVSS (SEQ ID NO: 277); and wherein the VL domain further comprises: FW-1 comprising sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 289), FW-2 comprising sequence WYQQKPGKAPKLLIY (SEQ ID NO: 290), FW-3 comprising sequence GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 291) and FW-4 comprising sequence FGGGTKVEIK (SEQ ID NO: 292).
31. A humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain;
Wherein the VH domain comprises:
CDR-H1 comprising the amino acid sequence GX 1 X 2 FX 3 X 4 X 5 Wherein X is 1 G, Y, S or A, X 2 T, S, G, R, N or H, X 3 S, T, R, H, Y, G or P, X 4 S, K, G, N, R, D, T or G, and X 5 Y, L, H or F (SEQ ID NO: 265),
CDR-H2 comprising an amino acid sequenceColumn X 1 PX 2 X 3 X 4 X 5 Wherein X is 1 I, N or M, X 2 G, N, H, S, R, I or A, X 3 A, N, H, S, T, F or Y, X 4 A, D or G, and X 5 T, E, K, V, Q or A (SEQ ID NO: 266), and
CDR-H3 comprising the amino acid sequence X 1 X 2 X 3 GX 4 X 5 LFX 6 X 7 Wherein X is 1 Is D or A, X 2 A, G, E, R, Y, K, N, Q, L or F, X 3 A, L, P or Y, X 4 Is I or L, X 5 R, A, Q or S, X 6 Is A or D, and X 7 D, E, A or S (SEQ ID NO: 267); and is also provided with
Wherein the VL domain comprises:
CDR-L1 comprising the amino acid sequence X 1 X 2 SX 3 X 4 IX 5 GX 6 LN, wherein X 1 R or G, X 2 Is A or T, X 3 Q or E, X 4 E, N, T, S, A, K, D, G, R or Q, X 5 Is Y or S, and X 6 A or V (SEQ ID NO: 262),
CDR-L2 comprising the amino acid sequence GX 1 X 2 X 3 LX 4 X 5 Wherein X is 1 Is A or S, X 2 T, S, E, Q or D, X 3 N, R, A, E or H, X 4 Q or A, and X 5 S or D (SEQ ID NO: 263), and
CDR-L3 comprising the amino acid sequence QX 1 X 2 X 3 X 4 X 5 PWT, wherein X 1 S, N, D, Q, A or E, X 2 T, I or S, X 3 Y, L or F, X 4 D, G, T, E, Q, A or Y, and X 5 A, T, R, S, K or Y (SEQ ID NO: 264).
32. The antibody of claim 31, wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 239 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228.
33. The antibody of claim 31, wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 243 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236.
34. The antibody of claim 31, wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 243 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228.
35. The antibody of any one of claims 31-34, wherein the VH domain further comprises: FW-1 comprising sequence QVQLVQSGAEVKKPGSSVKVSCKAS (SEQ ID NO: 278), FW-2 comprising sequence AISWVRQAPGQGLEWMGGI (SEQ ID NO: 279), FW-3 comprising sequence ANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 280) and FW-4 comprising sequence WGQGTLVTVSS (SEQ ID NO: 277); and wherein the VL domain further comprises: FW-1 comprising sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 289), FW-2 comprising sequence WYQQKPGKAPKLLIY (SEQ ID NO: 290), FW-3 comprising sequence GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 291) and FW-4 comprising sequence FGGGTKVEIK (SEQ ID NO: 292).
36. The antibody of claim 26 or claim 31, wherein the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 245; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO 246.
37. The antibody of claim 26 or claim 31, wherein the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 251, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 252; optionally, wherein the VH domain comprises the amino acid sequence SEQ ID NO. 251 and the VL domain comprises the amino acid sequence SEQ ID NO. 252.
38. The antibody of claim 26 or claim 31, wherein the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 253; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO. 254.
39. A humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain;
wherein the VH domain comprises:
CDR-H1 comprising the amino acid sequence X 1 YX 2 MS, wherein X 1 S, D, E, A or Q, and X 2 A, G or T (SEQ ID NO: 268),
CDR-H2 comprising the amino acid sequence DIX 1 X 2 X 3 GX 4 X 5 TX 6 YADSVKG, wherein X 1 T, N, S, Q, E, H, R or A, X 2 Y, W, F or H, X 3 A, S, Q, E or T, X 4 Is G or E, X 5 Is S or I, and X 6 Is A or G (SEQ ID NO: 269), and
CDR-H3 comprising the amino acid sequence X 1 X 2 X 3 YX 4 WX 5 X 6 AX 7 DX 8 Wherein X is 1 Is S or A, X 2 N, H, A, D, L, Q, Y or R, X 3 A, N, S or G, X 4 A, V, R, E or S, X 5 Is D or S, X 6 D, N, Q, E, S, T or L, X 7 L, F or M, and X 8 I, Y or V (SEQ ID NO: 270); and is also provided with
Wherein the VL domain comprises:
CDR-L1 comprising amino acid sequence RASQSVSSNLA (SEQ ID NO: 40),
CDR-L2 comprising the amino acid sequence GASSRAT (SEQ ID NO: 41), and
CDR-L3 comprising amino acid sequence QQYGSSPPVT (SEQ ID NO: 42).
40. The antibody of claim 39, wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 229, CDR-H2 comprising amino acid sequence SEQ ID NO. 230 and CDR-H3 comprising amino acid sequence SEQ ID NO. 231.
41. The antibody of claim 39, wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 229, CDR-H2 comprising amino acid sequence SEQ ID NO. 237 and CDR-H3 comprising amino acid sequence SEQ ID NO. 231.
42. The antibody of any one of claims 39-41, wherein said VH domain further comprises: FW-1 comprising sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 281), FW-2 comprising sequence WVRQAPGKGLEWVS (SEQ ID NO: 282), FW-3 comprising sequence RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 283) and FW-4 comprising sequence WGQGTMVTVSS (SEQ ID NO: 284) or WGQGTLVTVSS (SEQ ID NO: 285); and wherein the VL domain further comprises: FW-1 comprising sequence EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising sequence WYQQKPGQAPRLLIY (SEQ ID NO: 294), FW-3 comprising sequence GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 295) and FW-4 comprising sequence FGQGTKVEIK (SEQ ID NO: 296).
43. A humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain;
wherein the VH domain comprises:
CDR-H1 comprising the amino acid sequence GFTFX 1 X 2 Y, wherein X 1 S, D, E, Q, S or A, and X 2 S, D, E, A or Q (SEQ ID NO: 271),
CDR-H2 comprising the amino acid sequence X 1 X 2 X 3 GX 4 X 5 Wherein X is 1 T, N, S, Q, E, H, R or A, X 2 Y, W, F or H, X 3 A, S, Q, E or T, X 4 Is G or E, and X 5 S or I (SEQ ID NO: 272), and
CDR-H3 comprising the amino acid sequence X 1 X 2 X 3 YX 4 WX 5 X 6 AX 7 DX 8 Wherein X is 1 Is S or A, X 2 N, H, A, D, L, Q, Y or R, X 3 A, N, S or G, X 4 A, V, R, E or S, X 5 Is D or S, X 6 D, N, Q, E, S, T or L, X 7 L, F or M, and X 8 I, Y or V (SEQ ID NO: 273); and is also provided with
Wherein the VL domain comprises:
CDR-L1 comprising amino acid sequence RASQSVSSNLA (SEQ ID NO: 40),
CDR-L2 comprising the amino acid sequence GASSRAT (SEQ ID NO: 41), and
CDR-L3 comprising amino acid sequence QQYGSSPPVT (SEQ ID NO: 42).
