Stable polypeptides that bind to human complement c5

Abstract

FIELD: biotechnology.SUBSTANCE: invention relates to biotechnology, specifically to polynucleotides encoding polypeptides capable of binding human complement component 5 (C5), and can be used for recombinant production of such polypeptides. Encoded by the disclosed polynucleotide polypeptide has an amino acid sequence [BM]-[L2]-QSSELLSEAKKLX52X53X54Q, where [BM] is a C5-binding motif, [L2] is selected from DDPS and RQPE, and X52X53X54 is SES, ESS, NES or SDS. Invention also discloses a vector and a host cell for expression of polypeptide capable of binding C5.EFFECT: invention enables to obtain C5-binding polypeptides with improved stability without loss of their C5 binding affinity.21 cl, 7 dwg, 9 tbl, 9 ex

Description

[0001] FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0002] The present invention relates to polypeptides that bind to human complement component 5 (C5) and to the use of such polypeptides in therapy.

[0003] PRIOR ART

[0004] Complement protein C5 is a central component of the complement system, a core part of the innate immune system. The complement system is a complex immune surveillance system with multiple tasks in tightly controlled, heterogeneous processes. It functions as the host's first line of immune defense against infection by other organisms, as well as in distinguishing healthy body tissues from cellular debris and apoptotic and necrotic cells. Furthermore, it is involved in the clearance of immune complexes, regulation of the adaptive immune response, initiation of tissue regeneration, angiogenesis, stem cell mobilization, and central nervous system development (Woodruffet al. Mol Immunol 2011, 48 (14):1631–1642); Ricklinet al. Nat Immunol 2010, 11 (9): 785–795).Any triggering event, such as erroneous or unrestricted activation or deficient regulation, that disrupts the precise balance of complement activation and regulation can lead to pathological conditions involving an attack on the body's own immune cells, resulting in extensive tissue damage.

[0005] The complement system consists of approximately 30 proteins. There are three pathways for complement initiation: the classical pathway, which uses C1q to recognize immune complexes on the cell surface; the lectin pathway, which is initiated when mannose-binding lectin (MBL) recognizes certain sugars; and the alternative pathway, which is spontaneously initiated through the hydrolysis of complement factor 3 (C3), a process inhibited by certain mammalian cell surface molecules not present on invasive pathogens. The alternative pathway also acts as an amplification shunt for the complement system. All three pathways converge at the level of C3. Cleavage of C3 into C3a and C3b leads to the formation of convertase, which in turn cleaves complement factor 5 (C5) into C5a and C5b.C5a is a very potent attractant of various immune cells, while C5b oligomerizes with C6-9 to form a pore known as the membrane attack complex (MAC) or, sometimes, the terminal complement cascade (TCC). Activation of the complement system leads to a number of mechanisms with the aim of neutralizing the pathogen: formation of MAC on the surface of cells such as invading bacteria leads to lysis, deposition of C3 and C4 cleavage products, C3b and C4b, promotes opsonization leading to phagocytosis of the pathogen by macrophages, and anaphylatoxins such as C3a and C5a attract monocytes and neutrophils to the site of activation, upregulate surface markers, leading to increased immunological susceptibility and the release of cytokines.

[0006] C5 is a 190-kDa glycoprotein consisting of two disulfide-linked polypeptide chains, alpha and beta, with molecular weights of 115 and 75 kDa, respectively (Tacket al. Biochem 1979, 18:1490-1497). Haviland et al. (J Immun 1991, 146: 362-368) constructed the complete cDNA sequence of human complement pro-C5, which is predicted to encode a 1676-amino acid pro-molecule that contains an 18-amino acid leader peptide and a 4-amino acid linker separating the beta and alpha chains (SEQ ID NO: 251). Because C5 is common to all complement activation pathways, blocking C5 stops the progression of the cascade regardless of stimuli and thus prevents the damaging properties of terminal complement activation, while leaving the immunoprotective and immunoregulatory functions of the proximal complement cascade intact.

[0007] The key role of the complement system in defense against pathogens generally makes it an interesting target for pharmaceutical intervention. This is reinforced by the fact that many mutations or impaired regulation of complement are implicated in various diseases and conditions. The latter include increased susceptibility to autoimmune diseases such as systemic lupus erythematosus (SLE), where immune complex deposition triggers the classical pathway (Manderson et al. Annu Rev Immunol 2004, 22:431-456). Additionally, mutations in complement proteins C1-C5 often result in SLE or SLE-like symptoms. Other autoimmune diseases with strong complement involvement are rheumatoid arthritis (RA), where immune complexes can activate complement in the RA-affected joint, Sjögren's syndrome, dermatomyositis, and other autoimmune antibody-driven diseases such as Guillain-Barré syndrome (GBS), Fisher syndrome (Kaidaet al. J.Neuroimmun 2010, 223:5-12), various types of vasculitis, systemic sclerosis, pulmonary hemosiderosis with glomerulonephritis (anti-GBM nephritis), and antiphospholipid syndrome (APS) (Chenet al. J Autoimmun 2010, 34:J276-J286). Furthermore, complement inhibition has been shown to be effective in animal models of conditions as diverse as periodontitis (Abe et al. J Immunol 2012, 189:5442–5448), wound healing (Cazender et al. Clin Dev Immunol 2012, published online), tumor growth (Markiewski et al. Nat Immunol 2008, 9:1225–1235), and ocular diseases such as uveitis and age-related macular degeneration (AMD) (Copland et al. Clin Exp Immunol 2009, 159:303–314).

[0008] Antibodies targeting human complement C5 are known from, for example, WO 95 / 29697; WO 02 / 30985; and WO 2004 / 007553. Eculizumab (Soliris™) is a humanized monoclonal antibody directed against the C5 protein and prevents the cleavage of C5 into C5a and C5b. Eculizumab has been shown to be effective in the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare and sometimes life-threatening blood disorder characterized by intravascular hemolytic anemia, thrombophilia, and bone marrow failure, And approved for this indication. Eculizumab was also recently approved by the FDA for the treatment of atypical hemolytic syndrome (AHS), a rare but life-threatening disorder caused by loss of control of the alternative complement pathway, leading to overactivation manifesting as thrombotic microangiopathy (TMA), resulting in persistent risk of damage to vital organs such as the kidney, heart, and brain. In AHS, transplantation of the damaged organ only temporarily helps the patient, as the liver continues to produce a mutated form of the control protein (most commonly, complement factor H or other alternative pathway proteins). A related disorder with transient acute pathophysiology is Shiga toxin-positive E. coli infection-associated US (STEC-HUS), and there are encouraging clinical data suggesting efficacy for this condition as well (Lapeyraque et al, N Engl J Med 2011, 364:2561–2563).Finally, the C5-blocking antibody eculizumab has been shown to be effective in preventing antibody-mediated rejection (AMR) in recipients with highly mismatched kidneys (Stegall, MDet al. Am J Transplant 2011, 11:2405-2413) and in treating autoimmune neuropathies such as neuromyelitis optica and myasthenia gravis (Pittocket al. Lancet Neurol 2013, 12:554-562; Howardet al. Muscle Nerve 2013, 48:76-84).

[0009] In addition to full-length antibodies, single-chain variable fragments (scFV), minibodies, and aptamers targeting C5 have been described in the literature. These C5 inhibitors can bind to different sites (epitopes) on the C5 molecule and may have different mechanisms of action. For example, while eculizumab interacts with C5 at a distance from the convertase cleavage site, the minibody Mubodina® interacts with the C5 cleavage site. The Ornithodoros moubata Complement Inhibitor C5 (OmCI, Nunn, MA et al. J Immunol 2005, 174:2084-2091) protein from the soft tick Ornithodoros moubata is predicted to bind to the distal end of the CUB-C5d-MG8 superdomain, which is close to the convertase cleavage site (Fredslundet al. Nat Immunol 2008, 9 (7):753-760).Unlike the three proteins mentioned above that inhibit C5 cleavage, the monoclonal antibody TNX-558 binds to a C5a epitope present on both intact C5 and released C5a without inhibiting C5 cleavage. (Funget al. Clin Exp Immunol 2003, 133 (2):160-169).

[0010] C5-binding polypeptides comprising a C5-binding motif are disclosed in International Patent Application No. PCT / SE2013 / 050139, published as WO 2013 / 126006. In particular, WO 2013 / 126006 discloses a C5-binding motif, BM, consisting of the amino acid sequence

[0011] EX2X3X4A X6X7EID X 11 LPNL X 16 X 17 X 18 QW X 21 AFIX 25 X 26 LX 28 D,

[0012] where, independently of each other,

[0013] X2 is selected from H, Q, S, T and V;

[0014] X3 choose from I, L, M and V;

[0015] X4 choose from A, D, E, H, K, L, N, Q, R, S, T and Y;

[0016] X6 is selected from N and W;

[0017] X7 is selected from A, D, E, H, N, Q, R, S and T;

[0018] X 11 selected from A, E, G, H, K, L, Q, R, S, T and Y;

[0019] X 16 choose from N and T;

[0020] X 17 choose from I, L and V;

[0021] X 18 select from A, D, E, H, K, N, Q, R, S and T;

[0022] X 21 choose from I, L and V;

[0023] X 25 select from D, E, G, H, N, S and T;

[0024] X 26 choose from K and S; and

[0025] X 28 select from A, D, E, H, N, Q, S, T and Y.

[0026] Examples of specific C5-binding motifs, as previously disclosed in WO 2013 / 126006, are shown as SEQ ID NO: 1-248 in the present patent application.

[0027] It is known from WO 2013 / 126006 that such additional peptides or polypeptides can improve the stabilization of C5-binding polypeptides. One example of such a polypeptide is the albumin-binding domain (ABD), shown as SEQ ID NO: 250 herein. Other examples of suitable albumin-binding domains are disclosed in WO 2009 / 016043 and WO 2012 / 004384. The ABD-extended polypeptide binds to serum albumin in vivo and benefits from its longer half-life, which increases the overall half-life of the polypeptide itself (see, for example, WO 91 / 01743).

[0028] Further development of agents with comparable C5-blocking activity remains a topic of significant interest in this field. In particular, there is a continuing need for molecules that prevent the terminal complement cascade, as well as the formation of the proinflammatory molecule C5a. Developing applications for such molecules in disease treatment is also of great interest.

[0029] BRIEF DESCRIPTION OF DRAWINGS

[0030] Fig. 1 illustrates an SDS-PAGE gel where the bands represent the C5-binding compound PSI0242 (SEQ ID NO: 249) (0) before the stability test; and (2w) after the 2-week stability test.

[0031] Fig. 2 is a reversed-phase HPLC chromatogram of PSI0242 (SEQ ID NO: 249) before the stability test (solid line) and after the 2-week stability test (dotted line).

[0032] Fig. 3 illustrates an SDS-PAGE gel, where the first lane contains the SeeBlue 2P size marker, and the bands represent (0) initial samples; and (2w) samples after a 2-week stability test. Fig. 3A: SEQ ID NO: 249; Fig. 3B: SEQ ID NO: 261; Fig. 3C: SEQ ID NO: 262; Fig. 3D: SEQ ID NO: 264.

[0033] Fig. 4 is a reversed-phase HPLC chromatogram of the C5-binding compound (SEQ ID NO: 253) before the stability test (solid line) and after the 2-week stability test (dotted line).

[0034] Fig. 5 is a reversed-phase HPLC chromatogram of the C5-binding compound (SEQ ID NO: 264) before the stability test (solid line) and after the 2-week stability test (dotted line).

[0035] Fig. 6A-D show SDS-PAGE gel images comparing the original and modified polypeptide variants (0) before and (2w) after a 2-week stability test. The molecular size marker (Mw) was Novex ®pre-stained Sharp standard protein (216, 160, 110, 80, 60, 50, 40, 30, 20, 15, 10, 3.5 kDa). Fig. 6A shows a gel with HER2-binding polypeptides, where the lanes show lane 1: Mw, lane 2: (0) Z02891 (SEQ ID NO: 272), lane 3: (2w) Z02891 (SEQ ID NO: 272), lane 4: Mw, lane 5: (0) Z17341 (SEQ ID NO: 273), lane 6: (2w) Z17341 (SEQ ID NO: 273), lane 7: (0) Z17342 (SEQ ID NO: 274), lane 8: (2w) Z17342 (SEQ ID NO: 274). Fig. 6B is a gel with PDGF-Rβ-binding polypeptides, where the lanes show: lane 1: Mw, lane 2: (0) Z15805 (SEQ ID NO: 275), lane 3: (2w) Z15805 (SEQ ID NO: 275), lane 4: Mw, lane 5: (0) Z17343 (SEQ ID NO: 276), lane 6: (2w) Z17343 (SEQ ID NO: 276), lane 7: (0) Z17344 (SEQ ID NO: 277), lane 8: (2w) Z17344 (SEQ ID NO: 277). Fig.6C shows a gel with FcRn-binding polypeptides, where the lanes show: lane 1: (0) Z10103 (SEQ ID NO: 278), lane 2: (2w) Z10103 (SEQ ID NO: 278), lane 3: Mw, lane 4: (0) Z17347 (SEQ ID NO: 279), lane 5: (2w) Z17347 (SEQ ID NO: 279), lane 6: (0) Z17348 (SEQ ID NO: 280), lane 7: (2w) Z17348 (SEQ ID NO: 280). The diagonal bands seen in Fig. 6C are an artifact resulting from a print from a second gel stained in the same container. Fig.6D is a gel with CAIX-binding polypeptides, where the lanes show lane 1: Mw, lane 2: (0) Z09782 (SEQ ID NO: 281), lane 3: (2w) Z09782 (SEQ ID NO: 281), lane 4: Mw, lane 5: (0) Z17351 (SEQ ID NO: 282), lane 6: (2w) Z17351 (SEQ ID NO: 282), lane 7: (0) Z17352 (SEQ ID NO: 283), lane 8: (2w) Z17352 (SEQ ID NO: 283); Lane 9: (0) Z17355 (SEQ ID NO: 284), Lane 10: (2w) Z17355 (SEQ ID NO: 284), Lane 11: (0) Z17357 (SEQ ID NO: 285), Lane 12: (2w) Z17357 (SEQ ID NO: 285), Lane 13: (0) Z17359 (SEQ ID NO: 286), Lane 14: (2w) Z17359 (SEQ ID NO: 286), Lane 15: (0) Z17360 (SEQ ID NO: 287), Lane 16: (2w) Z17360 (SEQ ID NO: 287).

[0036] Fig. 7 is a table showing the amino acid sequences:

[0037] - examples of C5-binding motifs (SEQ ID NO: 1-248);

[0038] - C5-binding compound designated PSI0242 (SEQ NO: 249);

[0039] - albumin-binding domain (SEQ ID NO: 250);

[0040] - human C5 Swiss-Prot P01031 (SEQ ID NO:251), wherein the α-chain corresponds to amino acid residues 678-1676, and the α-chain corresponds to amino acid residues 19-673;

[0041] - examples of modified C5-binding polypeptides (SEQ ID NO: 260, 265-267).

[0042] - examples of modified C5-binding compounds (SEQ ID NO: 252-259, 261-264, 268-270).

[0043] - examples of polypeptide variants with binding affinity for other target molecules (SEQ ID NO: 272, 275, 278, 281)

[0044] - examples of polypeptide variants with improved stability with binding affinity for other targets (SEQ ID NO: 273-274, 276-277, 279-280, 282-287).

[0045] DISCLOSURE OF THE INVENTION

[0046] It was unexpectedly found that C5-binding polypeptides and compounds in which the amino acid sequences were modified at specific positions have improved stability compared to previously known C5-binding polypeptides and compounds.

[0047] Therefore, the present invention provides a polypeptide capable of binding human complement component 5 (C5), wherein said polypeptide is selected from:

[0048] (a) a polypeptide comprising an amino acid sequence

[0049] [BM]-[L2]-QSX 42 X 43 LLX 46 EAKKLX 52 X 53 X 54 Q

[0050] where, independently of each other,

[0051] [BM] represents the C5-binding motif;

[0052] [L2] select from DDPS and RQPE;

[0053] X 42 choose from A and S;

[0054] X 43 choose from N and E;

[0055] X 46 choose from A, S and C;

[0056] X52 choose from E, N and S;

[0057] X 53 choose from D, E and S, provided that X 53 is not

[0058] D when X 52 represents N; and

[0059] X 54 choose from A and S; and

[0060] (b) a polypeptide that has at least 89% amino acid sequence identity with the polypeptide of (a), provided that X 53 is not D when X 52 represents N.

[0061] The inventors have unexpectedly discovered that modification or substitution of amino acid residue(s) at certain position(s) of the amino acid sequence of C5-binding polypeptides, as described in WO 2013 / 126006, improves the stability of the C5-binding polypeptides, while biological activity, such as binding affinity for human complement component 5 (C5) and inhibition of complement pathway function, is maintained substantially the same. Thus, the biological activity of the modified C5-binding polypeptides is comparable to the biological activity of known C5-binding polypeptides. Stability testing of the C5-binding polypeptides of the present invention demonstrates that substitution of either X 52 , N to E or S, or X 53 , from D to E, or S, improves stability. Furthermore, it was found that substituting a specific amino acid in [L2] can independently promote stability.

[0062] The terms “C5 binding” and “binding affinity for C5,” as used herein, refer to a property of a polypeptide that can be tested, for example, by using surface plasmon resonance technology, such as in the Biacore instrument (GE Healthcare). The affinity of C5 binding can, for example, be tested in an experiment in which C5 is immobilized on a sensor chip of the Biacore instrument, and a sample containing the polypeptide to be tested is passed over the chip. Alternatively, the polypeptide to be tested is immobilized on the sensor chip of the instrument, and a sample containing C5, or a fragment thereof, is passed over the chip. A skilled artisan can then interpret the results obtained in such experiments to establish at least a qualitative measure of the binding of the polypeptide to C5. If a quantitative measure is desired, for example, to determine the apparent equilibrium dissociation constant K DSurface plasmon resonance methods can also be used for interactions. Binding values ​​can be determined, for example, on a Biacore 2000 instrument (GE Healthcare). C5 is immobilized on the sensor chip for measurement, and samples of the polypeptide whose affinity is to be determined are prepared by serial dilution and injected over the chip. K values D can then be calculated from the results using, for example, the 1:1 Langmuir binding model from the BIAevaluation software provided by the instrument manufacturer. C5 or its fragment used in determining K D , may, for example, comprise the amino acid sequence represented by SEQ ID NO: 251. Examples of how C5 binding affinity can be tested are provided herein, see Examples 3 and 5.

[0063] In a preferred form of the invention, said polypeptide is selected from

[0064] (a) a polypeptide comprising an amino acid sequence

[0065] AEAKYAK-[BM]-[L2]-QSX 42 X 43 LLX 46 EAKKLX 52 X 53 X 54 QAP

[0066] where, independently of each other,

[0067] [BM], [L2], X 42 , X 43 , X 46 , X 52 , X 53 and X 54 are as defined above;

[0068] and (b) a polypeptide that has at least 90% amino acid sequence identity with the polypeptide of (a), provided that X 53 is not D when X 52 represents N.

[0069] As previously disclosed in WO 2013 / 126006, the C5-binding polypeptide of the invention may form part of a three-helix bundle of a protein domain. Said C5-binding motif [BM] may essentially form part of two alpha helices, with an interconnecting loop, within said three-helix bundle. The second interconnecting loop, referred to herein as [L2], connects the C5-binding motif to the third alpha helix, referred to as the “Backbone”.

[0070] In one embodiment, the C5-binding motif [BM] is substantially as disclosed in WO 2013 / 126006. However, according to the present invention, the C5-binding motif preferably consists of 28 rather than 29 amino acids, and may further carry additional amino acid substitutions.

[0071] Thus, in one embodiment, said [BM] carries at least one additional amino acid substitution, for example at position 17, compared to [BM] as disclosed in WO 2013 / 126006. Thus, said [BM] is a polypeptide selected from:

[0072] (a) a polypeptide comprising an amino acid sequence

[0073] EX9X 10 X 11 AX 13 X 14 EIDX 17 X 18 LPNLX 23 X 24 X 25 QWX 28 AFIX 32 X 33 LX 35 ;

[0074] where, independently of each other,

[0075] X9 is selected from H, Q, S, T and V;

[0076] X 10 choose from I, L, M and V;

[0077] X 11 select from A, D, E, H, K, L, N, Q, R, S, T and Y;

[0078] X 13 choose from N and W;

[0079] X 14 select from A, D, E, H, N, Q, R, S and T;

[0080] X 17 choose from D and E;

[0081] X 18 selected from A, E, G, H, K, L, Q, R, S, T and Y;

[0082] X 23 choose from N and T;

[0083] X 24 choose from I, L and V;

[0084] X 25 select from A, D, E, H, K, N, Q, R, S and T;

[0085] X 28 choose from I, L and V;

[0086] X 32 select from A, D, E, G, H, N, S and T;

[0087] X 33 choose from K and S;

[0088] X 35 selected from A, D, E, H, N, Q, S, T and Y; and

[0089] (b) a polypeptide that has at least 85% amino acid sequence identity with the polypeptide of (a).

[0090] In a preferred embodiment, the C5-binding motif [BM] is essentially as disclosed in WO 2013 / 126006. Said [BM] is, accordingly, a polypeptide selected from:

[0091] (a) a polypeptide comprising an amino acid sequence

[0092] EX9X 10 X 11 AX13 X 14 EIDX 18 LPNLX 23 X 24 X 25 QWX 28 AFIX 32 X 33 LX 35 ;

[0093] where, independently of each other,

[0094] X9 choose from H, Q, S, T and V;

[0095] X 10 choose from I, L, M and V;

[0096] X 11 select from A, D, E, H, K, L, N, Q, R, S, T and Y;

[0097] X 13 choose from N and W;

[0098] X 14 select from A, D, E, H, N, Q, R, S and T;

[0099] X 18 selected from A, E, G, H, K, L, Q, R, S, T and Y;

[0100] X 23 choose from N and T;

[0101] X 24 choose from I, L and V;

[0102] X 25 select from A, D, E, H, K, N, Q, R, S and T;

[0103] X 28 choose from I, L and V;

[0104] X 32 select from D, E, G, H, N, S and T;

[0105] X 33 choose from K and S;

[0106] X 35selected from A, D, E, H, N, Q, S, T and Y; and

[0107] (b) a polypeptide that has at least 85% amino acid sequence identity with the polypeptide of (a).