44. The antibody of claim 43, wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 240, CDR-H2 comprising amino acid sequence SEQ ID NO. 241 and CDR-H3 comprising amino acid sequence SEQ ID NO. 242.
45. The antibody of claim 43, wherein the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 240, CDR-H2 comprising amino acid sequence SEQ ID NO. 244 and CDR-H3 comprising amino acid sequence SEQ ID NO. 242.
46. The antibody of any one of claims 43-45, wherein said VH domain further comprises: FW-1 comprising sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 286), FW-2 comprising sequence AMSWVRQAPGKGLEWVSDI (SEQ ID NO: 287), FW-3 comprising sequence TAYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 288) and FW-4 comprising sequence WGQGTMVTVSS (SEQ ID NO: 284) or WGQGTLVTVSS (SEQ ID NO: 285); and wherein the VL domain further comprises: FW-1 comprising sequence EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising sequence WYQQKPGQAPRLLIY (SEQ ID NO: 294), FW-3 comprising sequence GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 295) and FW-4 comprising sequence FGQGTKVEIK (SEQ ID NO: 296).
47. The antibody of claim 39 or claim 43, wherein the VH domain comprises an amino acid sequence at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 247; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO 248.
48. The antibody of claim 39 or claim 43, wherein said VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 249, and wherein said VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 250; optionally, wherein the VH domain comprises the amino acid sequence SEQ ID NO. 249 and the VL domain comprises the amino acid sequence SEQ ID NO. 250.
49. The antibody of claim 39 or claim 43, wherein said VH domain comprises an amino acid sequence at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 255; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO. 256.
50. The antibody of claim 39 or claim 43, wherein said VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 257; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO 258.
51. The antibody of any one of claims 1-50, wherein the antibody is a multispecific antibody.
52. The antibody of claim 51, wherein the antibody is a bispecific antibody.
53. A fusion protein comprising:
(a) A first portion comprising the antibody or fragment of any one of claims 1-52; and
(b) A second portion comprising a cytokine, chemokine or growth factor;
wherein the first portion is fused to the second portion directly or via a linker.
54. A fusion protein comprising:
(a) A first portion comprising a human or humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain, wherein:
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 13, CDR-H2 comprising amino acid sequence SEQ ID NO. 14 and CDR-H3 comprising amino acid sequence SEQ ID NO. 15; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 19, CDR-H2 comprising amino acid sequence SEQ ID NO. 20 and CDR-H3 comprising amino acid sequence SEQ ID NO. 21; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24;
The VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 25, CDR-H2 comprising amino acid sequence SEQ ID NO. 26 and CDR-H3 comprising amino acid sequence SEQ ID NO. 27; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 31, CDR-H2 comprising amino acid sequence SEQ ID NO. 32 and CDR-H3 comprising amino acid sequence SEQ ID NO. 33; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 37, CDR-H2 comprising amino acid sequence SEQ ID NO. 38 and CDR-H3 comprising amino acid sequence SEQ ID NO. 39; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 43, CDR-H2 comprising amino acid sequence SEQ ID NO. 44 and CDR-H3 comprising amino acid sequence SEQ ID NO. 45; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48;
The VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 1, CDR-H2 comprising amino acid sequence SEQ ID NO. 2 and CDR-H3 comprising amino acid sequence SEQ ID NO. 3; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 177, CDR-H2 comprising amino acid sequence SEQ ID NO. 178 and CDR-H3 comprising amino acid sequence SEQ ID NO. 179; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 226 and CDR-H3 comprising amino acid sequence SEQ ID NO. 227; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 229, CDR-H2 comprising amino acid sequence SEQ ID NO. 230 and CDR-H3 comprising amino acid sequence SEQ ID NO. 231; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42;
The VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 232 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 232 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; or (b)
The VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 229, CDR-H2 comprising amino acid sequence SEQ ID NO. 237 and CDR-H3 comprising amino acid sequence SEQ ID NO. 231; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42; and
(b) A second portion comprising a cytokine, chemokine or growth factor;
Wherein the first portion is fused to the second portion directly or via a linker.
55. A fusion protein comprising:
(a) A first portion comprising a human or humanized antibody or antigen-binding fragment thereof that specifically binds CD8b and/or CD8ab, wherein the antibody or fragment comprises a heavy chain Variable (VH) domain and a light chain Variable (VL) domain, wherein:
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 51, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 15; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 53, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 21; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 49, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 27; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30;
The VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 54, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 33; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 55, CDR-H2 comprising amino acid sequence SEQ ID NO. 56 and CDR-H3 comprising amino acid sequence SEQ ID NO. 39; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 55, CDR-H2 comprising amino acid sequence SEQ ID NO. 57 and CDR-H3 comprising amino acid sequence SEQ ID NO. 45; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 49, CDR-H2 comprising amino acid sequence SEQ ID NO. 50 and CDR-H3 comprising amino acid sequence SEQ ID NO. 3; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6;
The VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 183, CDR-H2 comprising amino acid sequence SEQ ID NO. 184 and CDR-H3 comprising amino acid sequence SEQ ID NO. 179; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 239 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 240, CDR-H2 comprising amino acid sequence SEQ ID NO. 241 and CDR-H3 comprising amino acid sequence SEQ ID NO. 242; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 243 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236;
The VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 243 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; or (b)
The VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 240, CDR-H2 comprising amino acid sequence SEQ ID NO. 244 and CDR-H3 comprising amino acid sequence SEQ ID NO. 242; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42; and
(b) A second portion comprising a cytokine, chemokine or growth factor;
wherein the first portion is fused to the second portion directly or via a linker.
56. The fusion protein of any one of claims 53-55, wherein the second moiety induces activation of cd8+ T cells.
57. The fusion protein of claim 56, wherein said fusion protein induces activation of cells expressing human CD8ab heterodimer with at least 10-fold greater potency than activation of cells expressing human CD8aa homodimer.
58. The fusion protein of claim 56, wherein said fusion protein induces activation of CD8+ T cells with at least 10-fold greater potency than activation of NK cells.
59. The fusion protein of claim 57 or claim 58, wherein activation efficacy is measured by EC50 as assessed by cell proliferation.
60. The fusion protein of any one of claims 53-59, wherein the first portion comprises: two antibody heavy chain polypeptides comprising from N-terminus to C-terminus a structure according to formula [ I ]:
VH-CH 1-hinge-CH 2-CH3 [ I ]
And two antibody light chain polypeptides comprising a structure according to formula [ II ] from N-terminus to C-terminus:
VL-CL [II]
wherein VH is said VH domain, wherein CH1 is an antibody CH1 domain, wherein the hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is said VL domain, and wherein CL is an antibody constant light chain domain; and is also provided with
Wherein the N-terminus of the second portion is fused to the C-terminus of one of the two CH3 domains.
61. The fusion protein of any one of claims 53-59, wherein the first portion comprises a first antibody heavy chain polypeptide comprising a structure according to formula [ I ] from N-terminus to C-terminus:
VH-CH 1-hinge-CH 2-CH 3I,
an antibody light chain polypeptide comprising a structure according to formula [ II ] from N-terminus to C-terminus:
VL-CL [II]，
and a second antibody heavy chain polypeptide comprising from N-terminus to C-terminus a structure according to formula [ III ]:
hinge-CH 2-CH3 III,
wherein VH is said VH domain, wherein CH1 is an antibody CH1 domain, wherein the hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is said VL domain, and wherein CL is an antibody constant light chain domain; and is also provided with
Wherein the N-terminus of the second portion is fused to the C-terminus of the CH3 domain of the second antibody heavy chain polypeptide.
62. The fusion protein of any one of claims 53-59, wherein the first portion comprises a first antibody heavy chain polypeptide comprising a structure according to formula [ I ] from N-terminus to C-terminus:
VH-CH 1-hinge-CH 2-CH 3I,
an antibody light chain polypeptide comprising a structure according to formula [ II ] from N-terminus to C-terminus:
VL-CL [II]，
and a second antibody heavy chain polypeptide comprising from N-terminus to C-terminus a structure according to formula [ III ]:
hinge-CH 2-CH3 III,
wherein VH is said VH domain, wherein CH1 is an antibody CH1 domain, wherein the hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is said VL domain, and wherein CL is an antibody constant light chain domain; and is also provided with
Wherein the C-terminus of the second portion is fused to the N-terminus of the hinge domain of the second antibody heavy chain polypeptide.
63. The fusion protein of any one of claims 53-59, wherein the first portion comprises a first antibody heavy chain polypeptide comprising a structure according to formula [ I ] from N-terminus to C-terminus:
VH-CH 1-hinge-CH 2-CH 3I,
an antibody light chain polypeptide comprising a structure according to formula [ II ] from N-terminus to C-terminus:
VL-CL [II]，
and a second antibody heavy chain polypeptide comprising from N-terminus to C-terminus a structure according to formula [ III ]:
hinge-CH 2-CH3 III,
wherein VH is said VH domain, wherein CH1 is an antibody CH1 domain, wherein the hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is said VL domain, and wherein CL is an antibody constant light chain domain; and is also provided with
Wherein the N-terminus of the second portion is fused to the C-terminus of the CH3 domain of the first antibody heavy chain polypeptide.
64. The fusion protein of claim 60, wherein:
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 13, CDR-H2 comprising amino acid sequence SEQ ID NO. 14 and CDR-H3 comprising amino acid sequence SEQ ID NO. 15; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18;
The VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 19, CDR-H2 comprising amino acid sequence SEQ ID NO. 20 and CDR-H3 comprising amino acid sequence SEQ ID NO. 21; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24;
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 25, CDR-H2 comprising amino acid sequence SEQ ID NO. 26 and CDR-H3 comprising amino acid sequence SEQ ID NO. 27; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30;
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 31, CDR-H2 comprising amino acid sequence SEQ ID NO. 32 and CDR-H3 comprising amino acid sequence SEQ ID NO. 33; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36;
The VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 37, CDR-H2 comprising amino acid sequence SEQ ID NO. 38 and CDR-H3 comprising amino acid sequence SEQ ID NO. 39; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42;
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 43, CDR-H2 comprising amino acid sequence SEQ ID NO. 44 and CDR-H3 comprising amino acid sequence SEQ ID NO. 45; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48;
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 1, CDR-H2 comprising amino acid sequence SEQ ID NO. 2 and CDR-H3 comprising amino acid sequence SEQ ID NO. 3; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6;
The VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 177, CDR-H2 comprising amino acid sequence SEQ ID NO. 178 and CDR-H3 comprising amino acid sequence SEQ ID NO. 179; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182;
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 226 and CDR-H3 comprising amino acid sequence SEQ ID NO. 227; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228;
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 229, CDR-H2 comprising amino acid sequence SEQ ID NO. 230 and CDR-H3 comprising amino acid sequence SEQ ID NO. 231; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42;
The VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 232 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236;
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 232 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; or (b)
The VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 229, CDR-H2 comprising amino acid sequence SEQ ID NO. 237 and CDR-H3 comprising amino acid sequence SEQ ID NO. 231; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42.
65. The fusion protein of claim 60, wherein:
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 51, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 15; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18;
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 53, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 21; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24;
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 49, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 27; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30;
The VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 54, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 33; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36;
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 55, CDR-H2 comprising amino acid sequence SEQ ID NO. 56 and CDR-H3 comprising amino acid sequence SEQ ID NO. 39; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42;
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 55, CDR-H2 comprising amino acid sequence SEQ ID NO. 57 and CDR-H3 comprising amino acid sequence SEQ ID NO. 45; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48;
The VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 49, CDR-H2 comprising amino acid sequence SEQ ID NO. 50 and CDR-H3 comprising amino acid sequence SEQ ID NO. 3; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6;
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 183, CDR-H2 comprising amino acid sequence SEQ ID NO. 184 and CDR-H3 comprising amino acid sequence SEQ ID NO. 179; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182;
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 239 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228;
The VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 240, CDR-H2 comprising amino acid sequence SEQ ID NO. 241 and CDR-H3 comprising amino acid sequence SEQ ID NO. 242; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42;
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 243 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236;
the VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 243 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; or (b)
The VH domains of both antibody heavy chain polypeptides comprise: CDR-H1 comprising amino acid sequence SEQ ID NO. 240, CDR-H2 comprising amino acid sequence SEQ ID NO. 244 and CDR-H3 comprising amino acid sequence SEQ ID NO. 242; and wherein the VL domains of both antibody light chain polypeptides comprise: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42.