[0108] In a further preferred aspect, [BM] consists of or comprises an amino acid sequence selected from the group consisting of positions 1-28 in SEQ ID NOS: 1-248. More preferably, [BM] consists of or comprises the amino acid sequence shown as positions 1-28 in SEQ ID NO: 1.

[0109] In a further aspect, the C5-binding polypeptide of the invention is selected from:

[0110] (a) a polypeptide comprising an amino acid sequence

[0111] AEAKYAKEX9X 10 X 11 AX 13 X 14 EIX 17 X 18 LPNLX 23 X 24 X 25 QWX 28 AFIX 32

[0112] X 33 LX 35 -[L2]-QSX 42 X 43 LLX 46EAKKLX 52 X 53 X 54 QAP;

[0113] where, independently of each other,

[0114] X9 is selected from H, Q, S, T and V;

[0115] X 10 choose from I, L, M and V;

[0116] X 11 select from A, D, E, H, K, L, N, Q, R, S, T and Y;

[0117] X 13 choose from N and W;

[0118] X 14 select from A, D, E, H, N, Q, R, S and T;

[0119] X 17 choose from D and E;

[0120] X 18 selected from A, E, G, H, K, L, Q, R, S, T and Y;

[0121] X 23 choose from N and T;

[0122] X 24 choose from I, L and V;

[0123] X 25 select from A, D, E, H, K, N, Q, R, S and T;

[0124] X 28 choose from I, L and V;

[0125] X 32 select from A, D, E, G, H, N, S and T;

[0126] X 33 choose from K and S;

[0127] X 35 select from A, D, E, H, N, Q, S, T and Y;

[0128] [L2] select from DDPS and RQPE;

[0129] X 42 choose from A and S;

[0130] X 43 choose from N and E;

[0131] X 46 choose from A, S and C;

[0132] X 52 choose from E, N and S;

[0133] X 53 choose from D, E and S, provided that X 53 is not

[0134] D when X 52 represents N; and

[0135] X 54 choose from A and S; and

[0136] (b) a polypeptide that has at least 90% amino acid sequence identity with the polypeptide of (a), provided that X 53 is not D when X 52 represents N.

[0137] In a preferred embodiment, the C5-binding polypeptide of the invention is selected from:

[0138] (a) a polypeptide comprising an amino acid sequence

[0139] AEAKYAKEX9X 10 X 11 AX 13 X 14 EIDX 18 LPNLX23 X 24 X 25 QWX 28 AFIX 32 X 33 LX 35 -[L2]-QSX 42 X 43 LLX 46 EAKKLX 52 X 53 X 54 QAP;

[0140] where, independently of each other,

[0141] X9 is selected from H, Q, S, T and V;

[0142] X 10 choose from I, L, M and V;

[0143] X 11 select from A, D, E, H, K, L, N, Q, R, S, T and Y;

[0144] X 13 choose from N and W;

[0145] X 14 select from A, D, E, H, N, Q, R, S and T;

[0146] X 18 selected from A, E, G, H, K, L, Q, R, S, T and Y;

[0147] X 23 choose from N and T;

[0148] X 24 choose from I, L and V;

[0149] X 25 select from A, D, E, H, K, N, Q, R, S and T;

[0150] X 28 choose from I, L and V;

[0151] X 32 select from D, E, G, H, N, S and T;

[0152] X 33 choose from K and S;

[0153] X 35 select from A, D, E, H, N, Q, S, T and Y;

[0154] [L2] select from DDPS and RQPE;

[0155] X 42 choose from A and S;

[0156] X 43 choose from N and E;

[0157] X 46 choose from A, S and C;

[0158] X 52 choose from E, N and S;

[0159] X 53 choose from D, E and S, provided that X 53 is not

[0160] D when X 52 represents N; and

[0161] X 54 choose from A and S; and

[0162] (b) a polypeptide that has at least 90% amino acid sequence identity with the polypeptide of (a), provided that X 53 is not D when X 52 represents N.

[0163] In preferred forms of the invention, at least one of the following eighteen, optionally nineteen, conditions is met:

[0164] X9 is V,

[0165] X 10represents L,

[0166] X 11 represents E,

[0167] X 13 represents W,

[0168] X 14 represents D,

[0169] optional X 17 represents D,

[0170] X 18 represents R,

[0171] X 23 represents T,

[0172] X 24 represents I,

[0173] X 25 represents E,

[0174] X 28 represents L,

[0175] X 32 represents N,

[0176] X 33 represents K,

[0177] X 35 represents D,

[0178] [L2] is DDPS,

[0179] X 42 represents S,

[0180] X 43 represents E,

[0181] X 46 represents S,

[0182] X 54 represents S.

[0183] More preferably, at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, or nineteen of the above conditions are met.

[0184] In the embodiment, X 52 and X 53 independently selected from E and S. Preferably, (a) X 52 represents S, and X 53 represents E, or (b) X 52 represents E, and X 53 represents S.

[0185] In the embodiment, X 52 represents S, and X 53 represents D.

[0186] In another embodiment, X 52 represents N, and X 53 represents E.

[0187] In a further aspect, the polypeptide of the invention comprises the amino acid sequence shown as SEQ ID NO: 260, SEQ ID NO: 265, SEQ ID NO: 266 or SEQ ID NO: 267.

[0188] In a further aspect, a compound capable of binding C5 is provided, said compound comprising:

[0189] (a) at least one C5-binding polypeptide as defined above;

[0190] (b) at least one albumin-binding domain of streptococcal protein G, or a derivative thereof; and

[0191] (c) optionally, at least one binding fragment for binding said at least one albumin-binding domain or derivative thereof to the C or N terminus of said at least one C5-binding polypeptide.

[0192] Preferably, said albumin-binding domain comprises an amino acid sequence shown as SEQ ID NO: 250.

[0193] Preferably, said binding fragment is a peptide comprising the amino acid sequence KVX 60 GS, where X 60 choose from D, E and A. When X 60is D, a preferred compound comprises or consists of the amino acid sequence shown as SEQ ID NO: 253. When X 60 is E, preferred compounds comprise or consist of the amino acid sequence shown as SEQ ID NO: 261, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 269 or SEQ ID NO: 270. When X 60 is A, a preferred compound comprises or consists of the amino acid sequence shown as SEQ ID NO: 262. In the above-listed amino acid sequences of the C5-binding compounds, amino acid residues 1-57 represent the amino acid sequence of the C5-binding polypeptide, residues 58-62 represent the amino acid sequence of the linker, and residues 63-108 represent the amino acid sequence of the albumin-binding domain.

[0194] In an embodiment, the linking fragment is absent.

[0195] As discussed above, preferred C5-binding polypeptides of the invention include those polypeptides wherein X 52 and X 53independently selected from E and S. Specifically, the compounds of the invention may be derivatives of PSI0242 (SEQ ID NO: 249), but have modifications in at least one of positions 52, 53 and 60. For example, as shown in Fig. 7 and in the sequence listing, a preferred compound designated PSI0378 (SEQ ID NO: 261) carries the amino acid substitutions N52S, D53E and D60E; a preferred compound designated PSI0379 (SEQ ID NO: 262) carries the amino acid substitutions N52S, D53E and D60A; a preferred compound designated PSI0381 (SEQ ID NO: 263) carries the amino acid substitutions N52E, D53S and D60E; and a preferred compound designated PSI0383 (SEQ ID NO: 264) carries the amino acid substitutions N52S, D53E and D60E. Additionally, SEQ ID NO: 264 also carries substitutions in the loop [L2], namely D36R, D37Q and S39E.In addition, a preferred compound designated PSI0403 (SEQ ID NO: 269) carries the amino acid substitutions D53E and D60E, and a preferred compound designated PSI0404 (SEQ ID NO: 270) carries the amino acid substitutions N52S and D60E.

[0196] In view of the above, the inventors unexpectedly found that amino acid substitutions at certain positions in the amino acid sequence of C5-binding polypeptides, as described in WO 2013 / 126006, can improve stability. Such substitutions improve the stability of C5-binding compounds, while maintaining biological activity, such as C5-binding ability and in vitro hemolysis inhibition. Stability testing of the C5-binding compounds of the present invention demonstrates that, for example, each of N52S (X 52 ) and D53E (X 53 ) (SEQ ID NO: 253) individually, as well as the deletion of D60 (X 60) (SEQ ID NO: 259 without the binding fragment) improves stability. The combination of substitutions N52S, D53E, and D60E or D60A further improves stability (SEQ ID NO: 261 and SEQ ID NO: 262). Similarly, each of the combined substitutions N52S and D60E (SEQ ID NO: 270) and D53E and D60E (SEQ ID NO: 269) was found to improve stability. This indicates that each of the listed amino acid substitutions is involved in improving the stability of the polypeptide, and thus, that each of these substitutions will provide additionally stabilized C5-binding polypeptides and compounds compared to previously known C5-binding polypeptides and compounds.

[0197] However, a skilled person will be able to identify polypeptides and / or compounds that have modifications in at least one of positions 52, 53 and 60 and / or in the loop [L2], but which also carry additional modifications, such as substitutions, small deletions, insertions or inversions, and, nevertheless, have essentially the disclosed biological activities and improved stability. Additionally, the C5-binding polypeptide and / or compound according to the invention may contain additional C-terminal and / or N-terminal amino acids that improve the production, purification, stabilization in vivo or in vitro, combination or detection of the polypeptide.

[0198] In a further aspect of the invention, there is provided a compound capable of binding C5, said compound comprising:

[0199] a. at least one C5-binding polypeptide, wherein said polypeptide is selected from:

[0200] a-1. polypeptide containing the amino acid sequence

[0201] [BM]-[L2]-QSX 42 X 43 LLX 46 EAKKLX 52 X 53 X 54 Q

[0202] where, independently of each other,

[0203] [BM] represents the C5-binding motif;

[0204] [L2] select from DDPS and RQPE;

[0205] X 42 choose from A and S;

[0206] X 43 choose from N and E;

[0207] X 46 choose from A, S and C;

[0208] X 52 choose from E, N and S;

[0209] X 53 choose from D, E and S;

[0210] X 54 choose from A and S; and

[0211] a-2. a polypeptide that has at least 89% amino acid sequence identity with the polypeptide of a-1.;

[0212] b. at least one albumin-binding domain of streptococcal protein G, or a derivative thereof; and

[0213] c. at least one binding fragment for binding said at least one albumin-binding domain or derivative thereof to the C- or N-terminus of said at least one C5-binding polypeptide; wherein the binding fragment comprises or consists of KVEGS or KVAGS; or, wherein said binding fragment is absent.

[0214] It was found that deletion of D60 or substitution of the amino acid at position 60 of SEQ ID NO: 249 individually improves the stability of the C5-binding compounds of the invention compared to previously known C5-binding compounds. Preferably, the binding moiety is KVEGS (X 60 =E), while X 52 X 53may be ND, and an example of a preferred compound carrying such a binding moiety is PSI0410 (SEQ ID NO: 268). In another preferred embodiment, D60 and the complete binding moiety are absent, and an example of such a compound is the preferred compound designated PSI0369 (SEQ ID NO: 259).

[0215] In the embodiments of the above aspect, [BM] and the albumin-binding domain are as defined above in the relevant aspects. Preferably, [L2] is DDPS.

[0216] In a further aspect, a compound capable of binding C5 is provided, said compound comprising:

[0217] a. at least one C5-binding polypeptide, wherein said polypeptide is selected from:

[0218] a-1. polypeptide comprising an amino acid sequence

[0219] [BM]-[L2]-QSX 42 X 43 LLX 46 EAKKLX 52 X 53 X 54 Q

[0220] where, independently of each other,

[0221] [BM] represents the C5-binding motif;

[0222] [L2] represents RQPE;

[0223] X 42 choose from A and S;

[0224] X 43 choose from N and E;

[0225] X 46 choose from A, S and C;

[0226] X 52 choose from E, N and S;

[0227] X 53 choose from D, E and S;

[0228] X 54 choose from A and S; and

[0229] a-2. a polypeptide that has at least 89% amino acid sequence identity with the polypeptide of a-1.;

[0230] b. at least one albumin-binding domain of streptococcal protein G or a derivative thereof; and

[0231] c. optionally, at least one binding fragment for binding said at least one albumin-binding domain or derivative thereof to the C- or N-terminus of said at least one C5-binding polypeptide.

[0232] It has been found that substitution of specific amino acids in the [L2] loop improves the stability of the C5-binding compounds (e.g., SEQ ID NO: 252) of the invention compared to previously known C5-binding compounds. In embodiments of the above aspect, said [BM] and albumin-binding domain are individually provided as defined above in the relevant aspects. Preferably, said binding fragment is a peptide comprising the amino acid sequence KVX 60 GS, where X 60 choose from D, E and A.

[0233] The invention includes polynucleotides that encode the polypeptides of the invention. Also included in the invention are vectors, such as expression vectors, containing polynucleotides that encode the polypeptides of the invention. Also included are host cells that contain such vectors.

[0234] Included in the invention are the C5-binding polypeptides and compounds described above for use in therapy. In particular, the C5-binding polypeptides and compounds of the invention are useful in methods of treating and / or preventing C-5-associated conditions such as inflammatory diseases; autoimmune diseases; infectious diseases; cardiovascular diseases; neurodegenerative diseases; transplant injury; eye diseases; kidney diseases; lung diseases; hematological diseases such as paroxysmal nocturnal hemoglobinuria (PNH); allergic diseases and dermatological diseases.

[0235] In the methods of treatment and / or prevention, said C5-binding polypeptide or compound can be preferably administered intravenously, subcutaneously, by inhalation, nasally, orally, intravitreally or locally.

[0236] EXAMPLES

[0237] EXAMPLE 1: Stability test of a known C5 inhibitor

[0238] The C5-binding compound designated PSI0242 (SEQ ID NO: 249) was formulated in 25 mM NaP / 125 mM NaCl, pH 7.0, and subjected to accelerated stability testing for 2 weeks at 37°C. Stability was measured for the emergence of new variants after stability testing by SDS-PAGE and reversed-phase HPLC (RPLC). For both assays, the original sample and the sample undergoing stability testing were analyzed in parallel. For SDS-PAGE, 7.5 μg of protein was loaded into each well. RPC was performed on an Agilent 1100 HPLC using mobile phase A consisting of 0.1% trifluoroacetic acid (TFA) in water and mobile phase B consisting of 0.1% TFA / 45% MeOH / 45% isopropylamine (IPA) / 10% water.

[0239] The results show that new forms of the protein are formed during incubation, with these new forms being visualized as bands on SDS-PAGE (Figure 1) and as new peaks on reversed-phase HPLC (RPLC) chromatograms (Figure 2). In Figure 2, the major peak after 2 weeks of incubation corresponds to 57% of the original protein sample.

[0240] Positions 1-60 of SEQ ID NO: 249 correspond to the Z06175a polypeptide previously disclosed in WO 2013 / 126006 as SEQ ID NO: 753. PSI0242 (SEQ ID NO: 249) was prepared essentially as disclosed in WO 2013 / 126006.

[0241] EXAMPLE 2: Stability of Modified C5-Binding Polypeptides and Compounds

[0242] Modified C5-binding polypeptides and compounds were synthesized and purified essentially as described in WO 2013 / 126006.

[0243] Briefly, DNA encoding C5-binding Z variants was codon optimized and synthesized in E. coli at GeneArt GmbH. Synthetic genes representing C5-binding Z variants were subcloned and expressed in E. coli.

[0244] Intracellularly expressed Z variants were purified using standard chromatographic methods. Homogenization and clarification were accomplished by sonication, followed by centrifugation and filtration. Anion-exchange chromatography was used as the capture step. Further purification was performed by hydrophobic interaction chromatography. Purification was performed in an acidic medium (pH 5.5). Desalting and buffer exchange were accomplished by size-exclusion chromatography.

[0245] Purified proteins were prepared in 25 mM NaP / 125 mM NaCl, pH 7.0, and subjected to accelerated stability testing for 2 weeks at 37°C. Stability was measured by the emergence of new variants after stability testing using SDS-PAGE and reversed-phase HPLC (RPLC). For both assays, the original sample and the sample undergoing stability testing were analyzed in parallel. For SDS-PAGE, 7.5 μg of protein was loaded into each well. An example of the resulting gel is shown in Fig. 3.

[0246] RPC was performed on an Agilent 1100 HPLC using mobile phase A consisting of 0.1% trifluoroacetic acid (TFA) in water and mobile phase B consisting of 0.1% TFA / 45% MeOH / 45% isopropylamine (IPA) / 10% water. An example of the resulting chromatogram is shown in Fig. 4 for SEQ ID NO: 253.

[0247] The stability test results are summarized in Table I below.

[0248] Table I SEQ ID NO: Name SDS-PAGE bands OFX pre-peaks Main peak (% total protein) OFH after-peaks 249 PSI0242 2 2 57 1 252 PSI0332 2 1 57 1 253 PSI0334 1 1 73 0 254 PSI0335 2 2 57 1 255 PSI0336 2 2 57 1 256 PSI0337 2 2 57 1 257 PSI0339 2 2 57 1 258 PSI0340 2 2 67 1 259 PSI0369 2 1 90 1 260 PSI0377 1 0 77 0 261 PSI0378 1 0 89 0 262 PSI0379 1 0 88 0 263 PSI0381 1 0 87 0 264 PSI0383 1 0 91 0 267 PSI0400 1 0 91 0 268 PSI0410 1 1 72 1 269 PSI0403 1 1 77 1 270 PSI0404 1 1 88 0

[0249] Based on the data in Table I, it can be concluded that some modified C5-binding polypeptides or compounds have improved properties such as increased stability when compared with PSI0242. Such improved C5-binding polypeptides or compounds include PSI0334 (SEQ ID NO: 253), PSI0340 (SEQ ID NO: 258), PSI0369 (SEQ ID NO: 259), PSI0377 (SEQ ID NO: 260), PSI0378 (SEQ ID NO: 261), PSI0379 (SEQ ID NO: 262), PSI0381 (SEQ ID NO: 263), PSI0383 (SEQ ID NO: 264), PSI0400 (SEQ ID NO: 267), PSI0410 (SEQ ID NO: 268), PSI0403 (SEQ ID NO: 269) and PSI0404 (SEQ ID NO: 270). In six of the variants (SEQ ID NOs: 253, 260, 261, 262, 264, and 267), amino acid residues at positions 52–53 were replaced with SE (see PSI0242) from ND. In SEQ ID NO: 263, the corresponding replacement was with ES from ND. In SEQ ID NO: 269, only the amino acid residue at position 53 was replaced with D from E, while in SEQ ID NO: 270, the amino acid residue at position 52 was replaced with N from S.

[0250] Additionally, PSI0378 (SEQ ID NO: 261), PSI0381 (SEQ ID NO: 263), PSI0383 (SEQ ID NO: 264), PSI0410 (SEQ ID NO: 268), PSI0403 (SEQ ID NO: 269), and PSI0404 (SEQ ID NO: 270) have, in general, a substitution of amino acid residue D to E at position 60.

[0251] The combined beneficial effect of the stability-enhancing substitutions at position 52 or 53 and position 60 can be seen in Fig. 5, which shows the chromatogram of PSI0383 (SEQ ID NO: 264). In PSI0379 (SEQ ID NO: 262), the substitution at position 60 is a D to A substitution.

[0252] In PSI0369 (SEQ ID NO: 259), the linker fragment (including D60) is completely removed, yielding a more stable C5-binding compound, indicating the influence of position 60 on the stability of C5-binding compounds.

[0253] EXAMPLE 3: Binding of modified compounds to human C5

[0254] Human serum albumin was immobilized on amine-reactive biosensors 2 гоDip and Read (AR2G) type generation (Pall Life sciences (ForteBio) Cat # 18-5092) via amine coupling. PSI0242 (SEQ ID NO: 249; 1 μM) and C5-binding compounds (1 μM) in read buffer (HBS-EP Buffer Ready to Use 200 ml, GE Healthcare #BR100188) were loaded, each onto the surface of an individual sensor, using HSA for 120 seconds followed by baseline recording for 60 seconds in read buffer before exposure to human C5 (Quidel Cat # 403) at concentrations ranging from 0.79 nM to 25 nM in read buffer with a regeneration cycle and baseline recording between each concentration. Regeneration conditions for the sensors were 10 mM glycine, pH 2 (three 30-second pulses, followed by running buffer for 60 seconds). A reference spectrogram obtained for a similar construct containing an albumin-binding domain (SEQ ID NO: 250) but lacking C5-binding capacity was subtracted.Data were analyzed according to the 1:1 Langmuir model using ForteBio Analysis 7.1 (kinetics software from Pall Life sciences (ForteBio)).

[0255] K D interactions with C5 relative to PSI0242 (SEQ ID NO: 249) are shown in Table II. K D PSI0242 varied from 1-3 nM in different batches.

[0256] The results in Table II indicate that the C5-binding compounds of the invention have a binding ability to human C5 that is similar to that of the PSI0242 polypeptide (SEQ ID NO: 249) disclosed in WO 2013 / 126006.

[0257] Table II SEQ ID NO: Name Rel. KD 249 PSI0242 1,0 253 PSI0334 1,1 261 PSI0378 1,3 263 PSI0381 23 264 PSI0383 2,1

[0258] EXAMPLE 4: Stability of chemically synthesized C5-binding polypeptide

[0259] Chemically synthesized PSI0400 (SEQ ID NO: 267) was obtained by order from BACHEM AG. The stability of the polypeptide was tested according to the same methodology as in Example 2. The stability test results are shown in Table III.

[0260] Table III SEQ ID NO: Name SDS-PAGE bands OFX pre-peaks Main peak (% of total protein) OFH after-peaks 267 PSI0400 1 0 91 0

[0261] The stability of PSI0400 was comparable to that of the polypeptides produced in E. coli in Example 2.

[0262] The integrity of the PSI0400 fold (SEQ ID NO: 267) was compared with the integrity of the C5-binding polypeptide (PSI0257, SEQ ID NO: 271) prepared according to the methods of Example 2 using far-UV circular dichroism (CD) spectra.