66. The fusion protein of claim 60, 64 or 65, wherein:
said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 62, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 63; optionally, the VH domains of both antibody heavy chain polypeptides comprise the amino acid sequence of SEQ ID No. 62 and the VL domains of both antibody light chain polypeptides comprise the amino acid sequence of SEQ ID No. 63;
said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 64, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 65; optionally, the VH domains of both antibody heavy chain polypeptides comprise the amino acid sequence SEQ ID No. 64, and the VL domains of both antibody light chain polypeptides comprise the amino acid sequence SEQ ID No. 65;
Said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 66, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 67; optionally, the VH domains of both antibody heavy chain polypeptides comprise the amino acid sequence SEQ ID No. 66 and the VL domains of both antibody light chain polypeptides comprise the amino acid sequence SEQ ID No. 67;
said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 68, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 69; optionally, the VH domains of both antibody heavy chain polypeptides comprise the amino acid sequence SEQ ID No. 68 and the VL domains of both antibody light chain polypeptides comprise the amino acid sequence SEQ ID No. 69;
said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 70, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 71; optionally, the VH domains of both antibody heavy chain polypeptides comprise the amino acid sequence SEQ ID No. 70, and the VL domains of both antibody light chain polypeptides comprise the amino acid sequence SEQ ID No. 71;
Said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 72, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 73; optionally, the VH domains of both antibody heavy chain polypeptides comprise the amino acid sequence SEQ ID NO:72, and the VL domains of both antibody light chain polypeptides comprise the amino acid sequence SEQ ID NO:73;
said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 185, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 186; optionally, the VH domains of both antibody heavy chain polypeptides comprise the amino acid sequence SEQ ID No. 185 and the VL domains of both antibody light chain polypeptides comprise the amino acid sequence SEQ ID No. 186;
said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 245, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 246; optionally, the VH domains of both antibody heavy chain polypeptides comprise the amino acid sequence SEQ ID No. 245 and the VL domains of both antibody light chain polypeptides comprise the amino acid sequence SEQ ID No. 246;
Said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 251, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 252; optionally, the VH domains of both antibody heavy chain polypeptides comprise the amino acid sequence SEQ ID NO. 251 and the VL domains of both antibody light chain polypeptides comprise the amino acid sequence SEQ ID NO. 252;
said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 253, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 254; optionally, the VH domains of both antibody heavy chain polypeptides comprise the amino acid sequence SEQ ID No. 253 and the VL domains of both antibody light chain polypeptides comprise the amino acid sequence SEQ ID No. 254;
said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 247, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 248; optionally, the VH domains of both antibody heavy chain polypeptides comprise the amino acid sequence SEQ ID No. 247 and the VL domains of both antibody light chain polypeptides comprise the amino acid sequence SEQ ID No. 248;
Said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 249, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 250; optionally, the VH domains of both antibody heavy chain polypeptides comprise the amino acid sequence SEQ ID No. 249, and the VL domains of both antibody light chain polypeptides comprise the amino acid sequence SEQ ID No. 250;
said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 255, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 256; optionally, the VH domains of both antibody heavy chain polypeptides comprise the amino acid sequence SEQ ID No. 255 and the VL domains of both antibody light chain polypeptides comprise the amino acid sequence SEQ ID No. 256; or (b)
Said VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 257, and wherein said VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 258; optionally, the VH domains of both antibody heavy chain polypeptides comprise the amino acid sequence SEQ ID NO:257 and the VL domains of both antibody light chain polypeptides comprise the amino acid sequence SEQ ID NO:258.
67. The fusion protein of any one of claims 61-63, wherein:
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 13, CDR-H2 comprising amino acid sequence SEQ ID NO. 14 and CDR-H3 comprising amino acid sequence SEQ ID NO. 15; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 19, CDR-H2 comprising amino acid sequence SEQ ID NO. 20 and CDR-H3 comprising amino acid sequence SEQ ID NO. 21; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 25, CDR-H2 comprising amino acid sequence SEQ ID NO. 26 and CDR-H3 comprising amino acid sequence SEQ ID NO. 27; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30;
The VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 31, CDR-H2 comprising amino acid sequence SEQ ID NO. 32 and CDR-H3 comprising amino acid sequence SEQ ID NO. 33; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 37, CDR-H2 comprising amino acid sequence SEQ ID NO. 38 and CDR-H3 comprising amino acid sequence SEQ ID NO. 39; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 43, CDR-H2 comprising amino acid sequence SEQ ID NO. 44 and CDR-H3 comprising amino acid sequence SEQ ID NO. 45; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 1, CDR-H2 comprising amino acid sequence SEQ ID NO. 2 and CDR-H3 comprising amino acid sequence SEQ ID NO. 3; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6;
The VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 177, CDR-H2 comprising amino acid sequence SEQ ID NO. 178 and CDR-H3 comprising amino acid sequence SEQ ID NO. 179; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 226 and CDR-H3 comprising amino acid sequence SEQ ID NO. 227; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 229, CDR-H2 comprising amino acid sequence SEQ ID NO. 230 and CDR-H3 comprising amino acid sequence SEQ ID NO. 231; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 232 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236;
The VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 225, CDR-H2 comprising amino acid sequence SEQ ID NO. 232 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; or (b)
The VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 229, CDR-H2 comprising amino acid sequence SEQ ID NO. 237 and CDR-H3 comprising amino acid sequence SEQ ID NO. 231; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42.
68. The fusion protein of any one of claims 61-63, wherein:
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 51, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 15; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 18;
The VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 53, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 21; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 22, CDR-L2 comprising amino acid sequence SEQ ID NO. 23 and CDR-L3 comprising amino acid sequence SEQ ID NO. 24;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 49, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 27; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 28, CDR-L2 comprising amino acid sequence SEQ ID NO. 29 and CDR-L3 comprising amino acid sequence SEQ ID NO. 30;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 54, CDR-H2 comprising amino acid sequence SEQ ID NO. 52 and CDR-H3 comprising amino acid sequence SEQ ID NO. 33; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 34, CDR-L2 comprising amino acid sequence SEQ ID NO. 35 and CDR-L3 comprising amino acid sequence SEQ ID NO. 36;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 55, CDR-H2 comprising amino acid sequence SEQ ID NO. 56 and CDR-H3 comprising amino acid sequence SEQ ID NO. 39; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42;
The VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 55, CDR-H2 comprising amino acid sequence SEQ ID NO. 57 and CDR-H3 comprising amino acid sequence SEQ ID NO. 45; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 46, CDR-L2 comprising amino acid sequence SEQ ID NO. 47 and CDR-L3 comprising amino acid sequence SEQ ID NO. 48;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 49, CDR-H2 comprising amino acid sequence SEQ ID NO. 50 and CDR-H3 comprising amino acid sequence SEQ ID NO. 3; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 4, CDR-L2 comprising amino acid sequence SEQ ID NO. 5 and CDR-L3 comprising amino acid sequence SEQ ID NO. 6;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 183, CDR-H2 comprising amino acid sequence SEQ ID NO. 184 and CDR-H3 comprising amino acid sequence SEQ ID NO. 179; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 180, CDR-L2 comprising amino acid sequence SEQ ID NO. 181 and CDR-L3 comprising amino acid sequence SEQ ID NO. 182;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 239 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228;
The VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 240, CDR-H2 comprising amino acid sequence SEQ ID NO. 241 and CDR-H3 comprising amino acid sequence SEQ ID NO. 242; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 243 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 234, CDR-L2 comprising amino acid sequence SEQ ID NO. 235 and CDR-L3 comprising amino acid sequence SEQ ID NO. 236;
the VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 238, CDR-H2 comprising amino acid sequence SEQ ID NO. 243 and CDR-H3 comprising amino acid sequence SEQ ID NO. 233; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 16, CDR-L2 comprising amino acid sequence SEQ ID NO. 17 and CDR-L3 comprising amino acid sequence SEQ ID NO. 228; or (b)
The VH domain comprises: CDR-H1 comprising amino acid sequence SEQ ID NO. 240, CDR-H2 comprising amino acid sequence SEQ ID NO. 244 and CDR-H3 comprising amino acid sequence SEQ ID NO. 242; and wherein the VL domain comprises: CDR-L1 comprising amino acid sequence SEQ ID NO. 40, CDR-L2 comprising amino acid sequence SEQ ID NO. 41 and CDR-L3 comprising amino acid sequence SEQ ID NO. 42.