[0263] CD spectra were recorded on a J-720 CD spectropolarimeter (Jasco, Japan). Samples were diluted to a protein concentration of 0.17 mg / mL using Pi buffer (5 mM Na-K-PO4, pH 7.0). The CD spectrum of Pi buffer was first recorded, then spectra were recorded for each of the samples, and finally for Pi buffer again. Since the two buffer spectra were the same, the initially recorded spectrum was used as the buffer spectrum. The buffer spectrum was smoothed using the Savitzky-Golay method with a convolution width of 25. The other spectra were smoothed according to the same method with a convolution width of 15. The smoothed buffer spectrum was then subtracted from each other smoothed spectrum. The CDNN program was used to estimate the secondary content of proteins, and the resulting estimates are presented in Table IV.The results showed that neither the two amino acid substitutions at positions 52 and 53 nor the production of the polypeptide by chemical synthesis affected the secondary structure content of the chemically synthesized polypeptide. The integrity of the secondary structure content was compared with that of recombinantly produced PSI0257 (SEQ ID NO: 271).

[0264] Table IV SEQ ID NO: 271 SEQ ID NO: 267 Spiral 63% 69% Antiparallel 3% 2% Parallel 3% 3% Beta bend 13% 12% Chaotic Spiral 13% 11%

[0265] EXAMPLE 5: Binding of modified compounds and polypeptides to human C5

[0266] The binding affinity of the C5-binding compounds PSI0242 (SEQ ID NO: 249), PSI0340 (SEQ ID NO: 258), PSI0378 (SEQ ID NO: 261), and PSI0410 (SEQ ID NO: 268) and the C5-binding polypeptide PSI0400 (SEQ ID NO: 267) for human C5 was analyzed using a Biacore T200 instrument (GE Healthcare). Human C5 (A403, Quidel Corporation) was coupled to the CM5 sensor chip (900 RU) using an amine coupling chemistry according to the manufacturer's protocol. The coupling was performed by injecting hC5 at a concentration of 7.5 μg / ml in 10 mM Na-acetate buffer, pH 5 (GE Healthcare). The reference element was treated with the same reagent, but without the injection of human C5.The binding of C5 binders to immobilized hC5 was studied using a single-cycle kinetics method in which five sample concentrations, typically 25, 12.5, 6.25, 3.12, and 1.56 nM in HBS-EP buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.005% surfactant P20, GE Healthcare), were injected one after another at a flow rate of 30 μL / min at 25°C in the same cycle without regeneration between injections. Data obtained from the reference element were subtracted to compensate for volumetric refractive index changes. In most cases, an HBS-EP injection was also included as a control so that the sensorgrams were compensated twice. Surfaces were regenerated in HBS-EP buffer. Kinetic constants were calculated from sensorgrams using the Langmuir 1:1 analyte model from the Biacore T200 evaluation software, version 1.0. The resulting K values ​​were D interactions are presented in Table V.

[0267] Table V SEQ ID NO: Name KD (nM) 249 PSI0242 1,3 258 PSI0340 2,5 261 PSI0378 2,1 267 PSI0400 0,53 268 PSI0410 1,3

[0268] Stability-enhancing amino acid substitutions are not detrimental to the ability of the molecules to bind to C5 and thus do not affect their biological activities.

[0269] EXAMPLE 6: Inhibition of hemolysis

[0270] To study the function of the classical complement pathway and its inhibition by the C5-binding compounds PSI0378 (SEQ ID NO: 261) and PSI0410 (SEQ ID NO: 268), and the C5-binding polypeptide PSI0400 (SEQ ID NO: 267), sheep erythrocytes (SRBCs) were obtained from fresh whole blood of rams in Olsver's solution (National Veterinary Institute, Sweden) and then treated with rabbit anti-sheep erythrocyte antiserum (Sigma) to obtain antibody-sensitized SRBCs (EA). The entire process was carried out under aseptic conditions. All other reagents were obtained from commercial sources.

[0271] The in vitro assay was performed in a 96-well U-shaped microtiter plate by sequential additions of the test protein, complement serum, and EA suspension. The final concentrations of all reagents, in a total reaction volume of 50 μl per well and at pH 7.3-7.4, were: 0.15 mM CaCl2; 0.5 mM MgCl2; 3 mM NaN3; 138 mM NaCl; 0.1% gelatin; 1.8 mM sodium barbital; 3.1 mM barbituric acid; 5 million EA; complement serum protein C5 at appropriate dilutions, and C5-binding compound or polypeptide at the desired concentrations.

[0272] C5-binding compounds and the polypeptide were pre-incubated with the above-described complement serum for 20 min on ice before starting the reaction by adding the EA suspension. The hemolytic reaction was carried out at 37°C with shaking for 45 min and then optionally terminated by adding 100 μl of ice-cold saline containing 0.02% Tween 20. The cells were centrifuged until completely sedimented, and the upper portion, corresponding to 100 μl of supernatant, was transferred to a transparent microplate with flat-bottomed wells with half the volume. The reaction results were analyzed by optical density using a microtiter plate reader at a wavelength of 415 nm.

[0273] In all testing cases, a control sample (PSI0242, SEQ ID NO: 249) and vehicle were included in each plate to determine values ​​for uninhibited and fully inhibited reactions, respectively. These values ​​were used to calculate the % inhibition of complement hemolysis at any given sample concentration. The inhibitory activities (IC50 values) of the test C5-binding compounds and polypeptide were determined using the same assay in the presence of a controlled concentration of human C5 added to C5-deficient serum. For highly active inhibitors (low nanomolar to subnanomolar), the final C5 concentration in the reaction mixture was controlled at 0.1 nM, which was optionally adjusted using C5-deficient or C5-deficient serum. The results are presented below in Table VI.

[0274] Table VI SEQ ID NO: Name Activity (%) IC50 (nM) 249 PSI0242 100 0,47 261 PSI0378 83 0,58 267 PSI0400 - 4 268 PSI0410 107 0,49

[0275] The results of the analytical hemolysis test show that the improved C5-binding compounds SEQ ID NOs: 261 and 268 are comparable to the reference compound. The C5-binding polypeptide SEQ ID NO: 267 was functional in the analytical test, but because it does not contain an albumin-binding domain, the results cannot be directly compared with the reference compound.

[0276] EXAMPLE 7: Binding to human albumin

[0277] To evaluate the binding affinity of C5-binding compounds for albumin, a human albumin ELISA was used using recombinant human albumin (coating) and commercially available antibodies (primary and detection) purchased from Novozymes, Affibody AB, and DakoCytomation, respectively. The method standard derived from PSI0242 (SEQ ID NO:249), containing the C5-binding polypeptide and the albumin-binding domain of streptococcal protein G, was used for quantification of samples. A 96-well microplate was coated with recombinant human albumin. The plate was then washed with phosphate-buffered saline containing 0.05% Tween 20 (PBST) and blocked for 1-2 hours with 1% casein in PBS. After washing the plate, the standard, method controls, control sample, and test samples were added. After incubation for 2 hours, unbound material was removed by washing. Goat anti-Affibody® IgG (Affibody AB, cat. no. 20.1000.01.0005) was added to the wells, and the plate was incubated for 1.5 hours to allow binding of bound C5-binding compounds. After washing, rabbit anti-goat IgG HRP was allowed to bind to goat antibodies for 1 hour. After a final wash, the amount of bound HRP was detected by adding TMB substrate, which was converted to a blue product by the enzyme. Addition of 1 M hydrochloric acid after 30 minutes stopped the reaction, and the color of the well contents changed from blue to yellow. Absorbance at 450 nm was measured photometrically using absorbance at 650 nm as a reference wavelength. Color intensity was proportional to the amount of PSI0242 (SEQ ID NO:249), and sample concentrations were determined using a standard curve.

[0278] C5-binding compounds containing the albumin-binding domain of streptococcal protein G were found to be capable of binding to human albumin, and the data are presented in Table VII below.

[0279] Table VII SEQ ID NO: Name % of total protein content 249 PSI0242 103 261 PSI0378 85 268 PSI0410 150

[0280] The analytical test results showed that both C5-binding compounds with improved stability investigated maintained their ability to bind to human albumin.

[0281] EXAMPLE 8: 3-Month Stability Test of C5-Binding Polypeptides / Compounds

[0282] C5-binding polypeptides / compounds, which showed improved stability compared to PSI0242 in the 2-week stability test at 37°C (Example 2), were subjected to a longer stability test for 3 months at 37°C. The stability test setup was the same as described in Example 2, and the stability was assessed by measuring the percentage of the main chromatogram peak from the total protein content using reversed-phase HPLC (RPC), with the RPC method being performed as described in Example 2. The data from the 2-week study from Example 2 are included in Table VIII below for ease of interpretation.

[0283] Table VIII SEQ ID NO: Name 2 weeks, 37°C Main peak (% of total protein) 3 months, 37°C Main peak (% of total protein) 253 PSI0334 73 16 261 PSI0378 89 59 262 PSI0379 88 58 263 PSI0381 87 46 264 PSI0383 91 59 268 PSI0410 72 16 269 PSI0403 77 35 270 PSI0404 88 46

[0284] C5-binding compounds with amino acid substitutions at positions 52 and 53 from ND to SE and a substitution at position 60 from D to E or A (SEQ ID NOs: 261, 264, and 262) have a higher proportion of protein in the original form after 3 months at 37°C than PSI0242 (SEQ ID NO: 249) after 2 weeks under the same conditions. Other compounds also showed increased stability.

[0285] EXAMPLE 9: Stability of similarly modified polypeptides

[0286] Previously known polypeptide variants that are derivatives of protein Z ( et al. J Biotechnol 2007, 128:162-183) with binding affinity for target molecules other than C5 were similarly modified at specific amino acid sequence positions to improve stability. The selection and generation of parent polypeptide variants with binding affinity for human epidermal growth factor receptor 2 (HER2), platelet-derived growth factor receptor beta (PDGF-Rβ), neonatal Fc receptor (FcRn), and carbonic anhydrase IX (CAIX) are disclosed, for example, in WO 2009 / 080810, WO 2009 / 077175, PCT / EP2014 / 055299, and WO 2014 / 096163. Polypeptide variants with improved stability were generated by site-directed mutagenesis at selected amino acid sequence positions.Stability-enhancing amino acid substitutions in the polypeptide variants Z02891 (SEQ ID NO: 272), targeting HER2; Z15805 (SEQ ID NO: 275), targeting PDGF-Rβ; Z10103 (SEQ ID NO: 278), targeting FcRn; and Z09782 (SEQ ID NO: 281), targeting CAIX, are provided below in Table IX. These polypeptide variants with improved stability differ from the C5-binding polypeptides of the present invention, for example, in that they have a [BM] binding motif with binding affinity for HER2, PDGF-Rβ, FcRn, and CAIX.

[0287] All variants were cloned with an N-terminal 6×Histidine-tag (His6) and had encoded polypeptide constructs in the format MGSSHHHHHHLQ-[Z#####]. Mutations were introduced into the polypeptide variant plasmids using overlapping pairs of oligonucleotide primers encoding the desired amino acid substitutions and established molecular biology techniques. Correct plasmid sequences were verified by DNA sequencing.

[0288] E coli cells (strain T7E2) (GeneBridge) were transformed with plasmids containing gene fragments encoding the original and modified polypeptides. Cells were cultured at 37°C in TSB-YE medium supplemented with 50 μg / ml kanamycin, and protein expression was sequentially induced by the addition of IPTG. Cells pelleted by centrifugation were disrupted using a FastPrep®-24 homogenizer (Nordic Biolabs), and cell debris was removed by centrifugation. Each supernatant, containing the polypeptide variant as a His6-tagged protein, was purified by immobilized metal ion affinity chromatography (IMAC) using His GraviTrap™ columns (GE Healthcare) according to the manufacturer's instructions. Purified polypeptide variants were buffer exchanged with phosphate-buffered saline (PBS; 1.47 mM KH2PO4, 8.1 mM Na2HPO4, 137 mM NaCl, 2.68 mM KCl, pH 7.4) using PD-10 desalting columns (GE Healthcare).The correct identity of each polypeptide was verified by SDS-PAGE and HPLC-MS.

[0289] Table IX SEQ ID NO: Name Target Amino acid substitutions Original versus modified 272 Z02891 HER2 - Original 273 Z17341 HER2 N52S, D53E Modified 274 Z17342 HER2 D36R, D37Q, S39E, N52S, D53E Modified 275 Z15805 PDGF-Rβ - Original 276 Z17343 PDGF-Rβ N52S, D53E Modified 277 Z17344 PDGF-Rβ D36R, D37Q, S39E, N52S, D53E Modified 278 Z10103 FcRn - Original 279 Z17347 FcRn N52S, D53E Modified 280 Z17348 FcRn D36R, D37Q, S39E, N52S, D53E Modified 281 Z09782 CAIX - Original 282 Z17351 CAIX N52S, D53E Modified 283 Z17352 CAIX D36R, D37Q, S39E, N52S, D53E Modified 284 Z17355 CAIX D53E Modified 285 Z17357 CAIX D36R, D37Q, S39E, D53E Modified 286 Z17359 CAIX N52S Modified 287 Z17360 CAIX D36R, D37Q, S39E, N52S Modified

[0290] In addition to substitutions of one of (SEQ ID NOs: 284-287) or both of (SEQ ID NOs: 273-274, 276-277, 279-280, 282-283) N52 and D53, substitutions were also made at positions corresponding to the [L2] loop. Thus, in the polypeptide variants of SEQ ID NOs: 274, 277, 280, 283, 285, and 287, [L2] is RQPE.

[0291] To perform stability testing, polypeptide variants formulated in PBS at pH 7.4 were diluted to 1 mg / mL, and 200 μL aliquots were incubated at 37°C for 2 weeks. Samples collected before and after the stability testing were analyzed by SDS-PAGE using 10% Bis-Tris NuPAGE gels (Invitrogen) and loading 5 μg of protein into each well. The resulting Coomassie blue-stained gels are shown in Fig. 6. Stability was assessed by the emergence of new variants after incubation at elevated temperatures, and mutated variants were compared with the corresponding parent polypeptide.

[0292] All polypeptide variants with modifications, as highlighted in Table IX, showed improved stability compared to the corresponding parent polypeptide in that the second band immediately above the main band observed for the parent polypeptide samples was not visible in the samples of modified polypeptides with the D53E and / or N52S substitution, see Fig. 6. Polypeptides with the D53E and / or N52S substitutions in combination with the D36R, D37Q, and S39E substitutions showed similar profiles on SDS-PAGE gel. The D53E substitution alone or in combination with the D36R, D37Q, and S39E substitutions appears to reduce the amount of the alternative conformation species observed as the second band on the SDS-PAGE gel, but cannot completely prevent the formation of this species.

[0293] Additionally, the binding activity of modified polypeptide variants was tested. All polypeptide variants retained their binding affinity for their target after modification (results not shown).

[0294] The results presented above for the polypeptide variants having binding affinity for target molecules other than C5 are in good agreement with the results presented for the C5-binding polypeptides and compounds of the present invention (see, for example, Examples 2 and 4). Thus, the specific amino acid modifications as described herein are likely to have a stabilizing effect regardless of the amino acid sequence [BM]. The amino acid modifications or substitutions described herein are thus considered to improve the stability of all C5-binding polypeptides and compounds described herein and in WO 2013 / 126006.

[0295] --->

[0296] SEQUENCE LIST

[0297] <110> Swedish Orphan Biovitrum AB

[0298] <120> Stable polypeptides that bind to human complement C5

[0299] <130> 21070713

[0300] <160> 287

[0301] <170> PatentIn version 3.5

[0302] <210> 1

[0303] <211> 29

[0304] <212> PROTEIN

[0305] <213> Artificial sequence

[0306] <220>

[0307] <223> Modified bacterial sequence

[0308] <400> 1

[0309] Glu Val Leu Glu Ala Trp Asp Glu Ile Asp Arg Leu Pro Asn Leu Thr

[0310] 1 5 10 15

[0311] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0312] 20 25

[0313] <210> 2

[0314] <211> 29

[0315] <212> PROTEIN

[0316] <213> Artificial sequence

[0317] <220>

[0318] <223> Modified bacterial sequence

[0319] <400> 2

[0320] Glu Val Leu Glu Ala Trp Asn Glu Ile Asp Arg Leu Pro Asn Leu Thr

[0321] 1 5 10 15

[0322] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0323] 20 25

[0324] <210> 3

[0325] <211> 29

[0326] <212> PROTEIN

[0327] <213> Artificial sequence

[0328] <220>

[0329] <223> Modified bacterial sequence

[0330] <400> 3

[0331] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Arg Leu Pro Asn Leu Thr

[0332] 1 5 10 15

[0333] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0334] 20 25

[0335] <210> 4

[0336] <211> 29

[0337] <212> PROTEIN

[0338] <213> Artificial sequence

[0339] <220>

[0340] <223> Modified bacterial sequence

[0341] <400> 4

[0342] Glu Val Leu Glu Ala Trp Asp Glu Ile Asp Arg Leu Pro Asn Leu Thr

[0343] 1 5 10 15

[0344] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0345] 20 25

[0346] <210> 5

[0347] <211> 29

[0348] <212> PROTEIN

[0349] <213> Artificial sequence

[0350] <220>

[0351] <223> Modified bacterial sequence

[0352] <400> 5

[0353] Glu Val Leu Asp Ala Trp Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[0354] 1 5 10 15

[0355] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0356] 20 25

[0357] <210> 6

[0358] <211> 29

[0359] <212> PROTEIN

[0360] <213> Artificial sequence

[0361] <220>

[0362] <223> Modified bacterial sequence

[0363] <400> 6

[0364] Glu Val Ile Asp Ala Trp Asp Glu Ile Asp Arg Leu Pro Asn Leu Thr

[0365] 1 5 10 15

[0366] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0367] 20 25

[0368] <210> 7

[0369] <211> 29

[0370] <212> PROTEIN

[0371] <213> Artificial sequence

[0372] <220>

[0373] <223> Modified bacterial sequence

[0374] <400> 7

[0375] Glu Thr Leu Glu Ala Trp Asp Glu Ile Asp Arg Leu Pro Asn Leu Thr

[0376] 1 5 10 15

[0377] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0378] 20 25

[0379] <210> 8

[0380] <211> 29

[0381] <212> PROTEIN

[0382] <213> Artificial sequence

[0383] <220>

[0384] <223> Modified bacterial sequence

[0385] <400> 8

[0386] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[0387] 1 5 10 15

[0388] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0389] 20 25

[0390] <210> 9

[0391] <211> 29

[0392] <212> PROTEIN

[0393] <213> Artificial sequence

[0394] <220>

[0395] <223> Modified bacterial sequence

[0396] <400> 9

[0397] Glu Val Leu Asp Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[0398] 1 5 10 15

[0399] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0400] 20 25

[0401] <210> 10

[0402] <211> 29

[0403] <212> PROTEIN

[0404] <213> Artificial sequence

[0405] <220>

[0406] <223> Modified bacterial sequence

[0407] <400> 10

[0408] Glu Val Leu Glu Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[0409] 1 5 10 15

[0410] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0411] 20 25

[0412] <210> 11

[0413] <211> 29

[0414] <212> PROTEIN

[0415] <213> Artificial sequence

[0416] <220>

[0417] <223> Modified bacterial sequence

[0418] <400> 11

[0419] Glu Val Leu Glu Ala Trp Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[0420] 1 5 10 15

[0421] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0422] 20 25

[0423] <210> 12

[0424] <211> 29

[0425] <212> PROTEIN

[0426] <213> Artificial sequence

[0427] <220>

[0428] <223> Modified bacterial sequence

[0429] <400> 12

[0430] Glu Val Leu Asp Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[0431] 1 5 10 15

[0432] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0433] 20 25

[0434] <210> 13

[0435] <211> 29

[0436] <212> PROTEIN

[0437] <213> Artificial sequence

[0438] <220>

[0439] <223> Modified bacterial sequence

[0440] <400> 13

[0441] Glu Thr Ile Thr Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[0442] 1 5 10 15

[0443] Ile Glu Gln Trp Leu Ala Phe Ile Gly Lys Leu Glu Asp

[0444] 20 25

[0445] <210> 14

[0446] <211> 29

[0447] <212> PROTEIN

[0448] <213> Artificial sequence

[0449] <220>

[0450] <223> Modified bacterial sequence

[0451] <400> 14

[0452] Glu Ser Met Lys Ala Trp Asp Glu Ile Asp Arg Leu Pro Asn Leu Asn

[0453] 1 5 10 15

[0454] Ile Asn Gln Trp Val Ala Phe Ile Asp Ser Leu Tyr Asp

[0455] 20 25

[0456] <210> 15

[0457] <211> 29

[0458] <212> PROTEIN

[0459] <213> Artificial sequence

[0460] <220>

[0461] <223> Modified bacterial sequence

[0462] <400> 15

[0463] Glu Ser Ile Glu Ala Trp Thr Glu Ile Asp His Leu Pro Asn Leu Thr

[0464] 1 5 10 15

[0465] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Thr Asp

[0466] 20 25

[0467] <210> 16

[0468] <211> 29

[0469] <212> PROTEIN

[0470] <213> Artificial sequence

[0471] <220>

[0472] <223> Modified bacterial sequence

[0473] <400> 16

[0474] Glu Val Leu Asp Ala Trp His Glu Ile Asp Thr Leu Pro Asn Leu Thr

[0475] 1 5 10 15

[0476] Val Arg Gln Trp Leu Ala Phe Ile Ser Lys Leu Glu Asp

[0477] 20 25

[0478] <210> 17

[0479] <211> 29

[0480] <212> PROTEIN

[0481] <213> Artificial sequence

[0482] <220>

[0483] <223> Modified bacterial sequence

[0484] <400> 17

[0485] Glu His Ile Gln Ala Asn Glu Glu Ile Asp Arg Leu Pro Asn Leu Thr

[0486] 1 5 10 15

[0487] Ile Lys Gln Trp Leu Ala Phe Ile Asn Lys Leu His Asp

[0488] 20 25

[0489] <210> 18

[0490] <211> 29

[0491] <212> PROTEIN

[0492] <213> Artificial sequence

[0493] <220>

[0494] <223> Modified bacterial sequence

[0495] <400> 18

[0496] Glu Val Leu His Ala Trp Ala Glu Ile Asp Ala Leu Pro Asn Leu Thr

[0497] 1 5 10 15

[0498] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0499] 20 25

[0500] <210> 19

[0501] <211> 29

[0502] <212> PROTEIN

[0503] <213> Artificial sequence

[0504] <220>

[0505] <223> Modified bacterial sequence

[0506] <400> 19

[0507] Glu Val Leu Ala Ala Trp Asp Glu Ile Asp Ser Leu Pro Asn Leu Thr

[0508] 1 5 10 15

[0509] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0510] 20 25

[0511] <210> 20

[0512] <211> 29

[0513] <212> PROTEIN

[0514] <213> Artificial sequence

[0515] <220>

[0516] <223> Modified bacterial sequence

[0517] <400> 20

[0518] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[0519] 1 5 10 15

[0520] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0521] 20 25

[0522] <210> 21

[0523] <211> 29

[0524] <212> PROTEIN

[0525] <213> Artificial sequence

[0526] <220>

[0527] <223> Modified bacterial sequence

[0528] <400> 21

[0529] Glu Val Leu Asp Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[0530] 1 5 10 15

[0531] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Ser Asp

[0532] 20 25

[0533] <210> 22

[0534] <211> 29

[0535] <212> PROTEIN

[0536] <213> Artificial sequence

[0537] <220>

[0538] <223> Modified bacterial sequence

[0539] <400> 22

[0540] Glu Val Ile Glu Ala Trp Asp Glu Ile Asp Gly Leu Pro Asn Leu Thr

[0541] 1 5 10 15

[0542] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0543] 20 25

[0544] <210> 23

[0545] <211> 29

[0546] <212> PROTEIN

[0547] <213> Artificial sequence

[0548] <220>

[0549] <223> Modified bacterial sequence

[0550] <400> 23

[0551] Glu Val Leu Glu Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[0552] 1 5 10 15

[0553] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0554] 20 25

[0555] <210> 24

[0556] <211> 29

[0557] <212> PROTEIN

[0558] <213> Artificial sequence

[0559] <220>

[0560] <223> Modified bacterial sequence

[0561] <400> 24

[0562] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[0563] 1 5 10 15

[0564] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0565] 20 25

[0566] <210> 25

[0567] <211> 29

[0568] <212> PROTEIN

[0569] <213> Artificial sequence

[0570] <220>

[0571] <223> Modified bacterial sequence

[0572] <400> 25

[0573] Glu Val Ile Ala Ala Trp Asn Glu Ile Asp Arg Leu Pro Asn Leu Thr

[0574] 1 5 10 15

[0575] Leu Thr Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0576] 20 25

[0577] <210> 26

[0578] <211> 29

[0579] <212> PROTEIN

[0580] <213> Artificial sequence

[0581] <220>

[0582] <223> Modified bacterial sequence

[0583] <400> 26

[0584] Glu Val Ile Glu Ala Trp Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[0585] 1 5 10 15

[0586] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0587] 20 25

[0588] <210> 27

[0589] <211> 29

[0590] <212> PROTEIN

[0591] <213> Artificial sequence

[0592] <220>

[0593] <223> Modified bacterial sequence

[0594] <400> 27

[0595] Glu Val Ile Ala Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[0596] 1 5 10 15

[0597] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0598] 20 25

[0599] <210> 28

[0600] <211> 29

[0601] <212> PROTEIN

[0602] <213> Artificial sequence

[0603] <220>

[0604] <223> Modified bacterial sequence

[0605] <400> 28

[0606] Glu Val Ile Ala Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[0607] 1 5 10 15

[0608] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0609] 20 25

[0610] <210> 29

[0611] <211> 29

[0612] <212> PROTEIN

[0613] <213> Artificial sequence

[0614] <220>

[0615] <223> Modified bacterial sequence

[0616] <400> 29

[0617] Glu Thr Ile Ala Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[0618] 1 5 10 15

[0619] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0620] 20 25

[0621] <210> 30

[0622] <211> 29

[0623] <212> PROTEIN

[0624] <213> Artificial sequence

[0625] <220>

[0626] <223> Modified bacterial sequence

[0627] <400> 30

[0628] Glu Thr Ile Glu Ala Trp Asn Glu Ile Asp Arg Leu Pro Asn Leu Thr

[0629] 1 5 10 15

[0630] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0631] 20 25

[0632] <210> 31

[0633] <211> 29

[0634] <212> PROTEIN

[0635] <213> Artificial sequence

[0636] <220>

[0637] <223> Modified bacterial sequence

[0638] <400> 31

[0639] Glu Val Leu Glu Ala Trp Arg Glu Ile Asp Ala Leu Pro Asn Leu Thr

[0640] 1 5 10 15

[0641] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0642] 20 25

[0643] <210> 32

[0644] <211> 29

[0645] <212> PROTEIN

[0646] <213> Artificial sequence

[0647] <220>

[0648] <223> Modified bacterial sequence

[0649] <400> 32

[0650] Glu Val Ile Glu Ala Trp Asp Glu Ile Asp Gln Leu Pro Asn Leu Thr

[0651] 1 5 10 15

[0652] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0653] 20 25

[0654] <210> 33

[0655] <211> 29

[0656] <212> PROTEIN

[0657] <213> Artificial sequence

[0658] <220>

[0659] <223> Modified bacterial sequence

[0660] <400> 33

[0661] Glu Val Leu Arg Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[0662] 1 5 10 15

[0663] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0664] 20 25

[0665] <210> 34

[0666] <211> 29

[0667] <212> PROTEIN

[0668] <213> Artificial sequence

[0669] <220>

[0670] <223> Modified bacterial sequence

[0671] <400> 34

[0672] Glu Val Leu Glu Ala Trp Asp Glu Ile Asp Arg Leu Pro Asn Leu Thr

[0673] 1 5 10 15

[0674] Leu Asn Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0675] 20 25

[0676] <210> 35

[0677] <211> 29

[0678] <212> PROTEIN

[0679] <213> Artificial sequence

[0680] <220>

[0681] <223> Modified bacterial sequence

[0682] <400> 35

[0683] Glu Val Leu Asp Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[0684] 1 5 10 15

[0685] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0686] 20 25

[0687] <210> 36

[0688] <211> 29

[0689] <212> PROTEIN

[0690] <213> Artificial sequence

[0691] <220>

[0692] <223> Modified bacterial sequence

[0693] <400> 36

[0694] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[0695] 1 5 10 15

[0696] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0697] 20 25

[0698] <210> 37

[0699] <211> 29

[0700] <212> PROTEIN

[0701] <213> Artificial sequence

[0702] <220>

[0703] <223> Modified bacterial sequence

[0704] <400> 37

[0705] Glu Thr Leu Glu Ala Trp Asp Glu Ile Asp Gln Leu Pro Asn Leu Thr

[0706] 1 5 10 15

[0707] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0708] 20 25

[0709] <210> 38

[0710] <211> 29

[0711] <212> PROTEIN

[0712] <213> Artificial sequence

[0713] <220>

[0714] <223> Modified bacterial sequence

[0715] <400> 38

[0716] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[0717] 1 5 10 15

[0718] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0719] 20 25

[0720] <210> 39

[0721] <211> 29

[0722] <212> PROTEIN

[0723] <213> Artificial sequence

[0724] <220>

[0725] <223> Modified bacterial sequence

[0726] <400> 39

[0727] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp Arg Leu Pro Asn Leu Thr

[0728] 1 5 10 15

[0729] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0730] 20 25

[0731] <210> 40

[0732] <211> 29

[0733] <212> PROTEIN

[0734] <213> Artificial sequence

[0735] <220>

[0736] <223> Modified bacterial sequence

[0737] <400> 40

[0738] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[0739] 1 5 10 15

[0740] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0741] 20 25

[0742] <210> 41

[0743] <211> 29

[0744] <212> PROTEIN

[0745] <213> Artificial sequence

[0746] <220>

[0747] <223> Modified bacterial sequence

[0748] <400> 41

[0749] Glu Thr Ile Ala Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[0750] 1 5 10 15

[0751] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0752] 20 25

[0753] <210> 42

[0754] <211> 29

[0755] <212> PROTEIN

[0756] <213> Artificial sequence

[0757] <220>

[0758] <223> Modified bacterial sequence

[0759] <400> 42

[0760] Glu Val Leu Gln Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[0761] 1 5 10 15

[0762] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Ser Asp

[0763] 20 25

[0764] <210> 43

[0765] <211> 29

[0766] <212> PROTEIN

[0767] <213> Artificial sequence

[0768] <220>

[0769] <223> Modified bacterial sequence

[0770] <400> 43

[0771] Glu Thr Leu His Ala Trp Ala Glu Ile Asp Arg Leu Pro Asn Leu Thr

[0772] 1 5 10 15

[0773] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0774] 20 25

[0775] <210> 44

[0776] <211> 29

[0777] <212> PROTEIN

[0778] <213> Artificial sequence

[0779] <220>

[0780] <223> Modified bacterial sequence

[0781] <400> 44

[0782] Glu Val Leu Glu Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[0783] 1 5 10 15

[0784] Leu Ala Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0785] 20 25

[0786] <210> 45

[0787] <211> 29

[0788] <212> PROTEIN

[0789] <213> Artificial sequence

[0790] <220>

[0791] <223> Modified bacterial sequence

[0792] <400> 45

[0793] Glu Val Ile Glu Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[0794] 1 5 10 15

[0795] Ile Ala Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0796] 20 25

[0797] <210> 46

[0798] <211> 29

[0799] <212> PROTEIN

[0800] <213> Artificial sequence

[0801] <220>

[0802] <223> Modified bacterial sequence

[0803] <400> 46

[0804] Glu Val Leu Asp Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[0805] 1 5 10 15

[0806] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0807] 20 25

[0808] <210> 47

[0809] <211> 29

[0810] <212> PROTEIN

[0811] <213> Artificial sequence

[0812] <220>

[0813] <223> Modified bacterial sequence

[0814] <400> 47

[0815] Glu Thr Ile Glu Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[0816] 1 5 10 15

[0817] Leu Thr Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0818] 20 25

[0819] <210> 48

[0820] <211> 29

[0821] <212> PROTEIN

[0822] <213> Artificial sequence

[0823] <220>

[0824] <223> Modified bacterial sequence

[0825] <400> 48

[0826] Glu Val Leu Glu Ala Trp Asn Glu Ile Asp Leu Leu Pro Asn Leu Thr

[0827] 1 5 10 15

[0828] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0829] 20 25

[0830] <210> 49

[0831] <211> 29

[0832] <212> PROTEIN

[0833] <213> Artificial sequence

[0834] <220>

[0835] <223> Modified bacterial sequence

[0836] <400> 49

[0837] Glu Val Ile Glu Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[0838] 1 5 10 15

[0839] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0840] 20 25

[0841] <210> 50

[0842] <211> 29

[0843] <212> PROTEIN

[0844] <213> Artificial sequence

[0845] <220>

[0846] <223> Modified bacterial sequence

[0847] <400> 50

[0848] Glu Val Ile Ser Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[0849] 1 5 10 15

[0850] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0851] 20 25

[0852] <210> 51

[0853] <211> 29

[0854] <212> PROTEIN

[0855] <213> Artificial sequence

[0856] <220>

[0857] <223> Modified bacterial sequence

[0858] <400> 51

[0859] Glu Val Ile Ala Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[0860] 1 5 10 15

[0861] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0862] 20 25

[0863] <210> 52

[0864] <211> 29

[0865] <212> PROTEIN

[0866] <213> Artificial sequence

[0867] <220>

[0868] <223> Modified bacterial sequence

[0869] <400> 52

[0870] Glu Thr Ile Glu Ala Trp Asn Glu Ile Asp Ser Leu Pro Asn Leu Thr

[0871] 1 5 10 15

[0872] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0873] 20 25

[0874] <210> 53

[0875] <211> 29

[0876] <212> PROTEIN

[0877] <213> Artificial sequence

[0878] <220>

[0879] <223> Modified bacterial sequence

[0880] <400> 53

[0881] Glu Val Leu Asp Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[0882] 1 5 10 15

[0883] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0884] 20 25

[0885] <210> 54

[0886] <211> 29

[0887] <212> PROTEIN

[0888] <213> Artificial sequence

[0889] <220>

[0890] <223> Modified bacterial sequence

[0891] <400> 54

[0892] Glu Val Leu Ala Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[0893] 1 5 10 15

[0894] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0895] 20 25

[0896] <210> 55

[0897] <211> 29

[0898] <212> PROTEIN

[0899] <213> Artificial sequence

[0900] <220>

[0901] <223> Modified bacterial sequence

[0902] <400> 55

[0903] Glu Val Leu Glu Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[0904] 1 5 10 15

[0905] Ile Thr Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0906] 20 25

[0907] <210> 56

[0908] <211> 29

[0909] <212> PROTEIN

[0910] <213> Artificial sequence

[0911] <220>

[0912] <223> Modified bacterial sequence

[0913] <400> 56

[0914] Glu Thr Ile Asp Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[0915] 1 5 10 15

[0916] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0917] 20 25

[0918] <210> 57

[0919] <211> 29

[0920] <212> PROTEIN

[0921] <213> Artificial sequence

[0922] <220>

[0923] <223> Modified bacterial sequence

[0924] <400> 57

[0925] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[0926] 1 5 10 15

[0927] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0928] 20 25

[0929] <210> 58

[0930] <211> 29

[0931] <212> PROTEIN

[0932] <213> Artificial sequence

[0933] <220>

[0934] <223> Modified bacterial sequence

[0935] <400> 58

[0936] Glu Val Ile Gln Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[0937] 1 5 10 15

[0938] Ile Ser Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0939] 20 25

[0940] <210> 59

[0941] <211> 29

[0942] <212> PROTEIN

[0943] <213> Artificial sequence

[0944] <220>

[0945] <223> Modified bacterial sequence

[0946] <400> 59

[0947] Glu Val Ile Ala Ala Trp Asp Glu Ile Asp Ser Leu Pro Asn Leu Thr

[0948] 1 5 10 15

[0949] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0950] 20 25

[0951] <210> 60

[0952] <211> 29

[0953] <212> PROTEIN

[0954] <213> Artificial sequence

[0955] <220>

[0956] <223> Modified bacterial sequence

[0957] <400> 60

[0958] Glu His Ile Glu Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[0959] 1 5 10 15

[0960] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Gln Asp

[0961] 20 25

[0962] <210> 61

[0963] <211> 29

[0964] <212> PROTEIN

[0965] <213> Artificial sequence

[0966] <220>

[0967] <223> Modified bacterial sequence

[0968] <400> 61

[0969] Glu Val Leu Glu Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[0970] 1 5 10 15

[0971] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0972] 20 25

[0973] <210> 62

[0974] <211> 29

[0975] <212> PROTEIN

[0976] <213> Artificial sequence

[0977] <220>

[0978] <223> Modified bacterial sequence

[0979] <400> 62

[0980] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[0981] 1 5 10 15

[0982] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[0983] 20 25

[0984] <210> 63

[0985] <211> 29

[0986] <212> PROTEIN

[0987] <213> Artificial sequence

[0988] <220>

[0989] <223> Modified bacterial sequence

[0990] <400> 63

[0991] Glu Thr Ile Asp Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[0992] 1 5 10 15

[0993] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[0994] 20 25

[0995] <210> 64

[0996] <211> 29

[0997] <212> PROTEIN

[0998] <213> Artificial sequence

[0999] <220>

[1000] <223> Modified bacterial sequence

[1001] <400> 64

[1002] Glu Val Ile Ala Ala Trp Asp Glu Ile Asp Leu Leu Pro Asn Leu Thr

[1003] 1 5 10 15

[1004] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[1005] 20 25

[1006] <210> 65

[1007] <211> 29

[1008] <212> PROTEIN

[1009] <213> Artificial sequence

[1010] <220>

[1011] <223> Modified bacterial sequence

[1012] <400> 65

[1013] Glu Val Ile His Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1014] 1 5 10 15

[1015] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1016] 20 25

[1017] <210> 66

[1018] <211> 29

[1019] <212> PROTEIN

[1020] <213> Artificial sequence

[1021] <220>

[1022] <223> Modified bacterial sequence

[1023] <400> 66

[1024] Glu Val Ile Ala Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[1025] 1 5 10 15

[1026] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1027] 20 25

[1028] <210> 67

[1029] <211> 29

[1030] <212> PROTEIN

[1031] <213> Artificial sequence

[1032] <220>

[1033] <223> Modified bacterial sequence

[1034] <400> 67

[1035] Glu Thr Leu Asp Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1036] 1 5 10 15

[1037] Leu Ser Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1038] 20 25

[1039] <210> 68

[1040] <211> 29

[1041] <212> PROTEIN

[1042] <213> Artificial sequence

[1043] <220>

[1044] <223> Modified bacterial sequence

[1045] <400> 68

[1046] Glu Val Leu Glu Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1047] 1 5 10 15

[1048] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1049] 20 25

[1050] <210> 69

[1051] <211> 29

[1052] <212> PROTEIN

[1053] <213> Artificial sequence

[1054] <220>

[1055] <223> Modified bacterial sequence

[1056] <400> 69

[1057] Glu Val Ile Gln Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[1058] 1 5 10 15

[1059] Ile Ser Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1060] 20 25

[1061] <210> 70

[1062] <211> 29

[1063] <212> PROTEIN

[1064] <213> Artificial sequence

[1065] <220>

[1066] <223> Modified bacterial sequence

[1067] <400> 70

[1068] Glu Val Leu Gln Ala Trp Asp Glu Ile Asp Ser Leu Pro Asn Leu Thr

[1069] 1 5 10 15

[1070] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1071] 20 25

[1072] <210> 71

[1073] <211> 29

[1074] <212> PROTEIN

[1075] <213> Artificial sequence

[1076] <220>

[1077] <223> Modified bacterial sequence

[1078] <400> 71

[1079] Glu Thr Leu Glu Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[1080] 1 5 10 15

[1081] Ile Ala Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1082] 20 25

[1083] <210> 72

[1084] <211> 29

[1085] <212> PROTEIN

[1086] <213> Artificial sequence

[1087] <220>

[1088] <223> Modified bacterial sequence

[1089] <400> 72

[1090] Glu Thr Ile Asp Ala Trp Asn Glu Ile Asp Arg Leu Pro Asn Leu Thr

[1091] 1 5 10 15

[1092] Ile Ser Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1093] 20 25

[1094] <210> 73

[1095] <211> 29

[1096] <212> PROTEIN

[1097] <213> Artificial sequence

[1098] <220>

[1099] <223> Modified bacterial sequence

[1100] <400> 73

[1101] Glu Val Leu Asp Ala Trp His Glu Ile Asp His Leu Pro Asn Leu Thr

[1102] 1 5 10 15

[1103] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1104] 20 25

[1105] <210> 74

[1106] <211> 29

[1107] <212> PROTEIN

[1108] <213> Artificial sequence

[1109] <220>

[1110] <223> Modified bacterial sequence

[1111] <400> 74

[1112] Glu Gln Ile Arg Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1113] 1 5 10 15

[1114] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[1115] 20 25

[1116] <210> 75

[1117] <211> 29

[1118] <212> PROTEIN

[1119] <213> Artificial sequence

[1120] <220>

[1121] <223> Modified bacterial sequence

[1122] <400> 75

[1123] Glu Thr Leu Tyr Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1124] 1 5 10 15

[1125] Ile Glu Gln Trp Leu Ala Phe Ile Glu Lys Leu Gln Asp

[1126] 20 25

[1127] <210> 76

[1128] <211> 29

[1129] <212> PROTEIN

[1130] <213> Artificial sequence

[1131] <220>

[1132] <223> Modified bacterial sequence

[1133] <400> 76

[1134] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1135] 1 5 10 15

[1136] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1137] 20 25

[1138] <210> 77

[1139] <211> 29

[1140] <212> PROTEIN

[1141] <213> Artificial sequence

[1142] <220>

[1143] <223> Modified bacterial sequence

[1144] <400> 77

[1145] Glu Val Leu Glu Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[1146] 1 5 10 15

[1147] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1148] 20 25

[1149] <210> 78

[1150] <211> 29

[1151] <212> PROTEIN

[1152] <213> Artificial sequence

[1153] <220>

[1154] <223> Modified bacterial sequence

[1155] <400> 78

[1156] Glu Thr Ile Glu Ala Trp Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1157] 1 5 10 15

[1158] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1159] 20 25

[1160] <210> 79

[1161] <211> 29

[1162] <212> PROTEIN

[1163] <213> Artificial sequence

[1164] <220>

[1165] <223> Modified bacterial sequence

[1166] <400> 79

[1167] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[1168] 1 5 10 15

[1169] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1170] 20 25

[1171] <210> 80

[1172] <211> 29

[1173] <212> PROTEIN

[1174] <213> Artificial sequence

[1175] <220>

[1176] <223> Modified bacterial sequence

[1177] <400> 80

[1178] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1179] 1 5 10 15

[1180] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1181] 20 25

[1182] <210> 81

[1183] <211> 29

[1184] <212> PROTEIN

[1185] <213> Artificial sequence

[1186] <220>

[1187] <223> Modified bacterial sequence

[1188] <400> 81

[1189] Glu Thr Leu Asp Ala Trp Ala Glu Ile Asp His Leu Pro Asn Leu Thr

[1190] 1 5 10 15

[1191] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1192] 20 25

[1193] <210> 82

[1194] <211> 29

[1195] <212> PROTEIN

[1196] <213> Artificial sequence

[1197] <220>

[1198] <223> Modified bacterial sequence

[1199] <400> 82

[1200] Glu His Ile Asp Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1201] 1 5 10 15

[1202] Leu Ser Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1203] 20 25

[1204] <210> 83

[1205] <211> 29

[1206] <212> PROTEIN

[1207] <213> Artificial sequence

[1208] <220>

[1209] <223> Modified bacterial sequence

[1210] <400> 83

[1211] Glu Val Leu Asp Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1212] 1 5 10 15

[1213] Ile Ala Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1214] 20 25

[1215] <210> 84

[1216] <211> 29

[1217] <212> PROTEIN

[1218] <213> Artificial sequence

[1219] <220>

[1220] <223> Modified bacterial sequence

[1221] <400> 84

[1222] Glu Val Ile Glu Ala Trp Thr Glu Ile Asp Tyr Leu Pro Asn Leu Thr

[1223] 1 5 10 15

[1224] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1225] 20 25

[1226] <210> 85

[1227] <211> 29

[1228] <212> PROTEIN

[1229] <213> Artificial sequence

[1230] <220>

[1231] <223> Modified bacterial sequence

[1232] <400> 85

[1233] Glu Thr Ile Glu Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[1234] 1 5 10 15