69. The fusion protein of any one of claims 61-63, 67, and 68, wherein:
the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 62, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 63; optionally, the VH domain comprises the amino acid sequence SEQ ID NO. 62 and the VL domain comprises the amino acid sequence SEQ ID NO. 63;
the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 64, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 65; optionally, the VH domain comprises the amino acid sequence SEQ ID NO. 64 and the VL domain comprises the amino acid sequence SEQ ID NO. 65;
the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 66, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 67; optionally, the VH domain comprises the amino acid sequence SEQ ID NO:66 and the VL domain comprises the amino acid sequence SEQ ID NO:67;
The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 68, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 69; optionally, the VH domain comprises the amino acid sequence SEQ ID No. 68 and the VL domain comprises the amino acid sequence SEQ ID No. 69;
the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 70, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 71; optionally, the VH domain comprises the amino acid sequence SEQ ID NO:70 and the VL domain comprises the amino acid sequence SEQ ID NO:71;
the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 72, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 73; optionally, the VH domain comprises the amino acid sequence SEQ ID NO:72 and the VL domain comprises the amino acid sequence SEQ ID NO:73;
The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 185, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 186; optionally, the VH domain comprises the amino acid sequence SEQ ID NO:185 and the VL domain comprises the amino acid sequence SEQ ID NO:186;
the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 245, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 246; optionally, the VH domain comprises the amino acid sequence SEQ ID NO. 245 and the VL domain comprises the amino acid sequence SEQ ID NO. 246;
the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 251, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 252; optionally, the VH domain comprises the amino acid sequence SEQ ID NO. 251 and the VL domain comprises the amino acid sequence SEQ ID NO. 252;
The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 253, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 254; optionally, the VH domain comprises amino acid sequence SEQ ID No. 253 and the VL domain comprises amino acid sequence SEQ ID No. 254;
the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 247, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 248; optionally, the VH domain comprises the amino acid sequence SEQ ID No. 247 and the VL domain comprises the amino acid sequence SEQ ID No. 248;
the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 249, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 250; optionally the VH domain comprises the amino acid sequence SEQ ID No. 249 and the VL domain comprises the amino acid sequence SEQ ID No. 250;
The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 255, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID No. 256; or optionally, the VH domain comprises the amino acid sequence SEQ ID No. 255 and the VL domain comprises the amino acid sequence SEQ ID No. 256; or (b)
The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 257, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO 258; optionally, the VH domain comprises the amino acid sequence SEQ ID NO:257 and the VL domain comprises the amino acid sequence SEQ ID NO:258.
70. The fusion protein of any one of claims 60-69, wherein one or both of the antibody heavy chain polypeptides comprises the following amino acid substitutions: L234A, L a and G237A, numbered according to EU index.
71. The fusion protein of any one of claims 60-70, wherein a first one of the antibody heavy chain polypeptides comprises amino acid substitutions Y349C and T366W and a second one of the antibody heavy chain polypeptides comprises amino acid substitutions S354C, T366S, L368A and Y407V, numbered according to the EU index.
72. The fusion protein of any one of claims 53-59, wherein the first portion comprises one or two antibody heavy chain polypeptides and one or two antibody light chain polypeptides.
73. The fusion protein of any one of claims 53-59, wherein the first portion comprises a single chain antibody or single chain variable fragment (scFv).
74. The fusion protein of any one of claims 53-59, wherein the first moiety comprises a VHH antibody.
75. The fusion protein of any one of claims 53-74, wherein the second portion comprises an IL-2 polypeptide.
76. The fusion protein of claim 75, wherein the IL-2 polypeptide is a mutant IL-2 polypeptide comprising one or more mutations relative to a human IL-2 polypeptide comprising sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 81).
77. The fusion protein of claim 76, wherein the binding affinity of the mutant IL-2 polypeptide for IL-2 ra is reduced by 50% or more compared to the binding affinity of a wild-type IL-2 polypeptide comprising sequence SEQ ID:81 for IL-2 ra.
78. The fusion protein of claim 77, wherein the binding affinity of the mutant IL-2 polypeptide to IL-2rβ is reduced by 50% or more compared to the binding affinity of a wild-type IL-2 polypeptide comprising sequence SEQ ID:81 to IL-2rβ; and/or
Wherein the binding affinity of the mutant IL-2 polypeptide for IL-2 Rgamma is reduced by 50% or more compared to the binding affinity of a wild-type IL-2 polypeptide comprising the sequence SEQ ID 81 for IL-2 Rgamma.
79. The fusion protein of any one of claims 63-78, wherein the IL-2 polypeptide comprises the sequence of SEQ ID No. 81 having one, two, three, four or five amino acid substitutions relative to SEQ ID No. 81, and wherein the one, two, three, four or five substitutions comprise a substitution at a position of SEQ ID No. 81 selected from the group consisting of: q11, H16, L18, L19, D20, Q22, R38, F42, K43, Y45, E62, P65, E68, V69, L72, D84, S87, N88, V91, I92, T123, Q126, S127, I129, and S130.
80. The fusion protein of claim 79, wherein the IL-2 polypeptide comprises the sequence of SEQ ID No. 81 having one of the following sets of amino acid substitutions (relative to sequence SEQ ID No. 81): R38E and F42A; R38D and F42A; F42A and E62Q; R38A and F42K; R38E, F a and N88S; R38E, F a and N88A; R38E, F a and N88G; R38E, F a and N88R; R38E, F a and N88T; R38E, F a and N88D; R38E, F a and V91E; R38E, F a and D84H; R38E, F a and D84K; R38E, F a and D84R; H16D, R E and F42A; H16E, R E and F42A; R38E, F a and Q126S; R38D, F a and N88S; R38D, F a and N88A; R38D, F a and N88G; R38D, F a and N88R; R38D, F a and N88T; R38D, F a and N88D; R38D, F a and V91E; R38D, F a and D84H; R38D, F a and D84K; R38D, F a and D84R; H16D, R D and F42A; H16E, R D and F42A; R38D, F a and Q126S; R38A, F K and N88S; R38A, F K and N88A; R38A, F K and N88G; R38A, F K and N88R; R38A, F K and N88T; R38A, F K and N88D; R38A, F K and V91E; R38A, F K and D84H; R38A, F K and D84K; R38A, F K and D84R; H16D, R a and F42K; H16E, R a and F42K; R38A, F K and Q126S; F42A, E Q and N88S; F42A, E Q and N88A; F42A, E Q and N88G; F42A, E Q and N88R; F42A, E Q and N88T; F42A, E Q and N88D; f42A, E Q and V91E; F42A, E Q and D84H; F42A, E Q and D84K; and F42A, E Q and D84R.