[1235] Ile Ala Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1236] 20 25

[1237] <210> 86

[1238] <211> 29

[1239] <212> PROTEIN

[1240] <213> Artificial sequence

[1241] <220>

[1242] <223> Modified bacterial sequence

[1243] <400> 86

[1244] Glu Val Ile Gln Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1245] 1 5 10 15

[1246] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1247] 20 25

[1248] <210> 87

[1249] <211> 29

[1250] <212> PROTEIN

[1251] <213> Artificial sequence

[1252] <220>

[1253] <223> Modified bacterial sequence

[1254] <400> 87

[1255] Glu Val Ile Glu Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[1256] 1 5 10 15

[1257] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1258] 20 25

[1259] <210> 88

[1260] <211> 29

[1261] <212> PROTEIN

[1262] <213> Artificial sequence

[1263] <220>

[1264] <223> Modified bacterial sequence

[1265] <400> 88

[1266] Glu Thr Ile Asp Ala Trp Asn Glu Ile Asp Leu Leu Pro Asn Leu Thr

[1267] 1 5 10 15

[1268] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1269] 20 25

[1270] <210> 89

[1271] <211> 29

[1272] <212> PROTEIN

[1273] <213> Artificial sequence

[1274] <220>

[1275] <223> Modified bacterial sequence

[1276] <400> 89

[1277] Glu His Ile Asp Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1278] 1 5 10 15

[1279] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1280] 20 25

[1281] <210> 90

[1282] <211> 29

[1283] <212> PROTEIN

[1284] <213> Artificial sequence

[1285] <220>

[1286] <223> Modified bacterial sequence

[1287] <400> 90

[1288] Glu Val Val Ala Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1289] 1 5 10 15

[1290] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asn Asp

[1291] 20 25

[1292] <210> 91

[1293] <211> 29

[1294] <212> PROTEIN

[1295] <213> Artificial sequence

[1296] <220>

[1297] <223> Modified bacterial sequence

[1298] <400> 91

[1299] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1300] 1 5 10 15

[1301] Leu Ala Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1302] 20 25

[1303] <210> 92

[1304] <211> 29

[1305] <212> PROTEIN

[1306] <213> Artificial sequence

[1307] <220>

[1308] <223> Modified bacterial sequence

[1309] <400> 92

[1310] Glu Val Leu Gln Ala Trp Asp Glu Ile Asp Arg Leu Pro Asn Leu Thr

[1311] 1 5 10 15

[1312] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1313] 20 25

[1314] <210> 93

[1315] <211> 29

[1316] <212> PROTEIN

[1317] <213> Artificial sequence

[1318] <220>

[1319] <223> Modified bacterial sequence

[1320] <400> 93

[1321] Glu Val Ile Asp Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[1322] 1 5 10 15

[1323] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Ser Asp

[1324] 20 25

[1325] <210> 94

[1326] <211> 29

[1327] <212> PROTEIN

[1328] <213> Artificial sequence

[1329] <220>

[1330] <223> Modified bacterial sequence

[1331] <400> 94

[1332] Glu Val Val Glu Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[1333] 1 5 10 15

[1334] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1335] 20 25

[1336] <210> 95

[1337] <211> 29

[1338] <212> PROTEIN

[1339] <213> Artificial sequence

[1340] <220>

[1341] <223> Modified bacterial sequence

[1342] <400> 95

[1343] Glu Val Ile Gln Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1344] 1 5 10 15

[1345] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1346] 20 25

[1347] <210> 96

[1348] <211> 29

[1349] <212> PROTEIN

[1350] <213> Artificial sequence

[1351] <220>

[1352] <223> Modified bacterial sequence

[1353] <400> 96

[1354] Glu Val Ile Gln Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1355] 1 5 10 15

[1356] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[1357] 20 25

[1358] <210> 97

[1359] <211> 29

[1360] <212> PROTEIN

[1361] <213> Artificial sequence

[1362] <220>

[1363] <223> Modified bacterial sequence

[1364] <400> 97

[1365] Glu Val Val Ala Ala Trp Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1366] 1 5 10 15

[1367] Leu Thr Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1368] 20 25

[1369] <210> 98

[1370] <211> 29

[1371] <212> PROTEIN

[1372] <213> Artificial sequence

[1373] <220>

[1374] <223> Modified bacterial sequence

[1375] <400> 98

[1376] Glu Val Ile Gln Ala Trp Asn Glu Ile Asp Gly Leu Pro Asn Leu Thr

[1377] 1 5 10 15

[1378] Leu Ser Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1379] 20 25

[1380] <210> 99

[1381] <211> 29

[1382] <212> PROTEIN

[1383] <213> Artificial sequence

[1384] <220>

[1385] <223> Modified bacterial sequence

[1386] <400> 99

[1387] Glu Thr Ile Glu Ala Trp Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1388] 1 5 10 15

[1389] Ile Thr Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1390] 20 25

[1391] <210> 100

[1392] <211> 29

[1393] <212> PROTEIN

[1394] <213> Artificial sequence

[1395] <220>

[1396] <223> Modified bacterial sequence

[1397] <400> 100

[1398] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[1399] 1 5 10 15

[1400] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[1401] 20 25

[1402] <210> 101

[1403] <211> 29

[1404] <212> PROTEIN

[1405] <213> Artificial sequence

[1406] <220>

[1407] <223> Modified bacterial sequence

[1408] <400> 101

[1409] Glu Thr Ile Glu Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1410] 1 5 10 15

[1411] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Glu Asp

[1412] 20 25

[1413] <210> 102

[1414] <211> 29

[1415] <212> PROTEIN

[1416] <213> Artificial sequence

[1417] <220>

[1418] <223> Modified bacterial sequence

[1419] <400> 102

[1420] Glu His Ile His Ala Trp Asn Glu Ile Asp Glu Leu Pro Asn Leu Thr

[1421] 1 5 10 15

[1422] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[1423] 20 25

[1424] <210> 103

[1425] <211> 29

[1426] <212> PROTEIN

[1427] <213> Artificial sequence

[1428] <220>

[1429] <223> Modified bacterial sequence

[1430] <400> 103

[1431] Glu Val Ile Asp Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[1432] 1 5 10 15

[1433] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Ser Asp

[1434] 20 25

[1435] <210> 104

[1436] <211> 29

[1437] <212> PROTEIN

[1438] <213> Artificial sequence

[1439] <220>

[1440] <223> Modified bacterial sequence

[1441] <400> 104

[1442] Glu Val Ile Asp Ala Asn Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1443] 1 5 10 15

[1444] Ile Ala Gln Trp Leu Ala Phe Ile Asn Lys Leu His Asp

[1445] 20 25

[1446] <210> 105

[1447] <211> 29

[1448] <212> PROTEIN

[1449] <213> Artificial sequence

[1450] <220>

[1451] <223> Modified bacterial sequence

[1452] <400> 105

[1453] Glu Thr Ile Glu Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1454] 1 5 10 15

[1455] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1456] 20 25

[1457] <210> 106

[1458] <211> 29

[1459] <212> PROTEIN

[1460] <213> Artificial sequence

[1461] <220>

[1462] <223> Modified bacterial sequence

[1463] <400> 106

[1464] Glu Val Leu Leu Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[1465] 1 5 10 15

[1466] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1467] 20 25

[1468] <210> 107

[1469] <211> 29

[1470] <212> PROTEIN

[1471] <213> Artificial sequence

[1472] <220>

[1473] <223> Modified bacterial sequence

[1474] <400> 107

[1475] Glu His Ile Asp Ala Trp Asn Glu Ile Asp Gly Leu Pro Asn Leu Thr

[1476] 1 5 10 15

[1477] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1478] 20 25

[1479] <210> 108

[1480] <211> 29

[1481] <212> PROTEIN

[1482] <213> Artificial sequence

[1483] <220>

[1484] <223> Modified bacterial sequence

[1485] <400> 108

[1486] Glu Val Ile Glu Ala Trp Ser Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1487] 1 5 10 15

[1488] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[1489] 20 25

[1490] <210> 109

[1491] <211> 29

[1492] <212> PROTEIN

[1493] <213> Artificial sequence

[1494] <220>

[1495] <223> Modified bacterial sequence

[1496] <400> 109

[1497] Glu Gln Leu Asn Ala Trp Ala Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1498] 1 5 10 15

[1499] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1500] 20 25

[1501] <210> 110

[1502] <211> 29

[1503] <212> PROTEIN

[1504] <213> Artificial sequence

[1505] <220>

[1506] <223> Modified bacterial sequence

[1507] <400> 110

[1508] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1509] 1 5 10 15

[1510] Ile Ala Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1511] 20 25

[1512] <210> 111

[1513] <211> 29

[1514] <212> PROTEIN

[1515] <213> Artificial sequence

[1516] <220>

[1517] <223> Modified bacterial sequence

[1518] <400> 111

[1519] Glu Thr Ile Asp Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[1520] 1 5 10 15

[1521] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1522] 20 25

[1523] <210> 112

[1524] <211> 29

[1525] <212> PROTEIN

[1526] <213> Artificial sequence

[1527] <220>

[1528] <223> Modified bacterial sequence

[1529] <400> 112

[1530] Glu Val Ile Glu Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1531] 1 5 10 15

[1532] Leu Ala Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1533] 20 25

[1534] <210> 113

[1535] <211> 29

[1536] <212> PROTEIN

[1537] <213> Artificial sequence

[1538] <220>

[1539] <223> Modified bacterial sequence

[1540] <400> 113

[1541] Glu Val Leu Tyr Ala Trp Ala Glu Ile Asp His Leu Pro Asn Leu Thr

[1542] 1 5 10 15

[1543] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1544] 20 25

[1545] <210> 114

[1546] <211> 29

[1547] <212> PROTEIN

[1548] <213> Artificial sequence

[1549] <220>

[1550] <223> Modified bacterial sequence

[1551] <400> 114

[1552] Glu Gln Ile Asp Ala Trp Asn Glu Ile Asp Arg Leu Pro Asn Leu Thr

[1553] 1 5 10 15

[1554] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1555] 20 25

[1556] <210> 115

[1557] <211> 29

[1558] <212> PROTEIN

[1559] <213> Artificial sequence

[1560] <220>

[1561] <223> Modified bacterial sequence

[1562] <400> 115

[1563] Glu Val Leu Ala Ala Trp Asp Glu Ile Asp Arg Leu Pro Asn Leu Thr

[1564] 1 5 10 15

[1565] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1566] 20 25

[1567] <210> 116

[1568] <211> 29

[1569] <212> PROTEIN

[1570] <213> Artificial sequence

[1571] <220>

[1572] <223> Modified bacterial sequence

[1573] <400> 116

[1574] Glu Val Ile Glu Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[1575] 1 5 10 15

[1576] Leu His Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1577] 20 25

[1578] <210> 117

[1579] <211> 29

[1580] <212> PROTEIN

[1581] <213> Artificial sequence

[1582] <220>

[1583] <223> Modified bacterial sequence

[1584] <400> 117

[1585] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1586] 1 5 10 15

[1587] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1588] 20 25

[1589] <210> 118

[1590] <211> 29

[1591] <212> PROTEIN

[1592] <213> Artificial sequence

[1593] <220>

[1594] <223> Modified bacterial sequence

[1595] <400> 118

[1596] Glu Val Ile Asp Ala Asn Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1597] 1 5 10 15

[1598] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu His Asp

[1599] 20 25

[1600] <210> 119

[1601] <211> 29

[1602] <212> PROTEIN

[1603] <213> Artificial sequence

[1604] <220>

[1605] <223> Modified bacterial sequence

[1606] <400> 119

[1607] Glu Val Ile Ala Ala Trp Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1608] 1 5 10 15

[1609] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1610] 20 25

[1611] <210> 120

[1612] <211> 29

[1613] <212> PROTEIN

[1614] <213> Artificial sequence

[1615] <220>

[1616] <223> Modified bacterial sequence

[1617] <400> 120

[1618] Glu Val Ile Glu Ala Trp Thr Glu Ile Asp Gln Leu Pro Asn Leu Thr

[1619] 1 5 10 15

[1620] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1621] 20 25

[1622] <210> 121

[1623] <211> 29

[1624] <212> PROTEIN

[1625] <213> Artificial sequence

[1626] <220>

[1627] <223> Modified bacterial sequence

[1628] <400> 121

[1629] Glu Val Ile Asn Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1630] 1 5 10 15

[1631] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1632] 20 25

[1633] <210> 122

[1634] <211> 29

[1635] <212> PROTEIN

[1636] <213> Artificial sequence

[1637] <220>

[1638] <223> Modified bacterial sequence

[1639] <400> 122

[1640] Glu His Ile Glu Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[1641] 1 5 10 15

[1642] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[1643] 20 25

[1644] <210> 123

[1645] <211> 29

[1646] <212> PROTEIN

[1647] <213> Artificial sequence

[1648] <220>

[1649] <223> Modified bacterial sequence

[1650] <400> 123

[1651] Glu His Leu Glu Ala Trp Arg Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1652] 1 5 10 15

[1653] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1654] 20 25

[1655] <210> 124

[1656] <211> 29

[1657] <212> PROTEIN

[1658] <213> Artificial sequence

[1659] <220>

[1660] <223> Modified bacterial sequence

[1661] <400> 124

[1662] Glu Val Leu Asp Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1663] 1 5 10 15

[1664] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1665] 20 25

[1666] <210> 125

[1667] <211> 29

[1668] <212> PROTEIN

[1669] <213> Artificial sequence

[1670] <220>

[1671] <223> Modified bacterial sequence

[1672] <400> 125

[1673] Glu Val Ile Ala Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[1674] 1 5 10 15

[1675] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1676] 20 25

[1677] <210> 126

[1678] <211> 29

[1679] <212> PROTEIN

[1680] <213> Artificial sequence

[1681] <220>

[1682] <223> Modified bacterial sequence

[1683] <400> 126

[1684] Glu Val Ile Gln Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1685] 1 5 10 15

[1686] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1687] 20 25

[1688] <210> 127

[1689] <211> 29

[1690] <212> PROTEIN

[1691] <213> Artificial sequence

[1692] <220>

[1693] <223> Modified bacterial sequence

[1694] <400> 127

[1695] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[1696] 1 5 10 15

[1697] Ile Ala Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1698] 20 25

[1699] <210> 128

[1700] <211> 29

[1701] <212> PROTEIN

[1702] <213> Artificial sequence

[1703] <220>

[1704] <223> Modified bacterial sequence

[1705] <400> 128

[1706] Glu Gln Leu Asp Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[1707] 1 5 10 15

[1708] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Ser Asp

[1709] 20 25

[1710] <210> 129

[1711] <211> 29

[1712] <212> PROTEIN

[1713] <213> Artificial sequence

[1714] <220>

[1715] <223> Modified bacterial sequence

[1716] <400> 129

[1717] Glu Val Leu Asn Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1718] 1 5 10 15

[1719] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1720] 20 25

[1721] <210> 130

[1722] <211> 29

[1723] <212> PROTEIN

[1724] <213> Artificial sequence

[1725] <220>

[1726] <223> Modified bacterial sequence

[1727] <400> 130

[1728] Glu Val Leu Glu Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[1729] 1 5 10 15

[1730] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1731] 20 25

[1732] <210> 131

[1733] <211> 29

[1734] <212> PROTEIN

[1735] <213> Artificial sequence

[1736] <220>

[1737] <223> Modified bacterial sequence

[1738] <400> 131

[1739] Glu Val Leu Leu Ala Trp Asp Glu Ile Asp Arg Leu Pro Asn Leu Thr

[1740] 1 5 10 15

[1741] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[1742] 20 25

[1743] <210> 132

[1744] <211> 29

[1745] <212> PROTEIN

[1746] <213> Artificial sequence

[1747] <220>

[1748] <223> Modified bacterial sequence

[1749] <400> 132

[1750] Glu Val Ile Ala Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[1751] 1 5 10 15

[1752] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1753] 20 25

[1754] <210> 133

[1755] <211> 29

[1756] <212> PROTEIN

[1757] <213> Artificial sequence

[1758] <220>

[1759] <223> Modified bacterial sequence

[1760] <400> 133

[1761] Glu Thr Leu Leu Ala Trp Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1762] 1 5 10 15

[1763] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1764] 20 25

[1765] <210> 134

[1766] <211> 29

[1767] <212> PROTEIN

[1768] <213> Artificial sequence

[1769] <220>

[1770] <223> Modified bacterial sequence

[1771] <400> 134

[1772] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp Thr Leu Pro Asn Leu Thr

[1773] 1 5 10 15

[1774] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1775] 20 25

[1776] <210> 135

[1777] <211> 29

[1778] <212> PROTEIN

[1779] <213> Artificial sequence

[1780] <220>

[1781] <223> Modified bacterial sequence

[1782] <400> 135

[1783] Glu Val Leu His Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[1784] 1 5 10 15

[1785] Leu Asn Gln Trp Leu Ala Phe Ile Asn Lys Leu Gln Asp

[1786] 20 25

[1787] <210> 136

[1788] <211> 29

[1789] <212> PROTEIN

[1790] <213> Artificial sequence

[1791] <220>

[1792] <223> Modified bacterial sequence

[1793] <400> 136

[1794] Glu Val Ile Gln Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1795] 1 5 10 15

[1796] Ile Ala Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1797] 20 25

[1798] <210> 137

[1799] <211> 29

[1800] <212> PROTEIN

[1801] <213> Artificial sequence

[1802] <220>

[1803] <223> Modified bacterial sequence

[1804] <400> 137

[1805] Glu Thr Val Asp Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1806] 1 5 10 15

[1807] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1808] 20 25

[1809] <210> 138

[1810] <211> 29

[1811] <212> PROTEIN

[1812] <213> Artificial sequence

[1813] <220>

[1814] <223> Modified bacterial sequence

[1815] <400> 138

[1816] Glu Val Ile Gln Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[1817] 1 5 10 15

[1818] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1819] 20 25

[1820] <210> 139

[1821] <211> 29

[1822] <212> PROTEIN

[1823] <213> Artificial sequence

[1824] <220>

[1825] <223> Modified bacterial sequence

[1826] <400> 139

[1827] Glu Val Leu Asp Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[1828] 1 5 10 15

[1829] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1830] 20 25

[1831] <210> 140

[1832] <211> 29

[1833] <212> PROTEIN

[1834] <213> Artificial sequence

[1835] <220>

[1836] <223> Modified bacterial sequence

[1837] <400> 140

[1838] Glu Thr Ile Glu Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1839] 1 5 10 15

[1840] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1841] 20 25

[1842] <210> 141

[1843] <211> 29

[1844] <212> PROTEIN

[1845] <213> Artificial sequence

[1846] <220>

[1847] <223> Modified bacterial sequence

[1848] <400> 141

[1849] Glu Val Ile Glu Ala Trp Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1850] 1 5 10 15

[1851] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1852] 20 25

[1853] <210> 142

[1854] <211> 29

[1855] <212> PROTEIN

[1856] <213> Artificial sequence

[1857] <220>

[1858] <223> Modified bacterial sequence

[1859] <400> 142

[1860] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[1861] 1 5 10 15

[1862] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1863] 20 25

[1864] <210> 143

[1865] <211> 29

[1866] <212> PROTEIN

[1867] <213> Artificial sequence

[1868] <220>

[1869] <223> Modified bacterial sequence

[1870] <400> 143

[1871] Glu Val Ile Glu Ala Trp Thr Glu Ile Asp His Leu Pro Asn Leu Thr

[1872] 1 5 10 15

[1873] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1874] 20 25

[1875] <210> 144

[1876] <211> 29

[1877] <212> PROTEIN

[1878] <213> Artificial sequence

[1879] <220>

[1880] <223> Modified bacterial sequence

[1881] <400> 144

[1882] Glu Val Ile Gln Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[1883] 1 5 10 15

[1884] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Glu Asp

[1885] 20 25

[1886] <210> 145

[1887] <211> 29

[1888] <212> PROTEIN

[1889] <213> Artificial sequence

[1890] <220>

[1891] <223> Modified bacterial sequence

[1892] <400> 145

[1893] Glu Val Ile Gln Ala Asn Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[1894] 1 5 10 15

[1895] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu His Asp

[1896] 20 25

[1897] <210> 146

[1898] <211> 29

[1899] <212> PROTEIN

[1900] <213> Artificial sequence

[1901] <220>

[1902] <223> Modified bacterial sequence

[1903] <400> 146

[1904] Glu Val Leu His Ala Trp Ser Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1905] 1 5 10 15

[1906] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1907] 20 25

[1908] <210> 147

[1909] <211> 29

[1910] <212> PROTEIN

[1911] <213> Artificial sequence

[1912] <220>

[1913] <223> Modified bacterial sequence

[1914] <400> 147

[1915] Glu Thr Ile Gln Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1916] 1 5 10 15

[1917] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Ser Asp

[1918] 20 25

[1919] <210> 148

[1920] <211> 29

[1921] <212> PROTEIN

[1922] <213> Artificial sequence

[1923] <220>

[1924] <223> Modified bacterial sequence

[1925] <400> 148

[1926] Glu Thr Leu Arg Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[1927] 1 5 10 15

[1928] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[1929] 20 25

[1930] <210> 149

[1931] <211> 29

[1932] <212> PROTEIN

[1933] <213> Artificial sequence

[1934] <220>

[1935] <223> Modified bacterial sequence

[1936] <400> 149

[1937] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[1938] 1 5 10 15

[1939] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Glu Asp

[1940] 20 25

[1941] <210> 150

[1942] <211> 29

[1943] <212> PROTEIN

[1944] <213> Artificial sequence

[1945] <220>

[1946] <223> Modified bacterial sequence

[1947] <400> 150

[1948] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[1949] 1 5 10 15

[1950] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[1951] 20 25

[1952] <210> 151

[1953] <211> 29

[1954] <212> PROTEIN

[1955] <213> Artificial sequence

[1956] <220>

[1957] <223> Modified bacterial sequence

[1958] <400> 151

[1959] Glu Thr Ile Asp Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[1960] 1 5 10 15

[1961] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1962] 20 25

[1963] <210> 152

[1964] <211> 29

[1965] <212> PROTEIN

[1966] <213> Artificial sequence

[1967] <220>

[1968] <223> Modified bacterial sequence

[1969] <400> 152

[1970] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[1971] 1 5 10 15

[1972] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1973] 20 25

[1974] <210> 153

[1975] <211> 29

[1976] <212> PROTEIN

[1977] <213> Artificial sequence

[1978] <220>

[1979] <223> Modified bacterial sequence

[1980] <400> 153

[1981] Glu Val Ile Arg Ala Trp Asp Glu Ile Asp Gln Leu Pro Asn Leu Thr

[1982] 1 5 10 15

[1983] Leu Ser Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1984] 20 25

[1985] <210> 154

[1986] <211> 29

[1987] <212> PROTEIN

[1988] <213> Artificial sequence

[1989] <220>

[1990] <223> Modified bacterial sequence

[1991] <400> 154

[1992] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Arg Leu Pro Asn Leu Thr

[1993] 1 5 10 15

[1994] Ile His Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[1995] 20 25

[1996] <210> 155

[1997] <211> 29

[1998] <212> PROTEIN

[1999] <213> Artificial sequence

[2000] <220>

[2001] <223> Modified bacterial sequence

[2002] <400> 155

[2003] Glu Thr Ile Glu Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[2004] 1 5 10 15

[2005] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2006] 20 25

[2007] <210> 156

[2008] <211> 29

[2009] <212> PROTEIN

[2010] <213> Artificial sequence

[2011] <220>

[2012] <223> Modified bacterial sequence

[2013] <400> 156

[2014] Glu Val Leu Thr Ala Trp Ala Glu Ile Asp Ala Leu Pro Asn Leu Thr

[2015] 1 5 10 15

[2016] Leu Ser Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2017] 20 25

[2018] <210> 157

[2019] <211> 29

[2020] <212> PROTEIN

[2021] <213> Artificial sequence

[2022] <220>

[2023] <223> Modified bacterial sequence

[2024] <400> 157

[2025] Glu Val Ile Glu Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2026] 1 5 10 15

[2027] Val Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2028] 20 25

[2029] <210> 158

[2030] <211> 29

[2031] <212> PROTEIN

[2032] <213> Artificial sequence

[2033] <220>

[2034] <223> Modified bacterial sequence

[2035] <400> 158

[2036] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[2037] 1 5 10 15

[2038] Leu Thr Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2039] 20 25

[2040] <210> 159

[2041] <211> 29

[2042] <212> PROTEIN

[2043] <213> Artificial sequence

[2044] <220>

[2045] <223> Modified bacterial sequence

[2046] <400> 159

[2047] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[2048] 1 5 10 15

[2049] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2050] 20 25

[2051] <210> 160

[2052] <211> 29

[2053] <212> PROTEIN

[2054] <213> Artificial sequence

[2055] <220>

[2056] <223> Modified bacterial sequence

[2057] <400> 160

[2058] Glu Thr Leu Gln Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[2059] 1 5 10 15

[2060] Leu Asn Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2061] 20 25

[2062] <210> 161

[2063] <211> 29

[2064] <212> PROTEIN

[2065] <213> Artificial sequence

[2066] <220>

[2067] <223> Modified bacterial sequence

[2068] <400> 161

[2069] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[2070] 1 5 10 15

[2071] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2072] 20 25

[2073] <210> 162

[2074] <211> 29

[2075] <212> PROTEIN

[2076] <213> Artificial sequence

[2077] <220>

[2078] <223> Modified bacterial sequence

[2079] <400> 162

[2080] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Leu Leu Pro Asn Leu Thr

[2081] 1 5 10 15

[2082] Leu Ser Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2083] 20 25

[2084] <210> 163

[2085] <211> 29

[2086] <212> PROTEIN

[2087] <213> Artificial sequence

[2088] <220>

[2089] <223> Modified bacterial sequence

[2090] <400> 163

[2091] Glu Val Ile Asp Ala Trp Asp Glu Ile Asp Arg Leu Pro Asn Leu Thr

[2092] 1 5 10 15

[2093] Leu Lys Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2094] 20 25

[2095] <210> 164

[2096] <211> 29

[2097] <212> PROTEIN

[2098] <213> Artificial sequence

[2099] <220>

[2100] <223> Modified bacterial sequence

[2101] <400> 164

[2102] Glu Thr Leu His Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2103] 1 5 10 15

[2104] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2105] 20 25

[2106] <210> 165

[2107] <211> 29

[2108] <212> PROTEIN

[2109] <213> Artificial sequence

[2110] <220>

[2111] <223> Modified bacterial sequence

[2112] <400> 165

[2113] Glu Val Ile Lys Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[2114] 1 5 10 15

[2115] Leu Asn Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2116] 20 25

[2117] <210> 166

[2118] <211> 29

[2119] <212> PROTEIN

[2120] <213> Artificial sequence

[2121] <220>

[2122] <223> Modified bacterial sequence

[2123] <400> 166

[2124] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[2125] 1 5 10 15

[2126] Leu Ala Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2127] 20 25

[2128] <210> 167

[2129] <211> 29

[2130] <212> PROTEIN

[2131] <213> Artificial sequence

[2132] <220>

[2133] <223> Modified bacterial sequence

[2134] <400> 167

[2135] Glu Val Ile Gln Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[2136] 1 5 10 15

[2137] Ile Asp Gln Trp Leu Ala Phe Ile Thr Lys Leu Glu Asp

[2138] 20 25

[2139] <210> 168

[2140] <211> 29

[2141] <212> PROTEIN

[2142] <213> Artificial sequence

[2143] <220>

[2144] <223> Modified bacterial sequence

[2145] <400> 168

[2146] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Arg Leu Pro Asn Leu Thr

[2147] 1 5 10 15

[2148] Ile Lys Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2149] 20 25

[2150] <210> 169

[2151] <211> 29

[2152] <212> PROTEIN

[2153] <213> Artificial sequence

[2154] <220>

[2155] <223> Modified bacterial sequence

[2156] <400> 169

[2157] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Ser Leu Pro Asn Leu Thr

[2158] 1 5 10 15

[2159] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2160] 20 25

[2161] <210> 170

[2162] <211> 29

[2163] <212> PROTEIN

[2164] <213> Artificial sequence

[2165] <220>

[2166] <223> Modified bacterial sequence

[2167] <400> 170

[2168] Glu Thr Ile Asp Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2169] 1 5 10 15

[2170] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2171] 20 25

[2172] <210> 171

[2173] <211> 29

[2174] <212> PROTEIN

[2175] <213> Artificial sequence

[2176] <220>

[2177] <223> Modified bacterial sequence

[2178] <400> 171

[2179] Glu Val Leu Glu Ala Trp Ala Glu Ile Asp Ala Leu Pro Asn Leu Thr

[2180] 1 5 10 15

[2181] Ile Ala Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2182] 20 25

[2183] <210> 172

[2184] <211> 29

[2185] <212> PROTEIN

[2186] <213> Artificial sequence

[2187] <220>

[2188] <223> Modified bacterial sequence

[2189] <400> 172

[2190] Glu Thr Ile Asp Ala Trp Asn Glu Ile Asp Arg Leu Pro Asn Leu Thr

[2191] 1 5 10 15

[2192] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2193] 20 25

[2194] <210> 173

[2195] <211> 29

[2196] <212> PROTEIN

[2197] <213> Artificial sequence

[2198] <220>

[2199] <223> Modified bacterial sequence

[2200] <400> 173

[2201] Glu Thr Leu Lys Ala Trp Asp Glu Ile Asp Arg Leu Pro Asn Leu Thr

[2202] 1 5 10 15

[2203] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2204] 20 25

[2205] <210> 174

[2206] <211> 29

[2207] <212> PROTEIN

[2208] <213> Artificial sequence

[2209] <220>

[2210] <223> Modified bacterial sequence

[2211] <400> 174

[2212] Glu Thr Ile Ala Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[2213] 1 5 10 15

[2214] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2215] 20 25

[2216] <210> 175

[2217] <211> 29

[2218] <212> PROTEIN

[2219] <213> Artificial sequence

[2220] <220>

[2221] <223> Modified bacterial sequence

[2222] <400> 175

[2223] Glu Val Leu Gln Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[2224] 1 5 10 15

[2225] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2226] 20 25

[2227] <210> 176

[2228] <211> 29

[2229] <212> PROTEIN

[2230] <213> Artificial sequence

[2231] <220>

[2232] <223> Modified bacterial sequence

[2233] <400> 176

[2234] Glu Val Ile Glu Ala Trp Ser Glu Ile Asp His Leu Pro Asn Leu Thr

[2235] 1 5 10 15

[2236] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2237] 20 25

[2238] <210> 177

[2239] <211> 29

[2240] <212> PROTEIN

[2241] <213> Artificial sequence

[2242] <220>

[2243] <223> Modified bacterial sequence

[2244] <400> 177

[2245] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp Gly Leu Pro Asn Leu Thr

[2246] 1 5 10 15

[2247] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2248] 20 25

[2249] <210> 178

[2250] <211> 29

[2251] <212> PROTEIN

[2252] <213> Artificial sequence

[2253] <220>

[2254] <223> Modified bacterial sequence

[2255] <400> 178

[2256] Glu Val Ile His Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[2257] 1 5 10 15

[2258] Leu Asn Gln Trp Leu Ala Phe Ile Asn Lys Leu Glu Asp

[2259] 20 25

[2260] <210> 179

[2261] <211> 29

[2262] <212> PROTEIN

[2263] <213> Artificial sequence

[2264] <220>

[2265] <223> Modified bacterial sequence

[2266] <400> 179

[2267] Glu Val Leu Asp Ala Trp Asn Glu Ile Asp Ser Leu Pro Asn Leu Thr

[2268] 1 5 10 15

[2269] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2270] 20 25

[2271] <210> 180

[2272] <211> 29

[2273] <212> PROTEIN

[2274] <213> Artificial sequence

[2275] <220>

[2276] <223> Modified bacterial sequence

[2277] <400> 180

[2278] Glu Gln Ile Glu Ala Trp Asn Glu Ile Asp Arg Leu Pro Asn Leu Thr

[2279] 1 5 10 15

[2280] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2281] 20 25

[2282] <210> 181

[2283] <211> 29

[2284] <212> PROTEIN

[2285] <213> Artificial sequence

[2286] <220>

[2287] <223> Modified bacterial sequence

[2288] <400> 181

[2289] Glu Val Val Asp Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[2290] 1 5 10 15

[2291] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2292] 20 25

[2293] <210> 182

[2294] <211> 29

[2295] <212> PROTEIN

[2296] <213> Artificial sequence

[2297] <220>

[2298] <223> Modified bacterial sequence

[2299] <400> 182

[2300] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2301] 1 5 10 15

[2302] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2303] 20 25

[2304] <210> 183

[2305] <211> 29

[2306] <212> PROTEIN

[2307] <213> Artificial sequence

[2308] <220>

[2309] <223> Modified bacterial sequence

[2310] <400> 183

[2311] Glu Val Ile Glu Ala Asn Asp Glu Ile Asp Arg Leu Pro Asn Leu Thr

[2312] 1 5 10 15

[2313] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu His Asp

[2314] 20 25

[2315] <210> 184

[2316] <211> 29

[2317] <212> PROTEIN

[2318] <213> Artificial sequence

[2319] <220>

[2320] <223> Modified bacterial sequence

[2321] <400> 184

[2322] Glu Thr Leu Gln Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2323] 1 5 10 15

[2324] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2325] 20 25

[2326] <210> 185

[2327] <211> 29

[2328] <212> PROTEIN

[2329] <213> Artificial sequence

[2330] <220>

[2331] <223> Modified bacterial sequence

[2332] <400> 185

[2333] Glu Val Ile Glu Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[2334] 1 5 10 15

[2335] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[2336] 20 25

[2337] <210> 186

[2338] <211> 29

[2339] <212> PROTEIN

[2340] <213> Artificial sequence

[2341] <220>

[2342] <223> Modified bacterial sequence

[2343] <400> 186

[2344] Glu Thr Ile Asp Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[2345] 1 5 10 15

[2346] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[2347] 20 25

[2348] <210> 187

[2349] <211> 29

[2350] <212> PROTEIN

[2351] <213> Artificial sequence

[2352] <220>

[2353] <223> Modified bacterial sequence

[2354] <400> 187

[2355] Glu Val Ile Asp Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2356] 1 5 10 15

[2357] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2358] 20 25

[2359] <210> 188

[2360] <211> 29

[2361] <212> PROTEIN

[2362] <213> Artificial sequence

[2363] <220>

[2364] <223> Modified bacterial sequence

[2365] <400> 188

[2366] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2367] 1 5 10 15

[2368] Leu Ala Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2369] 20 25

[2370] <210> 189

[2371] <211> 29

[2372] <212> PROTEIN

[2373] <213> Artificial sequence

[2374] <220>

[2375] <223> Modified bacterial sequence

[2376] <400> 189

[2377] Glu Val Leu Gln Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2378] 1 5 10 15

[2379] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2380] 20 25

[2381] <210> 190

[2382] <211> 29

[2383] <212> PROTEIN

[2384] <213> Artificial sequence

[2385] <220>

[2386] <223> Modified bacterial sequence

[2387] <400> 190

[2388] Glu Val Ile Ala Ala Trp Asn Glu Ile Asp Gly Leu Pro Asn Leu Thr

[2389] 1 5 10 15

[2390] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2391] 20 25

[2392] <210> 191

[2393] <211> 29

[2394] <212> PROTEIN

[2395] <213> Artificial sequence

[2396] <220>

[2397] <223> Modified bacterial sequence

[2398] <400> 191

[2399] Glu Thr Leu Asn Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[2400] 1 5 10 15

[2401] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2402] 20 25

[2403] <210> 192

[2404] <211> 29

[2405] <212> PROTEIN

[2406] <213> Artificial sequence

[2407] <220>

[2408] <223> Modified bacterial sequence

[2409] <400> 192

[2410] Glu Val Leu Ser Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[2411] 1 5 10 15

[2412] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2413] 20 25

[2414] <210> 193

[2415] <211> 29

[2416] <212> PROTEIN

[2417] <213> Artificial sequence

[2418] <220>

[2419] <223> Modified bacterial sequence

[2420] <400> 193

[2421] Glu Thr Leu Glu Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[2422] 1 5 10 15

[2423] Leu His Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2424] 20 25

[2425] <210> 194

[2426] <211> 29

[2427] <212> PROTEIN

[2428] <213> Artificial sequence

[2429] <220>

[2430] <223> Modified bacterial sequence

[2431] <400> 194

[2432] Glu Gln Ile Glu Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[2433] 1 5 10 15

[2434] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[2435] 20 25

[2436] <210> 195

[2437] <211> 29

[2438] <212> PROTEIN

[2439] <213> Artificial sequence

[2440] <220>

[2441] <223> Modified bacterial sequence

[2442] <400> 195

[2443] Glu Val Val Glu Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2444] 1 5 10 15

[2445] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2446] 20 25

[2447] <210> 196

[2448] <211> 29

[2449] <212> PROTEIN

[2450] <213> Artificial sequence

[2451] <220>

[2452] <223> Modified bacterial sequence

[2453] <400> 196

[2454] Glu Val Leu Glu Ala Trp Asn Glu Ile Asp Glu Leu Pro Asn Leu Thr

[2455] 1 5 10 15

[2456] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2457] 20 25

[2458] <210> 197

[2459] <211> 29

[2460] <212> PROTEIN

[2461] <213> Artificial sequence

[2462] <220>

[2463] <223> Modified bacterial sequence

[2464] <400> 197

[2465] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[2466] 1 5 10 15

[2467] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2468] 20 25

[2469] <210> 198

[2470] <211> 29

[2471] <212> PROTEIN

[2472] <213> Artificial sequence

[2473] <220>

[2474] <223> Modified bacterial sequence

[2475] <400> 198

[2476] Glu Thr Ile Asp Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2477] 1 5 10 15

[2478] Leu Ser Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2479] 20 25

[2480] <210> 199

[2481] <211> 29

[2482] <212> PROTEIN

[2483] <213> Artificial sequence

[2484] <220>

[2485] <223> Modified bacterial sequence

[2486] <400> 199

[2487] Glu Thr Ile Asp Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[2488] 1 5 10 15

[2489] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2490] 20 25

[2491] <210> 200

[2492] <211> 29

[2493] <212> PROTEIN

[2494] <213> Artificial sequence

[2495] <220>

[2496] <223> Modified bacterial sequence

[2497] <400> 200

[2498] Glu Val Ile Gln Ala Trp Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[2499] 1 5 10 15

[2500] Leu Asn Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2501] 20 25

[2502] <210> 201

[2503] <211> 29

[2504] <212> PROTEIN

[2505] <213> Artificial sequence

[2506] <220>

[2507] <223> Modified bacterial sequence

[2508] <400> 201

[2509] Glu Val Leu Asp Ala Trp Ala Glu Ile Asp Gln Leu Pro Asn Leu Thr

[2510] 1 5 10 15

[2511] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2512] 20 25

[2513] <210> 202

[2514] <211> 29

[2515] <212> PROTEIN

[2516] <213> Artificial sequence

[2517] <220>

[2518] <223> Modified bacterial sequence

[2519] <400> 202

[2520] Glu His Ile Ala Ala Trp Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[2521] 1 5 10 15

[2522] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2523] 20 25

[2524] <210> 203

[2525] <211> 29

[2526] <212> PROTEIN

[2527] <213> Artificial sequence

[2528] <220>

[2529] <223> Modified bacterial sequence

[2530] <400> 203

[2531] Glu Val Ile Arg Ala Trp Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[2532] 1 5 10 15

[2533] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2534] 20 25

[2535] <210> 204

[2536] <211> 29

[2537] <212> PROTEIN

[2538] <213> Artificial sequence

[2539] <220>

[2540] <223> Modified bacterial sequence

[2541] <400> 204

[2542] Glu Val Ile Asp Ala Trp Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[2543] 1 5 10 15

[2544] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[2545] 20 25

[2546] <210> 205

[2547] <211> 29

[2548] <212> PROTEIN

[2549] <213> Artificial sequence

[2550] <220>

[2551] <223> Modified bacterial sequence

[2552] <400> 205

[2553] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp Arg Leu Pro Asn Leu Thr

[2554] 1 5 10 15

[2555] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2556] 20 25

[2557] <210> 206

[2558] <211> 29

[2559] <212> PROTEIN

[2560] <213> Artificial sequence

[2561] <220>

[2562] <223> Modified bacterial sequence

[2563] <400> 206

[2564] Glu Val Ile Thr Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[2565] 1 5 10 15

[2566] Leu Ser Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2567] 20 25

[2568] <210> 207

[2569] <211> 29

[2570] <212> PROTEIN

[2571] <213> Artificial sequence

[2572] <220>

[2573] <223> Modified bacterial sequence

[2574] <400> 207

[2575] Glu Val Ile Asp Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[2576] 1 5 10 15

[2577] Ile His Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2578] 20 25

[2579] <210> 208

[2580] <211> 29

[2581] <212> PROTEIN

[2582] <213> Artificial sequence

[2583] <220>

[2584] <223> Modified bacterial sequence

[2585] <400> 208

[2586] Glu Gln Leu Lys Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2587] 1 5 10 15

[2588] Ile Glu Gln Trp Leu Ala Phe Ile Glu Lys Leu Gln Asp

[2589] 20 25

[2590] <210> 209

[2591] <211> 29

[2592] <212> PROTEIN

[2593] <213> Artificial sequence

[2594] <220>

[2595] <223> Modified bacterial sequence

[2596] <400> 209

[2597] Glu His Ile Asp Ala Trp Thr Glu Ile Asp His Leu Pro Asn Leu Thr

[2598] 1 5 10 15

[2599] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2600] 20 25

[2601] <210> 210

[2602] <211> 29

[2603] <212> PROTEIN

[2604] <213> Artificial sequence

[2605] <220>

[2606] <223> Modified bacterial sequence

[2607] <400> 210

[2608] Glu Gln Leu Arg Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2609] 1 5 10 15

[2610] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Gln Asp

[2611] 20 25

[2612] <210> 211

[2613] <211> 29

[2614] <212> PROTEIN

[2615] <213> Artificial sequence

[2616] <220>

[2617] <223> Modified bacterial sequence

[2618] <400> 211

[2619] Glu Val Leu Glu Ala Trp Arg Glu Ile Asp Ser Leu Pro Asn Leu Thr

[2620] 1 5 10 15

[2621] Ile Ala Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2622] 20 25

[2623] <210> 212

[2624] <211> 29

[2625] <212> PROTEIN

[2626] <213> Artificial sequence

[2627] <220>

[2628] <223> Modified bacterial sequence

[2629] <400> 212

[2630] Glu Val Ile Gln Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2631] 1 5 10 15

[2632] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2633] 20 25

[2634] <210> 213

[2635] <211> 29

[2636] <212> PROTEIN

[2637] <213> Artificial sequence

[2638] <220>

[2639] <223> Modified bacterial sequence

[2640] <400> 213

[2641] Glu His Val Glu Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[2642] 1 5 10 15

[2643] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[2644] 20 25

[2645] <210> 214

[2646] <211> 29

[2647] <212> PROTEIN

[2648] <213> Artificial sequence

[2649] <220>

[2650] <223> Modified bacterial sequence

[2651] <400> 214

[2652] Glu Val Ile Asp Ala Trp Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[2653] 1 5 10 15

[2654] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Ser Asp

[2655] 20 25

[2656] <210> 215

[2657] <211> 29

[2658] <212> PROTEIN

[2659] <213> Artificial sequence

[2660] <220>

[2661] <223> Modified bacterial sequence

[2662] <400> 215

[2663] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[2664] 1 5 10 15

[2665] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2666] 20 25

[2667] <210> 216

[2668] <211> 29

[2669] <212> PROTEIN

[2670] <213> Artificial sequence

[2671] <220>

[2672] <223> Modified bacterial sequence

[2673] <400> 216

[2674] Glu Val Leu Gln Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2675] 1 5 10 15