81. The fusion protein of claim 79, wherein the IL-2 polypeptide comprises the sequence of SEQ ID No. 81 having another amino acid substitution at position C125 relative to SEQ ID No. 81.
82. The method of claim 81, wherein the IL-2 polypeptide comprises the sequence of SEQ ID No. 81 having one of the following sets of amino acid substitutions (relative to sequence SEQ ID No. 81): R38E, F a and C125A; R38D, F a and C125A; F42A, E Q and C125A; R38A, F K and C125A; R38E, F42A, N S and C125A; R38E, F42A, N a and C125A; R38E, F42A, N G and C125A; R38E, F42A, N R and C125A; R38E, F42A, N D and C125A; R38E, F42A, N T and C125A; R38E, F, 42, A, V E and C125A; R38E, F42A, D H and C125A; R38E, F42A, D K and C125A; R38E, F42A, D R and C125A; H16D, R E, F a and C125A; H16E, R E, F a and C125A; R38E, F42A, C a and Q126S; R38D, F42A, N S and C125A; R38D, F42A, N a and C125A; R38D, F42A, N G and C125A; R38D, F42A, N R and C125A; R38D, F42A, N T and C125A; R38D, F42A, N D and C125A; R38D, F, 42, A, V E and C125A; R38D, F42A, D H and C125A; R38D, F42A, D K and C125A; R38D, F42A, D R and C125A; H16D, R D, F a and C125A; H16E, R D, F a and C125A; R38D, F42A, C a and Q126S; R38A, F42K, N S and C125A; R38A, F42K, N G and C125A; R38A, F42K, N R and C125A; R38A, F42K, N T and C125A; R38A, F42K, N D and C125A; R38A, F42K, N a and C125A; R38A, F, 42, K, V E and C125A; R38A, F42K, D H and C125A; R38A, F42K, D K and C125A; R38A, F42K, D R and C125A; H16D, R A, F K and C125A; H16E, R A, F K and C125A; R38A, F42K, C a and Q126S; F42A, E62Q, N S and C125A; F42A, E62Q, N a and C125A; F42A, E62Q, N G and C125A; F42A, E62Q, N88R and C125A; F42A, E62Q, N T and C125A; F42A, E62Q, N88D and C125A; F42A, E62Q, V E and C125A; F42A, E Q and D84H and C125A; F42A, E Q and D84K and C125A; F42A, E Q and D84R and C125A; H16D, F a and E62Q and C125A; H16E, F, 42, A, E Q and C125A; F42A, E62Q, C a and Q126S; F42A, N S and C125A; F42A, N a and C125A; F42A, N G and C125A; F42A, N R and C125A; F42A, N T and C125A; F42A, N D and C125A; F42A, V91E and C125A; F42A, D H and C125A; F42A, D K and C125A; F42A, D R and C125A; H16D, F a and C125A; H16E, F a and C125A; and F42A, C125A and Q126S.
83. The fusion protein of any one of claims 63-78, wherein the IL-2 polypeptide comprises sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 80) or sequence APTSSSTKKTQLQLEELLLDLQMILN GINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLN LAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFL NRWITFAQSIISTLT (SEQ ID NO: 297).
84. The fusion protein of any one of claims 75-78, wherein the IL-2 polypeptide comprises a sequence selected from the group consisting of seq id nos: SEQ ID NOS 80, 85-155, 190-216, 297 and 354-383.
85. The fusion protein of any one of claims 53-74, wherein the second portion comprises a polypeptide that induces signaling via IL2rβγ.
86. The fusion protein of any one of claims 53-74, wherein the second portion comprises an IL-21 polypeptide.
87. The fusion protein of any one of claims 60-86, wherein one or both of the antibody Fc domains comprises a human IgG1 Fc domain with the following amino acid substitutions: L234A, L a and G237A, numbered according to EU index; optionally, the one or both of the antibody Fc domains do not have a C-terminal lysine.
88. The fusion protein of any one of claims 60-87, wherein a first of the two Fc domains comprises a human IgG1 Fc domain having amino acid substitutions Y349C and T366W, and a second of the two Fc domains comprises a human IgG1 Fc domain having amino acid substitutions S354C, T366S, L368A and Y407V, numbered according to the EU index; optionally, the one or both of the antibody Fc domains do not have a C-terminal lysine.
89. The fusion protein of any one of claims 53-88, wherein the linker comprises the sequence (GGGS) xGn (SEQ ID NO: 74), (GGGGS) xGn (SEQ ID NO: 75) or (GGGGGS) xGn (SEQ ID NO: 76), S (GGGS) xGn (SEQ ID NO: 386), S (GGGGS) xGn (SEQ ID NO: 387) or S (GGGGGS) xGn (SEQ ID NO: 388), wherein x = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and wherein n = 0, 1, 2 or 3.
90. The fusion protein of any one of claims 53-88, wherein the linker comprises the sequence ggggsggggsgggggs (SEQ ID NO: 79) or SGGGGSGGG GSGGGGS (SEQ ID NO: 389).