[2676] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Ser Asp

[2677] 20 25

[2678] <210> 217

[2679] <211> 29

[2680] <212> PROTEIN

[2681] <213> Artificial sequence

[2682] <220>

[2683] <223> Modified bacterial sequence

[2684] <400> 217

[2685] Glu Val Ile Lys Ala Trp Asn Glu Ile Asp Ser Leu Pro Asn Leu Thr

[2686] 1 5 10 15

[2687] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2688] 20 25

[2689] <210> 218

[2690] <211> 29

[2691] <212> PROTEIN

[2692] <213> Artificial sequence

[2693] <220>

[2694] <223> Modified bacterial sequence

[2695] <400> 218

[2696] Glu Val Leu Glu Ala Trp His Glu Ile Asp Leu Leu Pro Asn Leu Thr

[2697] 1 5 10 15

[2698] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2699] 20 25

[2700] <210> 219

[2701] <211> 29

[2702] <212> PROTEIN

[2703] <213> Artificial sequence

[2704] <220>

[2705] <223> Modified bacterial sequence

[2706] <400> 219

[2707] Glu Val Leu Glu Ala Trp Thr Glu Ile Asp Arg Leu Pro Asn Leu Thr

[2708] 1 5 10 15

[2709] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2710] 20 25

[2711] <210> 220

[2712] <211> 29

[2713] <212> PROTEIN

[2714] <213> Artificial sequence

[2715] <220>

[2716] <223> Modified bacterial sequence

[2717] <400> 220

[2718] Glu Gln Leu Tyr Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[2719] 1 5 10 15

[2720] Ile Glu Gln Trp Leu Ala Phe Ile Glu Lys Leu Gln Asp

[2721] 20 25

[2722] <210> 221

[2723] <211> 29

[2724] <212> PROTEIN

[2725] <213> Artificial sequence

[2726] <220>

[2727] <223> Modified bacterial sequence

[2728] <400> 221

[2729] Glu Val Leu Asn Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2730] 1 5 10 15

[2731] Ile Lys Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2732] 20 25

[2733] <210> 222

[2734] <211> 29

[2735] <212> PROTEIN

[2736] <213> Artificial sequence

[2737] <220>

[2738] <223> Modified bacterial sequence

[2739] <400> 222

[2740] Glu Val Ile Arg Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2741] 1 5 10 15

[2742] Val Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2743] 20 25

[2744] <210> 223

[2745] <211> 29

[2746] <212> PROTEIN

[2747] <213> Artificial sequence

[2748] <220>

[2749] <223> Modified bacterial sequence

[2750] <400> 223

[2751] Glu Val Val Gln Ala Trp Asp Glu Ile Asp Gln Leu Pro Asn Leu Thr

[2752] 1 5 10 15

[2753] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2754] 20 25

[2755] <210> 224

[2756] <211> 29

[2757] <212> PROTEIN

[2758] <213> Artificial sequence

[2759] <220>

[2760] <223> Modified bacterial sequence

[2761] <400> 224

[2762] Glu Val Ile Arg Ala Trp Asp Glu Ile Asp Gln Leu Pro Asn Leu Thr

[2763] 1 5 10 15

[2764] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2765] 20 25

[2766] <210> 225

[2767] <211> 29

[2768] <212> PROTEIN

[2769] <213> Artificial sequence

[2770] <220>

[2771] <223> Modified bacterial sequence

[2772] <400> 225

[2773] Glu Thr Ile Asp Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[2774] 1 5 10 15

[2775] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2776] 20 25

[2777] <210> 226

[2778] <211> 29

[2779] <212> PROTEIN

[2780] <213> Artificial sequence

[2781] <220>

[2782] <223> Modified bacterial sequence

[2783] <400> 226

[2784] Glu Val Val Ala Ala Trp Thr Glu Ile Asp Leu Leu Pro Asn Leu Thr

[2785] 1 5 10 15

[2786] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Glu Asp

[2787] 20 25

[2788] <210> 227

[2789] <211> 29

[2790] <212> PROTEIN

[2791] <213> Artificial sequence

[2792] <220>

[2793] <223> Modified bacterial sequence

[2794] <400> 227

[2795] Glu Val Val Ala Ala Trp Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[2796] 1 5 10 15

[2797] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Ser Asp

[2798] 20 25

[2799] <210> 228

[2800] <211> 29

[2801] <212> PROTEIN

[2802] <213> Artificial sequence

[2803] <220>

[2804] <223> Modified bacterial sequence

[2805] <400> 228

[2806] Glu Thr Leu Glu Ala Trp Arg Glu Ile Asp Ser Leu Pro Asn Leu Thr

[2807] 1 5 10 15

[2808] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2809] 20 25

[2810] <210> 229

[2811] <211> 29

[2812] <212> PROTEIN

[2813] <213> Artificial sequence

[2814] <220>

[2815] <223> Modified bacterial sequence

[2816] <400> 229

[2817] Glu Val Ile Lys Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[2818] 1 5 10 15

[2819] Leu Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2820] 20 25

[2821] <210> 230

[2822] <211> 29

[2823] <212> PROTEIN

[2824] <213> Artificial sequence

[2825] <220>

[2826] <223> Modified bacterial sequence

[2827] <400> 230

[2828] Glu Val Leu Glu Ala Trp Thr Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2829] 1 5 10 15

[2830] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2831] 20 25

[2832] <210> 231

[2833] <211> 29

[2834] <212> PROTEIN

[2835] <213> Artificial sequence

[2836] <220>

[2837] <223> Modified bacterial sequence

[2838] <400> 231

[2839] Glu Thr Leu Glu Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2840] 1 5 10 15

[2841] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2842] 20 25

[2843] <210> 232

[2844] <211> 29

[2845] <212> PROTEIN

[2846] <213> Artificial sequence

[2847] <220>

[2848] <223> Modified bacterial sequence

[2849] <400> 232

[2850] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2851] 1 5 10 15

[2852] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2853] 20 25

[2854] <210> 233

[2855] <211> 29

[2856] <212> PROTEIN

[2857] <213> Artificial sequence

[2858] <220>

[2859] <223> Modified bacterial sequence

[2860] <400> 233

[2861] Glu Thr Ile Asp Ala Trp Asn Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2862] 1 5 10 15

[2863] Leu Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2864] 20 25

[2865] <210> 234

[2866] <211> 29

[2867] <212> PROTEIN

[2868] <213> Artificial sequence

[2869] <220>

[2870] <223> Modified bacterial sequence

[2871] <400> 234

[2872] Glu Thr Leu Asp Ala Trp Asp Glu Ile Asp Ala Leu Pro Asn Leu Thr

[2873] 1 5 10 15

[2874] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Glu Asp

[2875] 20 25

[2876] <210> 235

[2877] <211> 29

[2878] <212> PROTEIN

[2879] <213> Artificial sequence

[2880] <220>

[2881] <223> Modified bacterial sequence

[2882] <400> 235

[2883] Glu Val Leu Ser Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[2884] 1 5 10 15

[2885] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2886] 20 25

[2887] <210> 236

[2888] <211> 29

[2889] <212> PROTEIN

[2890] <213> Artificial sequence

[2891] <220>

[2892] <223> Modified bacterial sequence

[2893] <400> 236

[2894] Glu Val Ile Gln Ala Asn Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2895] 1 5 10 15

[2896] Ile Glu Gln Trp Leu Ala Phe Ile His Lys Leu His Asp

[2897] 20 25

[2898] <210> 237

[2899] <211> 29

[2900] <212> PROTEIN

[2901] <213> Artificial sequence

[2902] <220>

[2903] <223> Modified bacterial sequence

[2904] <400> 237

[2905] Glu His Leu Asp Ala Trp Asp Glu Ile Asp His Leu Pro Asn Leu Thr

[2906] 1 5 10 15

[2907] Ile Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[2908] 20 25

[2909] <210> 238

[2910] <211> 29

[2911] <212> PROTEIN

[2912] <213> Artificial sequence

[2913] <220>

[2914] <223> Modified bacterial sequence

[2915] <400> 238

[2916] Glu Val Ile Gln Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[2917] 1 5 10 15

[2918] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2919] 20 25

[2920] <210> 239

[2921] <211> 29

[2922] <212> PROTEIN

[2923] <213> Artificial sequence

[2924] <220>

[2925] <223> Modified bacterial sequence

[2926] <400> 239

[2927] Glu Val Ile Glu Ala Trp Asn Glu Ile Asp Tyr Leu Pro Asn Leu Thr

[2928] 1 5 10 15

[2929] Ile Ala Gln Trp Ile Ala Phe Ile Asn Lys Leu Asp Asp

[2930] 20 25

[2931] <210> 240

[2932] <211> 29

[2933] <212> PROTEIN

[2934] <213> Artificial sequence

[2935] <220>

[2936] <223> Modified bacterial sequence

[2937] <400> 240

[2938] Glu Thr Ile Gln Ala Trp Asp Glu Ile Asp Arg Leu Pro Asn Leu Thr

[2939] 1 5 10 15

[2940] Leu Gln Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2941] 20 25

[2942] <210> 241

[2943] <211> 29

[2944] <212> PROTEIN

[2945] <213> Artificial sequence

[2946] <220>

[2947] <223> Modified bacterial sequence

[2948] <400> 241

[2949] Glu Thr Ile Gln Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2950] 1 5 10 15

[2951] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2952] 20 25

[2953] <210> 242

[2954] <211> 29

[2955] <212> PROTEIN

[2956] <213> Artificial sequence

[2957] <220>

[2958] <223> Modified bacterial sequence

[2959] <400> 242

[2960] Glu Thr Leu Asp Ala Trp Ala Glu Ile Asp His Leu Pro Asn Leu Thr

[2961] 1 5 10 15

[2962] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2963] 20 25

[2964] <210> 243

[2965] <211> 29

[2966] <212> PROTEIN

[2967] <213> Artificial sequence

[2968] <220>

[2969] <223> Modified bacterial sequence

[2970] <400> 243

[2971] Glu Val Ile Glu Ala Trp Asp Glu Ile Asp Lys Leu Pro Asn Leu Thr

[2972] 1 5 10 15

[2973] Leu Asn Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2974] 20 25

[2975] <210> 244

[2976] <211> 29

[2977] <212> PROTEIN

[2978] <213> Artificial sequence

[2979] <220>

[2980] <223> Modified bacterial sequence

[2981] <400> 244

[2982] Glu Val Leu Asp Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[2983] 1 5 10 15

[2984] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[2985] 20 25

[2986] <210> 245

[2987] <211> 29

[2988] <212> PROTEIN

[2989] <213> Artificial sequence

[2990] <220>

[2991] <223> Modified bacterial sequence

[2992] <400> 245

[2993] Glu Val Leu His Ala Trp Asn Glu Ile Asp His Leu Pro Asn Leu Thr

[2994] 1 5 10 15

[2995] Ile Glu Gln Trp Leu Ala Phe Ile Glu Lys Leu Glu Asp

[2996] 20 25

[2997] <210> 246

[2998] <211> 29

[2999] <212> PROTEIN

[3000] <213> Artificial sequence

[3001] <220>

[3002] <223> Modified bacterial sequence

[3003] <400> 246

[3004] Glu Val Ile Glu Ala Trp Gln Glu Ile Asp Lys Leu Pro Asn Leu Thr

[3005] 1 5 10 15

[3006] Ile Asp Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[3007] 20 25

[3008] <210> 247

[3009] <211> 29

[3010] <212> PROTEIN

[3011] <213> Artificial sequence

[3012] <220>

[3013] <223> Modified bacterial sequence

[3014] <400> 247

[3015] Glu Val Val Asp Ala Trp Asn Glu Ile Asp Gln Leu Pro Asn Leu Thr

[3016] 1 5 10 15

[3017] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Asp Asp

[3018] 20 25

[3019] <210> 248

[3020] <211> 29

[3021] <212> PROTEIN

[3022] <213> Artificial sequence

[3023] <220>

[3024] <223> Modified bacterial sequence

[3025] <400> 248

[3026] Glu Gln Ile Glu Ala Trp Asn Glu Ile Asp Ala Leu Pro Asn Leu Thr

[3027] 1 5 10 15

[3028] Ile Glu Gln Trp Leu Ala Phe Ile Asn Lys Leu Ala Asp

[3029] 20 25

[3030] <210> 249

[3031] <211> 108

[3032] <212> PROTEIN

[3033] <213> Artificial sequence

[3034] <220>

[3035] <223> Modified bacterial sequence

[3036] <400> 249

[3037] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3038] 1 5 10 15

[3039] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3040] 20 25 30

[3041] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3042] 35 40 45

[3043] Lys Lys Leu Asn Asp Ser Gln Ala Pro Lys Val Asp Gly Ser Leu Ala

[3044] 50 55 60

[3045] Glu Ala Lys Glu Ala Ala Asn Ala Glu Leu Asp Ser Tyr Gly Val Ser

[3046] 65 70 75 80

[3047] Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu Gly Val

[3048] 85 90 95

[3049] Glu Ala Leu Lys Asp Ala Ile Leu Ala Ala Leu Pro

[3050] 100 105

[3051] <210> 250

[3052] <211> 46

[3053] <212> PROTEIN

[3054] <213> Artificial sequence

[3055] <220>

[3056] <223> Modified bacterial sequence

[3057] <400> 250

[3058] Leu Ala Glu Ala Lys Glu Ala Asn Ala Glu Leu Asp Ser Tyr Gly

[3059] 1 5 10 15

[3060] Val Ser Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu

[3061] 20 25 30

[3062] Gly Val Glu Leo Wing Lys Asp Leopard Wing Lew Wing Pro

[3063] 35 40 45

[3064] <210> 251

[3065] <211> 1676

[3066] <212> PROTEIN

[3067] <213> Homo sapiens

[3068] <400> 251

[3069] Met Gly Leu Leu Gly Ile Leu Cys Phe Leu Ile Phe Leu Gly Lys Thr

[3070] 1 5 10 15

[3071] Trp Gly Gln Glu Gln Thr Tyr Val Ile Ser Ala Pro Lys Ile Phe Arg

[3072] 20 25 30

[3073] Val Gly Only Ser Glu Asn Ile Val Ile Gln Val Tyr Gly Tyr Thr Glu

[3074] 35 40 45

[3075] Ala Phe Asp Ala Thr Ile Ser Ile Lys Ser Tyr Pro Asp Lys Lys Phe

[3076] 50 55 60

[3077] Ser Tyr Ser Ser Gly His Val His Leu Ser Ser Glu Asn Lys Phe Gln

[3078] 65 70 75 80

[3079] Asn Ser Ala Ile Leu Thr Ile Gln Pro Lys Gln Leu Pro Gly Gly Gln

[3080] 85 90 95

[3081] Asn Pro Val Ser Tyr Val Tyr Leu Glu Val Val Ser Lys His Phe Ser

[3082] 100 105 110

[3083] Lys Ser Lys Arg Met Pro Ile Thr Tyr Asp Asn Gly Phe Leu Phe Ile

[3084] 115 120 125

[3085] His Thr Asp Lys Pro Val Tyr Thr Pro Asp Gln Ser Val Lys Val Arg

[3086] 130 135 140

[3087] Val Tyr Ser Leu Asn Asp Asp Leu Lys Pro Ala Lys Arg Glu Thr Val

[3088] 145 150 155 160

[3089] Leu Thr Phe Ile Asp Pro Glu Gly Ser Glu Val Asp Met Val Glu Glu

[3090] 165 170 175

[3091] Ile Asp His Ile Gly Ile Ile Ser Phe Pro Asp Phe Lys Ile Pro Ser

[3092] 180 185 190

[3093] Asn Pro Arg Tyr Gly Met Trp Thr Ile Lys Ala Lys Tyr Lys Glu Asp

[3094] 195 200 205

[3095] Phe Ser Thr Thr Gly Thr Ala Tyr Phe Glu Val Lys Glu Tyr Val Leu

[3096] 210 215 220

[3097] Pro His Phe Ser Val Ser Ile Glu Pro Glu Tyr Asn Phe Ile Gly Tyr

[3098] 225 230 235 240

[3099] Lys Asn Phe Lys Asn Phe Glu Ile Thr Ile Lys Ala Arg Tyr Phe Tyr

[3100] 245 250 255

[3101] Asn Lys Val Val Thr Glu Ala Asp Val Tyr Ile Thr Phe Gly Ile Arg

[3102] 260 265 270

[3103] Glu Asp Leu Lys Asp Asp Gln Lys Glu Met Met Gln Thr Ala Met Gln

[3104] 275 280 285

[3105] Asn Thr Met Leu Ile Asn Gly Ile Ala Gln Val Thr Phe Asp Ser Glu

[3106] 290 295 300

[3107] Thr Ala Val Lys Glu Leu Ser Tyr Tyr Ser Leu Glu Asp Leu Asn Asn

[3108] 305 310 315 320

[3109] Lys Tyr Leu Tyr Ile Ala Val Thr Val Ile Glu Ser Thr Gly Gly Phe

[3110] 325 330 335

[3111] Ser Glu Glu Ala Glu Ile Pro Gly Ile Lys Tyr Val Leu Ser Pro Tyr

[3112] 340 345 350

[3113] Lys Leu Asn Leu Val Ala Thr Pro Leu Phe Leu Lys Pro Gly Ile Pro

[3114] 355 360 365

[3115] Tyr Pro Ile Lys Val Gln Val Lys Asp Ser Leu Asp Gln Leu Val Gly

[3116] 370 375 380

[3117] Gly Val Pro Val Thr Leu Asn Ala Gln Thr Ile Asp Val Asn Gln Glu

[3118] 385 390 395 400

[3119] Thr Ser Asp Leu Asp Pro Ser Lys Ser Val Thr Arg Val Asp Asp Gly

[3120] 405 410 415

[3121] Val Ala Ser Phe Val Leu Asn Leu Pro Ser Gly Val Thr Val Leu Glu

[3122] 420 425 430

[3123] Phe Asn Val Lys Thr Asp Ala Pro Asp Leu Pro Glu Glu Asn Gln Ala

[3124] 435 440 445

[3125] Arg Glu Gly Tyr Arg Ala Ile Ala Tyr Ser Ser Leu Ser Gln Ser Tyr

[3126] 450 455 460

[3127] Leu Tyr Ile Asp Trp Thr Asp Asn His Lys Ala Leu Leu Val Gly Glu

[3128] 465 470 475 480

[3129] His Leu Asn Ile Ile Val Thr Pro Lys Ser Pro Tyr Ile Asp Lys Ile

[3130] 485 490 495

[3131] Thr His Tyr Asn Tyr Leu Ile Leu Ser Lys Gly Lys Ile Ile His Phe

[3132] 500 505 510

[3133] Gly Thr Arg Glu Lys Phe Ser Asp Ala Ser Tyr Gln Ser Ile Asn Ile

[3134] 515 520 525

[3135] Pro Val Thr Gln Asn Met Val Pro Ser Ser Arg Leu Leu Val Tyr Tyr

[3136] 530 535 540

[3137] Ile Val Thr Gly Glu Gln Thr Ala Glu Leu Val Ser Asp Ser Val Trp

[3138] 545 550 555 560

[3139] Leu Asn Ile Glu Glu Lys Cys Gly Asn Gln Leu Gln Val His Leu Ser

[3140] 565 570 575

[3141] Pro Asp Ala Asp Ala Tyr Ser Pro Gly Gln Thr Val Ser Leu Asn Met

[3142] 580 585 590

[3143] Ala Thr Gly Met Asp Ser Trp Val Ala Leu Ala Ala Val Asp Ser Ala

[3144] 595 600 605

[3145] Val Tyr Gly Val Gln Arg Gly Ala Lys Lys Pro Leu Glu Arg Val Phe

[3146] 610 615 620

[3147] Gln Phe Leu Glu Lys Ser Asp Leu Gly Cys Gly Ala Gly Gly Gly Leu

[3148] 625 630 635 640

[3149] Asn Asn Ala Asn Val Phe His Leu Ala Gly Leu Thr Phe Leu Thr Asn

[3150] 645 650 655

[3151] Ala Asn Ala Asp Asp Ser Gln Glu Asn Asp Glu Pro Cys Lys Glu Ile

[3152] 660 665 670

[3153] Leu Arg Pro Arg Arg Thr Leu Gln Lys Lys Ile Glu Glu Ile Ala Ala

[3154] 675 680 685

[3155] Lys Tyr Lys His Ser Val Val Lys Lys Cys Cys Tyr Asp Gly Ala Cys

[3156] 690 695 700

[3157] Val Asn Asn Asp Glu Thr Cys Glu Gln Arg Ala Ala Arg Ile Ser Leu

[3158] 705 710 715 720

[3159] Gly Pro Arg Cys Ile Lys Ala Phe Thr Glu Cys Cys Val Val Ala Ser

[3160] 725 730 735

[3161] Gln Leu Arg Ala Asn Ile Ser His Lys Asp Met Gln Leu Gly Arg Leu

[3162] 740 745 750

[3163] His Met Lys Thr Leu Leu Pro Val Ser Lys Pro Glu Ile Arg Ser Tyr

[3164] 755 760 765

[3165] Phe Pro Glu Ser Trp Leu Trp Glu Val His Leu Val Pro Arg Arg Lys

[3166] 770 775 780

[3167] Gln Leu Gln Phe Ala Leu Pro Asp Ser Leu Thr Thr Trp Glu Ile Gln

[3168] 785 790 795 800

[3169] Gly Val Gly Ile Ser Asn Thr Gly Ile Cys Val Ala Asp Thr Val Lys

[3170] 805 810 815

[3171] Ala Lys Val Phe Lys Asp Val Phe Leu Glu Met Asn Ile Pro Tyr Ser

[3172] 820 825 830

[3173] Val Val Arg Gly Glu Gln Ile Gln Leu Lys Gly Thr Val Tyr Asn Tyr

[3174] 835 840 845

[3175] Arg Thr Ser Gly Met Gln Phe Cys Val Lys Met Ser Ala Val Glu Gly

[3176] 850 855 860

[3177] Ile Cys Thr Ser Glu Ser Pro Val Ile Asp His Gln Gly Thr Lys Ser

[3178] 865 870 875 880

[3179] Ser Lys Cys Val Arg Gln Lys Val Glu Gly Ser Ser Ser His Leu Val

[3180] 885 890 895

[3181] Thr Phe Thr Val Leu Pro Leu Glu Ile Gly Leu His Asn Ile Asn Phe

[3182] 900 905 910

[3183] Ser Leu Glu Thr Trp Phe Gly Lys Glu Ile Leu Val Lys Thr Leu Arg

[3184] 915 920 925

[3185] Val Val Pro Glu Gly Val Lys Arg Glu Ser Tyr Ser Gly Val Thr Leu

[3186] 930 935 940

[3187] Asp Pro Arg Gly Ile Tyr Gly Thr Ile Ser Arg Arg Lys Glu Phe Pro

[3188] 945 950 955 960

[3189] Tyr Arg Ile Pro Leu Asp Leu Val Pro Lys Thr Glu Ile Lys Arg Ile

[3190] 965 970 975

[3191] Leu Ser Val Lys Gly Leu Leu Val Gly Glu Ile Leu Ser Ala Val Leu

[3192] 980 985 990

[3193] Ser Gln Glu Gly Ile Asn Ile Leu Thr His Leu Pro Lys Gly Ser Ala

[3194] 995 1000 1005

[3195] Glu Ala Glu Leu Met Ser Val Val Pro Val Phe Tyr Val Phe His

[3196] 1010 1015 1020

[3197] Tyr Leu Glu Thr Gly Asn His Trp Asn Ile Phe His Ser Asp Pro

[3198] 1025 1030 1035

[3199] Leu Ile Glu Lys Gln Lys Leu Lys Lys Leu Lys Glu Gly Met

[3200] 1040 1045 1050

[3201] Leu Ser Ile Met Ser Tyr Arg Asn Ala Asp Tyr Ser Tyr Ser Val

[3202] 1055 1060 1065

[3203] Trp Lys Gly Gly Ser Ala Ser Thr Trp Leu Thr Ala Phe Ala Leu

[3204] 1070 1075 1080

[3205] Arg Val Leu Gly Gln Val Asn Lys Tyr Val Glu Gln Asn Gln Asn

[3206] 1085 1090 1095

[3207] Ser Ile Cys Asn Ser Leu Leu Trp Leu Val Glu Asn Tyr Gln Leu

[3208] 1100 1105 1110

[3209] Asp Asn Gly Ser Phe Lys Glu Asn Ser Gln Tyr Gln Pro Ile Lys

[3210] 1115 1120 1125

[3211] Leu Gln Gly Thr Leu Pro Val Glu Ala Arg Glu Asn Ser Leu Tyr

[3212] 1130 1135 1140

[3213] Leu Thr Ala Phe Thr Val Ile Gly Ile Arg Lys Ala Phe Asp Ile

[3214] 1145 1150 1155

[3215] Cys Pro Leu Val Lys Ile Asp Thr Ala Leu Ile Lys Ala Asp Asn

[3216] 1160 1165 1170

[3217] Phe Leu Leu Glu Asn Thr Leu Pro Ala Gln Ser Thr Phe Thr Leu

[3218] 1175 1180 1185

[3219] Ala Ile Ser Ala Tyr Ala Leu Ser Leu Gly Asp Lys Thr His Pro

[3220] 1190 1195 1200

[3221] Gln Phe Arg Ser Ile Val Ser Ala Leu Lys Arg Glu Ala Leu Val

[3222] 1205 1210 1215

[3223] Lys Gly Asn Pro Pro Ile Tyr Arg Phe Trp Lys Asp Asn Leu Gln

[3224] 1220 1225 1230

[3225] His Lys Asp Ser Ser Val Pro Asn Thr Gly Thr Ala Arg Met Val

[3226] 1235 1240 1245

[3227] Glu Thr Thr Ala Tyr Ala Leu Leu Thr Ser Leu Asn Leu Lys Asp

[3228] 1250 1255 1260

[3229] Ile Asn Tyr Val Asn Pro Val Ile Lys Trp Leu Ser Glu Glu Gln

[3230] 1265 1270 1275

[3231] Arg Tyr Gly Gly Gly Phe Tyr Ser Thr Gln Asp Thr Ile Asn Ala

[3232] 1280 1285 1290

[3233] Ile Glu Gly Leu Thr Glu Tyr Ser Leu Leu Val Lys Gln Leu Arg

[3234] 1295 1300 1305

[3235] Leu Ser Met Asp Ile Asp Val Ser Tyr Lys His Lys Gly Ala Leu

[3236] 1310 1315 1320

[3237] His Asn Tyr Lys Met Thr Asp Lys Asn Phe Leu Gly Arg Pro Val

[3238] 1325 1330 1335

[3239] Glu Val Leu Leu Asn Asp Asp Leu Ile Val Ser Thr Gly Phe Gly

[3240] 1340 1345 1350

[3241] Ser Gly Leu Ala Thr Val His Val Thr Thr Val Val His Lys Thr

[3242] 1355 1360 1365

[3243] Ser Thr Ser Glu Glu Val Cys Ser Phe Tyr Leu Lys Ile Asp Thr

[3244] 1370 1375 1380

[3245] Gln Asp Ile Glu Ala Ser His Tyr Arg Gly Tyr Gly Asn Ser Asp

[3246] 1385 1390 1395

[3247] Tyr Lys Arg Ile Val Ala Cys Ala Ser Tyr Lys Pro Ser Arg Glu

[3248] 1400 1405 1410

[3249] Glu Ser Ser Ser Gly Ser Ser His Ala Val Met Asp Ile Ser Leu

[3250] 1415 1420 1425

[3251] Pro Thr Gly Ile Ser Ala Asn Glu Glu Asp Leu Lys Ala Leu Val

[3252] 1430 1435 1440

[3253] Glu Gly Val Asp Gln Leu Phe Thr Asp Tyr Gln Ile Lys Asp Gly

[3254] 1445 1450 1455

[3255] His Val Ile Leu Gln Leu Asn Ser Ile Pro Ser Ser Asp Phe Leu

[3256] 1460 1465 1470

[3257] Cys Val Arg Phe Arg Ile Phe Glu Leu Phe Glu Val Gly Phe Leu

[3258] 1475 1480 1485

[3259] Ser Pro Ala Thr Phe Thr Val Tyr Glu Tyr His Arg Pro Asp Lys

[3260] 1490 1495 1500

[3261] Gln Cys Thr Met Phe Tyr Ser Thr Ser Asn Ile Lys Ile Gln Lys

[3262] 1505 1510 1515

[3263] Val Cys Glu Gly Ala Ala Cys Lys Cys Val Glu Ala Asp Cys Gly

[3264] 1520 1525 1530

[3265] Gln Met Gln Glu Glu Leu Asp Leu Thr Ile Ser Ala Glu Thr Arg

[3266] 1535 1540 1545

[3267] Lys Gln Thr Ala Cys Lys Pro Glu Ile Ala Tyr Ala Tyr Lys Val

[3268] 1550 1555 1560

[3269] Ser Ile Thr Ser Ile Thr Val Glu Asn Val Phe Val Lys Tyr Lys

[3270] 1565 1570 1575

[3271] Ala Thr Leu Leu Asp Ile Tyr Lys Thr Gly Glu Ala Val Ala Glu

[3272] 1580 1585 1590

[3273] Lys Asp Ser Glu Ile Thr Phe Ile Lys Lys Val Thr Cys Thr Asn

[3274] 1595 1600 1605

[3275] Ala Glu Leu Val Lys Gly Arg Gln Tyr Leu Ile Met Gly Lys Glu

[3276] 1610 1615 1620

[3277] Ala Leu Gln Ile Lys Tyr Asn Phe Ser Phe Arg Tyr Ile Tyr Pro

[3278] 1625 1630 1635

[3279] Leu Asp Ser Leu Thr Trp Ile Glu Tyr Trp Pro Arg Asp Thr Thr

[3280] 1640 1645 1650

[3281] Cys Ser Ser Cys Gln Ala Phe Leu Ala Asn Leu Asp Glu Phe Ala

[3282] 1655 1660 1665

[3283] Glu Asp Ile Phe Leu Asn Gly Cys

[3284] 1670 1675

[3285] <210> 252

[3286] <211> 108

[3287] <212> PROTEIN

[3288] <213> Artificial sequence

[3289] <220>

[3290] <223> Modified bacterial sequence

[3291] <400> 252

[3292] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3293] 1 5 10 15

[3294] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3295] 20 25 30

[3296] Lys Leu Asp Arg Gln Pro Glu Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3297] 35 40 45

[3298] Lys Lys Leu Asn Asp Ser Gln Ala Pro Lys Val Asp Gly Ser Leu Ala

[3299] 50 55 60

[3300] Glu Ala Lys Glu Ala Ala Asn Ala Glu Leu Asp Ser Tyr Gly Val Ser

[3301] 65 70 75 80

[3302] Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu Gly Val

[3303] 85 90 95

[3304] Glu Ala Leu Lys Asp Ala Ile Leu Ala Ala Leu Pro

[3305] 100 105

[3306] <210> 253

[3307] <211> 108

[3308] <212> PROTEIN

[3309] <213> Artificial sequence

[3310] <220>

[3311] <223> Modified bacterial sequence

[3312] <400> 253

[3313] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3314] 1 5 10 15

[3315] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3316] 20 25 30

[3317] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3318] 35 40 45

[3319] Lys Lys Leu Ser Glu Ser Gln Ala Pro Lys Val Asp Gly Ser Leu Ala

[3320] 50 55 60

[3321] Glu Ala Lys Glu Ala Ala Asn Ala Glu Leu Asp Ser Tyr Gly Val Ser

[3322] 65 70 75 80

[3323] Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu Gly Val

[3324] 85 90 95

[3325] Glu Ala Leu Lys Asp Ala Ile Leu Ala Ala Leu Pro

[3326] 100 105

[3327] <210> 254

[3328] <211> 108

[3329] <212> PROTEIN

[3330] <213> Artificial sequence

[3331] <220>

[3332] <223> Modified bacterial sequence

[3333] <400> 254

[3334] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3335] 1 5 10 15

[3336] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3337] 20 25 30

[3338] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3339] 35 40 45

[3340] Lys Lys Leu Asn Asp Ser Gln Ala Pro Lys Val Asp Gly Ser Leu Ala

[3341] 50 55 60

[3342] Glu Ala Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser

[3343] 65 70 75 80

[3344] Asp Phe Tyr Lys Arg Leu Ile Asn Lys Ala Lys Thr Val Glu Gly Val

[3345] 85 90 95

[3346] Glu Ala Leu Lys Leu His Ile Leu Ala Ala Leu Pro

[3347] 100 105

[3348] <210> 255

[3349] <211> 108

[3350] <212> PROTEIN

[3351] <213> Artificial sequence

[3352] <220>

[3353] <223> Modified bacterial sequence

[3354] <400> 255

[3355] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Ser Glu Ile

[3356] 1 5 10 15

[3357] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3358] 20 25 30

[3359] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3360] 35 40 45

[3361] Lys Lys Leu Asn Asp Ser Gln Ala Pro Lys Val Asp Gly Ser Leu Ala

[3362] 50 55 60

[3363] Glu Ala Lys Glu Ala Ala Asn Ala Glu Leu Asp Ser Tyr Gly Val Ser

[3364] 65 70 75 80

[3365] Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu Gly Val

[3366] 85 90 95

[3367] Glu Ala Leu Lys Asp Ala Ile Leu Ala Ala Leu Pro

[3368] 100 105

[3369] <210> 256

[3370] <211> 108

[3371] <212> PROTEIN

[3372] <213> Artificial sequence

[3373] <220>

[3374] <223> Modified bacterial sequence

[3375] <400> 256

[3376] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3377] 1 5 10 15

[3378] Glu Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3379] 20 25 30

[3380] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3381] 35 40 45

[3382] Lys Lys Leu Asn Asp Ser Gln Ala Pro Lys Val Asp Gly Ser Leu Ala

[3383] 50 55 60

[3384] Glu Ala Lys Glu Ala Ala Asn Ala Glu Leu Asp Ser Tyr Gly Val Ser

[3385] 65 70 75 80

[3386] Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu Gly Val

[3387] 85 90 95

[3388] Glu Ala Leu Lys Asp Ala Ile Leu Ala Ala Leu Pro

[3389] 100 105

[3390] <210> 257

[3391] <211> 108

[3392] <212> PROTEIN

[3393] <213> Artificial sequence

[3394] <220>

[3395] <223> Modified bacterial sequence

[3396] <400> 257

[3397] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3398] 1 5 10 15

[3399] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Ala

[3400] 20 25 30

[3401] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3402] 35 40 45

[3403] Lys Lys Leu Asn Asp Ser Gln Ala Pro Lys Val Asp Gly Ser Leu Ala

[3404] 50 55 60

[3405] Glu Ala Lys Glu Ala Ala Asn Ala Glu Leu Asp Ser Tyr Gly Val Ser

[3406] 65 70 75 80

[3407] Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu Gly Val

[3408] 85 90 95

[3409] Glu Ala Leu Lys Asp Ala Ile Leu Ala Ala Leu Pro

[3410] 100 105

[3411] <210> 258

[3412] <211> 108

[3413] <212> PROTEIN

[3414] <213> Artificial sequence

[3415] <220>

[3416] <223> Modified bacterial sequence

[3417] <400> 258

[3418] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3419] 1 5 10 15

[3420] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3421] 20 25 30

[3422] Lys Leu Glu Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3423] 35 40 45

[3424] Lys Lys Leu Asn Asp Ser Gln Ala Pro Lys Val Asp Gly Ser Leu Ala

[3425] 50 55 60

[3426] Glu Ala Lys Glu Ala Ala Asn Ala Glu Leu Asp Ser Tyr Gly Val Ser

[3427] 65 70 75 80

[3428] Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu Gly Val

[3429] 85 90 95

[3430] Glu Ala Leu Lys Asp Ala Ile Leu Ala Ala Leu Pro

[3431] 100 105

[3432] <210> 259

[3433] <211> 103

[3434] <212> PROTEIN

[3435] <213> Artificial sequence

[3436] <220>

[3437] <223> Modified bacterial sequence

[3438] <400> 259

[3439] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3440] 1 5 10 15

[3441] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3442] 20 25 30

[3443] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3444] 35 40 45

[3445] Lys Lys Leu Asn Asp Ser Gln Ala Pro Leu Ala Glu Ala Lys Glu Ala

[3446] 50 55 60

[3447] Ala Asn Ala Glu Leu Asp Ser Tyr Gly Val Ser Asp Phe Tyr Lys Arg

[3448] 65 70 75 80

[3449] Leu Ile Asp Lys Ala Lys Thr Val Glu Gly Val Glu Ala Leu Lys Asp

[3450] 85 90 95

[3451] Ala Ile Leu Ala Ala Leu Pro

[3452] 100

[3453] <210> 260

[3454] <211> 57

[3455] <212> PROTEIN

[3456] <213> Artificial sequence

[3457] <220>

[3458] <223> Modified bacterial sequence

[3459] <400> 260

[3460] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3461] 1 5 10 15

[3462] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3463] 20 25 30

[3464] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3465] 35 40 45

[3466] Lys Lys Leu Ser Glu Ser Gln Ala Pro

[3467] 50 55

[3468] <210> 261

[3469] <211> 108

[3470] <212> PROTEIN

[3471] <213> Artificial sequence

[3472] <220>

[3473] <223> Modified bacterial sequence

[3474] <400> 261

[3475] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3476] 1 5 10 15

[3477] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3478] 20 25 30

[3479] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3480] 35 40 45

[3481] Lys Lys Leu Ser Glu Ser Gln Ala Pro Lys Val Glu Gly Ser Leu Ala

[3482] 50 55 60

[3483] Glu Ala Lys Glu Ala Ala Asn Ala Glu Leu Asp Ser Tyr Gly Val Ser

[3484] 65 70 75 80

[3485] Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu Gly Val

[3486] 85 90 95

[3487] Glu Ala Leu Lys Asp Ala Ile Leu Ala Ala Leu Pro

[3488] 100 105

[3489] <210> 262

[3490] <211> 108

[3491] <212> PROTEIN

[3492] <213> Artificial sequence

[3493] <220>

[3494] <223> Modified bacterial sequence

[3495] <400> 262

[3496] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3497] 1 5 10 15

[3498] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3499] 20 25 30

[3500] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3501] 35 40 45

[3502] Lys Lys Leu Ser Glu Ser Gln Ala Pro Lys Val Ala Gly Ser Leu Ala

[3503] 50 55 60

[3504] Glu Ala Lys Glu Ala Ala Asn Ala Glu Leu Asp Ser Tyr Gly Val Ser

[3505] 65 70 75 80

[3506] Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu Gly Val

[3507] 85 90 95

[3508] Glu Ala Leu Lys Asp Ala Ile Leu Ala Ala Leu Pro

[3509] 100 105

[3510] <210> 263

[3511] <211> 108

[3512] <212> PROTEIN

[3513] <213> Artificial sequence

[3514] <220>

[3515] <223> Modified bacterial sequence

[3516] <400> 263

[3517] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3518] 1 5 10 15

[3519] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3520] 20 25 30

[3521] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3522] 35 40 45

[3523] Lys Lys Leu Glu Ser Ser Gln Ala Pro Lys Val Glu Gly Ser Leu Ala

[3524] 50 55 60

[3525] Glu Ala Lys Glu Ala Ala Asn Ala Glu Leu Asp Ser Tyr Gly Val Ser

[3526] 65 70 75 80

[3527] Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu Gly Val

[3528] 85 90 95

[3529] Glu Ala Leu Lys Asp Ala Ile Leu Ala Ala Leu Pro

[3530] 100 105

[3531] <210> 264

[3532] <211> 108

[3533] <212> PROTEIN

[3534] <213> Artificial sequence

[3535] <220>

[3536] <223> Modified bacterial sequence

[3537] <400> 264

[3538] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3539] 1 5 10 15

[3540] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3541] 20 25 30

[3542] Lys Leu Asp Arg Gln Pro Glu Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3543] 35 40 45

[3544] Lys Lys Leu Ser Glu Ser Gln Ala Pro Lys Val Glu Gly Ser Leu Ala

[3545] 50 55 60

[3546] Glu Ala Lys Glu Ala Ala Asn Ala Glu Leu Asp Ser Tyr Gly Val Ser

[3547] 65 70 75 80

[3548] Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu Gly Val

[3549] 85 90 95

[3550] Glu Ala Leu Lys Asp Ala Ile Leu Ala Ala Leu Pro

[3551] 100 105

[3552] <210> 265

[3553] <211> 57

[3554] <212> PROTEIN

[3555] <213> Artificial sequence

[3556] <220>

[3557] <223> Modified bacterial sequence

[3558] <400> 265

[3559] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3560] 1 5 10 15

[3561] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3562] 20 25 30

[3563] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3564] 35 40 45

[3565] Lys Lys Leu Glu Ser Ser Gln Ala Pro

[3566] 50 55

[3567] <210> 266

[3568] <211> 57

[3569] <212> PROTEIN

[3570] <213> Artificial sequence

[3571] <220>

[3572] <223> Modified bacterial sequence

[3573] <400> 266

[3574] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3575] 1 5 10 15

[3576] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3577] 20 25 30

[3578] Lys Leu Asp Arg Gln Pro Glu Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3579] 35 40 45

[3580] Lys Lys Leu Ser Glu Ser Gln Ala Pro

[3581] 50 55

[3582] <210> 267

[3583] <211> 58

[3584] <212> PROTEIN

[3585] <213> Artificial sequence

[3586] <220>

[3587] <223> Modified bacterial sequence

[3588] <400> 267

[3589] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3590] 1 5 10 15

[3591] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3592] 20 25 30

[3593] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3594] 35 40 45

[3595] Lys Lys Leu Ser Glu Ser Gln Ala Pro Lys

[3596] 50 55

[3597] <210> 268

[3598] <211> 108

[3599] <212> PROTEIN

[3600] <213> Artificial sequence

[3601] <220>

[3602] <223> Modified bacterial sequence

[3603] <400> 268

[3604] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3605] 1 5 10 15

[3606] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3607] 20 25 30

[3608] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3609] 35 40 45

[3610] Lys Lys Leu Asn Asp Ser Gln Ala Pro Lys Val Glu Gly Ser Leu Ala

[3611] 50 55 60

[3612] Glu Ala Lys Glu Ala Ala Asn Ala Glu Leu Asp Ser Tyr Gly Val Ser

[3613] 65 70 75 80

[3614] Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu Gly Val

[3615] 85 90 95

[3616] Glu Ala Leu Lys Asp Ala Ile Leu Ala Ala Leu Pro

[3617] 100 105

[3618] <210> 269

[3619] <211> 108

[3620] <212> PROTEIN

[3621] <213> Artificial sequence

[3622] <220>

[3623] <223> Modified bacterial sequence

[3624] <400> 269

[3625] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3626] 1 5 10 15

[3627] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3628] 20 25 30

[3629] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3630] 35 40 45

[3631] Lys Lys Leu Asn Glu Ser Gln Ala Pro Lys Val Glu Gly Ser Leu Ala

[3632] 50 55 60

[3633] Glu Ala Lys Glu Ala Ala Asn Ala Glu Leu Asp Ser Tyr Gly Val Ser

[3634] 65 70 75 80

[3635] Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu Gly Val

[3636] 85 90 95

[3637] Glu Ala Leu Lys Asp Ala Ile Leu Ala Ala Leu Pro

[3638] 100 105

[3639] <210> 270

[3640] <211> 108

[3641] <212> PROTEIN

[3642] <213> Artificial sequence

[3643] <220>

[3644] <223> Modified bacterial sequence

[3645] <400> 270

[3646] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3647] 1 5 10 15

[3648] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3649] 20 25 30

[3650] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3651] 35 40 45

[3652] Lys Lys Leu Ser Asp Ser Gln Ala Pro Lys Val Glu Gly Ser Leu Ala

[3653] 50 55 60

[3654] Glu Ala Lys Glu Ala Ala Asn Ala Glu Leu Asp Ser Tyr Gly Val Ser

[3655] 65 70 75 80

[3656] Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu Gly Val

[3657] 85 90 95

[3658] Glu Ala Leu Lys Asp Ala Ile Leu Ala Ala Leu Pro

[3659] 100 105

[3660] <210> 271

[3661] <211> 62

[3662] <212> PROTEIN

[3663] <213> Artificial sequence

[3664] <220>

[3665] <223> Modified bacterial sequence

[3666] <400> 271

[3667] Ala Glu Ala Lys Tyr Ala Lys Glu Val Leu Glu Ala Trp Asp Glu Ile

[3668] 1 5 10 15

[3669] Asp Arg Leu Pro Asn Leu Thr Ile Glu Gln Trp Leu Ala Phe Ile Asn

[3670] 20 25 30

[3671] Lys Leu Asp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3672] 35 40 45

[3673] Lys Lys Leu Asn Asp Ser Gln Ala Pro Lys Val Asp Gly Ser

[3674] 50 55 60

[3675