91. The fusion protein of any one of claims 53-88, wherein the fusion protein comprises:
one or two light chains comprising the amino acid sequence SEQ ID NO. 156, a heavy chain comprising the amino acid sequence SEQ ID NO. 157 and a heavy chain comprising the amino acid sequence SEQ ID NO. 158;
One or two light chains comprising the amino acid sequence SEQ ID NO. 159, a heavy chain comprising the amino acid sequence SEQ ID NO. 160 and a heavy chain comprising the amino acid sequence SEQ ID NO. 161;
one or two light chains comprising the amino acid sequence SEQ ID NO. 162, a heavy chain comprising the amino acid sequence SEQ ID NO. 163 and a heavy chain comprising the amino acid sequence SEQ ID NO. 164;
one or two light chains comprising the amino acid sequence SEQ ID NO. 165, a heavy chain comprising the amino acid sequence SEQ ID NO. 166 and a heavy chain comprising the amino acid sequence SEQ ID NO. 167;
one or two light chains comprising the amino acid sequence SEQ ID NO. 168, a heavy chain comprising the amino acid sequence SEQ ID NO. 169 and a heavy chain comprising the amino acid sequence SEQ ID NO. 170;
one or two light chains comprising the amino acid sequence SEQ ID NO. 171, a heavy chain comprising the amino acid sequence SEQ ID NO. 172 and a heavy chain comprising the amino acid sequence SEQ ID NO. 173;
one or two light chains comprising the amino acid sequence SEQ ID NO. 174, a heavy chain comprising the amino acid sequence SEQ ID NO. 175 and a heavy chain comprising the amino acid sequence SEQ ID NO. 176;
one or two light chains comprising the amino acid sequence SEQ ID NO. 187, a heavy chain comprising the amino acid sequence SEQ ID NO. 188 and a heavy chain comprising the amino acid sequence SEQ ID NO. 189;
One or two light chains comprising the amino acid sequence SEQ ID NO. 298, a heavy chain comprising the amino acid sequence SEQ ID NO. 299 and a heavy chain comprising the amino acid sequence SEQ ID NO. 300;
one or two light chains comprising the amino acid sequence SEQ ID NO. 302, a heavy chain comprising the amino acid sequence SEQ ID NO. 303 and a heavy chain comprising the amino acid sequence SEQ ID NO. 304;
one or two light chains comprising amino acid sequence SEQ ID NO. 306, a heavy chain comprising amino acid sequence SEQ ID NO. 307 and a heavy chain comprising amino acid sequence SEQ ID NO. 308;
one or two light chains comprising the amino acid sequence SEQ ID NO. 310, a heavy chain comprising the amino acid sequence SEQ ID NO. 311 and a heavy chain comprising the amino acid sequence SEQ ID NO. 312;
one or two light chains comprising the amino acid sequence SEQ ID NO. 314, a heavy chain comprising the amino acid sequence SEQ ID NO. 315 and a heavy chain comprising the amino acid sequence SEQ ID NO. 316;
one or two light chains comprising the amino acid sequence SEQ ID NO. 318, a heavy chain comprising the amino acid sequence SEQ ID NO. 319 and a heavy chain comprising the amino acid sequence SEQ ID NO. 320;
one or two light chains comprising the amino acid sequence SEQ ID NO. 322, a heavy chain comprising the amino acid sequence SEQ ID NO. 323 and a heavy chain comprising the amino acid sequence SEQ ID NO. 324;
One or two light chains comprising the amino acid sequence SEQ ID NO. 326, a heavy chain comprising the amino acid sequence SEQ ID NO. 327 and a heavy chain comprising the amino acid sequence SEQ ID NO. 328;
one or two light chains comprising the amino acid sequence SEQ ID NO. 330, a heavy chain comprising the amino acid sequence SEQ ID NO. 331 and a heavy chain comprising the amino acid sequence SEQ ID NO. 332;
one or two light chains comprising the amino acid sequence SEQ ID NO. 334, a heavy chain comprising the amino acid sequence SEQ ID NO. 335 and a heavy chain comprising the amino acid sequence SEQ ID NO. 336;
one or two light chains comprising the amino acid sequence SEQ ID NO. 338, a heavy chain comprising the amino acid sequence SEQ ID NO. 339 and a heavy chain comprising the amino acid sequence SEQ ID NO. 340;
one or two light chains comprising the amino acid sequence SEQ ID NO. 342, a heavy chain comprising the amino acid sequence SEQ ID NO. 343 and a heavy chain comprising the amino acid sequence SEQ ID NO. 344;
one or two light chains comprising the amino acid sequence SEQ ID NO. 346, a heavy chain comprising the amino acid sequence SEQ ID NO. 347 and a heavy chain comprising the amino acid sequence SEQ ID NO. 348;
one or two light chains comprising the amino acid sequence SEQ ID NO. 350, a heavy chain comprising the amino acid sequence SEQ ID NO. 351 and a heavy chain comprising the amino acid sequence SEQ ID NO. 352;
One or two light chains comprising the amino acid sequence SEQ ID NO. 156, a heavy chain comprising the amino acid sequence SEQ ID NO. 157 and a heavy chain comprising the amino acid sequence SEQ ID NO. 217;
one or two light chains comprising the amino acid sequence SEQ ID NO. 159, a heavy chain comprising the amino acid sequence SEQ ID NO. 160 and a heavy chain comprising the amino acid sequence SEQ ID NO. 218;
one or two light chains comprising the amino acid sequence SEQ ID NO. 162, a heavy chain comprising the amino acid sequence SEQ ID NO. 163 and a heavy chain comprising the amino acid sequence SEQ ID NO. 219;
one or two light chains comprising the amino acid sequence SEQ ID NO. 165, a heavy chain comprising the amino acid sequence SEQ ID NO. 166 and a heavy chain comprising the amino acid sequence SEQ ID NO. 220;
one or two light chains comprising the amino acid sequence SEQ ID NO. 168, a heavy chain comprising the amino acid sequence SEQ ID NO. 169 and a heavy chain comprising the amino acid sequence SEQ ID NO. 221;
one or two light chains comprising the amino acid sequence SEQ ID NO. 171, a heavy chain comprising the amino acid sequence SEQ ID NO. 172 and a heavy chain comprising the amino acid sequence SEQ ID NO. 222;
one or two light chains comprising the amino acid sequence SEQ ID NO. 174, a heavy chain comprising the amino acid sequence SEQ ID NO. 175 and a heavy chain comprising the amino acid sequence SEQ ID NO. 223;
One or two light chains comprising the amino acid sequence SEQ ID NO. 187, a heavy chain comprising the amino acid sequence SEQ ID NO. 188 and a heavy chain comprising the amino acid sequence SEQ ID NO. 224;
one or two light chains comprising the amino acid sequence SEQ ID NO. 298, a heavy chain comprising the amino acid sequence SEQ ID NO. 299 and a heavy chain comprising the amino acid sequence SEQ ID NO. 301;
one or two light chains comprising the amino acid sequence SEQ ID NO. 302, a heavy chain comprising the amino acid sequence SEQ ID NO. 303 and a heavy chain comprising the amino acid sequence SEQ ID NO. 305;
one or two light chains comprising amino acid sequence SEQ ID NO. 306, a heavy chain comprising amino acid sequence SEQ ID NO. 307 and a heavy chain comprising amino acid sequence SEQ ID NO. 309;
one or two light chains comprising the amino acid sequence SEQ ID NO. 310, a heavy chain comprising the amino acid sequence SEQ ID NO. 311 and a heavy chain comprising the amino acid sequence SEQ ID NO. 313;
one or two light chains comprising the amino acid sequence SEQ ID NO. 314, a heavy chain comprising the amino acid sequence SEQ ID NO. 315 and a heavy chain comprising the amino acid sequence SEQ ID NO. 317;
one or two light chains comprising the amino acid sequence SEQ ID NO. 318, a heavy chain comprising the amino acid sequence SEQ ID NO. 319 and a heavy chain comprising the amino acid sequence SEQ ID NO. 321;
One or two light chains comprising the amino acid sequence SEQ ID NO. 322, a heavy chain comprising the amino acid sequence SEQ ID NO. 323 and a heavy chain comprising the amino acid sequence SEQ ID NO. 325;
one or two light chains comprising the amino acid sequence SEQ ID NO. 326, a heavy chain comprising the amino acid sequence SEQ ID NO. 327 and a heavy chain comprising the amino acid sequence SEQ ID NO. 329;
one or two light chains comprising the amino acid sequence SEQ ID NO. 330, a heavy chain comprising the amino acid sequence SEQ ID NO. 331 and a heavy chain comprising the amino acid sequence SEQ ID NO. 333;
one or two light chains comprising the amino acid sequence SEQ ID NO. 334, a heavy chain comprising the amino acid sequence SEQ ID NO. 335 and a heavy chain comprising the amino acid sequence SEQ ID NO. 337;
one or two light chains comprising the amino acid sequence SEQ ID NO. 338, a heavy chain comprising the amino acid sequence SEQ ID NO. 339 and a heavy chain comprising the amino acid sequence SEQ ID NO. 341;
one or two light chains comprising the amino acid sequence SEQ ID NO. 342, a heavy chain comprising the amino acid sequence SEQ ID NO. 343 and a heavy chain comprising the amino acid sequence SEQ ID NO. 345;
one or two light chains comprising the amino acid sequence SEQ ID NO. 346, a heavy chain comprising the amino acid sequence SEQ ID NO. 347 and a heavy chain comprising the amino acid sequence SEQ ID NO. 349; or (b)
One or two light chains comprising the amino acid sequence SEQ ID NO. 350, a heavy chain comprising the amino acid sequence SEQ ID NO. 351 and a heavy chain comprising the amino acid sequence SEQ ID NO. 353.
92. A fusion protein comprising a first portion that binds to human CD8b and a second portion comprising an IL2 polypeptide, wherein the fusion protein comprises four polypeptide chains, wherein:
the first polypeptide chain comprises the amino acid sequence SEQ ID NO. 334, the second polypeptide chain comprises the amino acid sequence SEQ ID NO. 335, the third polypeptide chain comprises the amino acid sequence SEQ ID NO. 336, and the fourth polypeptide chain comprises the amino acid sequence SEQ ID NO. 334;
the first polypeptide chain comprises the amino acid sequence SEQ ID NO. 334, the second polypeptide chain comprises the amino acid sequence SEQ ID NO. 335, the third polypeptide chain comprises the amino acid sequence SEQ ID NO. 337, and the fourth polypeptide chain comprises the amino acid sequence SEQ ID NO. 334;
the first polypeptide chain comprises the amino acid sequence SEQ ID NO. 338, the second polypeptide chain comprises the amino acid sequence SEQ ID NO. 339, the third polypeptide chain comprises the amino acid sequence SEQ ID NO. 340, and the fourth polypeptide chain comprises the amino acid sequence SEQ ID NO. 338; or (b)
The first polypeptide chain comprises the amino acid sequence SEQ ID NO. 338, the second polypeptide chain comprises the amino acid sequence SEQ ID NO. 339, the third polypeptide chain comprises the amino acid sequence SEQ ID NO. 341, and the fourth polypeptide chain comprises the amino acid sequence SEQ ID NO. 338.
93. One or more polynucleotides encoding the antibody or fusion protein of any one of claims 1-92.
94. One or more vectors comprising one or more polynucleotides of claim 93.
95. The one or more vectors of claim 94, wherein the vector is an expression vector.
96. An isolated host cell comprising one or more polynucleotides or vectors of any one of claims 93-95.
97. A method of producing an antibody or fusion protein comprising culturing the host cell of claim 96 under conditions suitable for production of the antibody or fusion protein.
98. The method of claim 97, further comprising recovering the antibody or fusion protein from the host cell.
99. A pharmaceutical composition comprising the antibody or fusion protein of any one of claims 1-92 and a pharmaceutically acceptable carrier.
100. The antibody or fusion protein of any one of claims 1-92 for use as a medicament.
101. A method of treating cancer, the method comprising administering to an individual having cancer an effective amount of the antibody or fusion protein of any one of claims 1-92 or the composition of claim 99.
102. The method of claim 101, further comprising administering to the individual a T cell therapy, a cancer vaccine, a chemotherapeutic agent, or an Immune Checkpoint Inhibitor (ICI).
103. A method as in claim 102 wherein the ICI is a PD-1, PD-L1 or CTLA-4 inhibitor.
104. The method of claim 102, wherein the T cell therapy comprises Chimeric Antigen Receptor (CAR) based T cell therapy, tumor Infiltrating Lymphocyte (TIL) based therapy, or therapy using T cells bearing a transduced TCR.
105. The antibody or fusion protein of any one of claims 1-92 for use in a method of treating cancer, the method comprising administering an effective amount of the antibody or fusion protein to an individual having cancer.
106. A method of treating an infection, the method comprising administering to an individual in need thereof an effective amount of the antibody or fusion protein of any one of claims 1-92 or the composition of claim 99.
107. The method of claim 106, wherein the infection is a viral infection.
108. Use of the antibody or fusion protein of any one of claims 1-92 in the manufacture of a medicament for the treatment of cancer or chronic infection.
109. A method of expanding T cells ex vivo, the method comprising contacting one or more T cells ex vivo with an effective amount of the antibody or fusion protein of any one of claims 1-92 or the composition of claim 99.
110. The method of claim 109, wherein the one or more T cells are Tumor Infiltrating Lymphocytes (TILs).
CN202180084033.7A 2020-10-23 2021-10-22 Fusion comprising CD8 antigen binding molecules that modulate immune cell function Pending CN116997362A (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US63/105,162 2020-10-23
US63/121,663 2020-12-04
US202163190669P 2021-05-19 2021-05-19
US63/190,669 2021-05-19
PCT/US2021/056312 WO2022087458A1 (en) 2020-10-23 2021-10-22 Fusions with cd8 antigen binding molecules for modulating immune cell function

Publications (1)

Publication Number Publication Date
CN116997362A true CN116997362A (en) 2023-11-03

Family

ID=88527072

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202180084033.7A Pending CN116997362A (en) 2020-10-23 2021-10-22 Fusion comprising CD8 antigen binding molecules that modulate immune cell function

Country Status (1)

Country Link
CN (1) CN116997362A (en)

Similar Documents

Publication Publication Date Title
US11084863B2 (en) Targeted heterodimeric Fc fusion proteins containing IL-15 IL-15alpha and antigen binding domains
US20220251202A1 (en) Fusions of mutant interleukin-2 polypeptides with antigen binding molecules for modulating immune cell function
US11001633B2 (en) NK cell engaging antibody fusion constructs
JP2023051968A (en) Multispecific nkp46 binding proteins
EP3464367A1 (en) Bispecific binding proteins binding an immunomodulatory protein and a tumor antigen
KR20230112632A (en) Fusion with CD8 antigen binding molecules to modulate immune cell function
JP2022513432A (en) Bispecific antibodies for immune cell activation
CN102958942A (en) Heterodimer binding proteins and uses thereof
CA3145387A1 (en) Fusion proteins comprising a ligand-receptor pair and a biologically functional protein
CN114127112A (en) Multifunctional molecules that bind to T cells and their use to treat autoimmune disorders
JP2023547506A (en) Combination therapy of anti-CD19 agents and B-cell targeting agents to treat B-cell malignancies
CN116997362A (en) Fusion comprising CD8 antigen binding molecules that modulate immune cell function
US20240010695A1 (en) Fusions of mutant interleukin-10 polypeptides with antigen binding molecules for modulating immune cell function
US20230357343A1 (en) Il-21 polypeptides and targeted constructs
CN116829577A (en) Fusion of mutant interleukin-10 polypeptides with antigen binding molecules for modulating immune cell function
TW202400664A (en) Combination of cytokine fusion proteins with cd8 antigen binding molecules
JP2024522069A (en) IL-21 Polypeptides and Targeting Constructs

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination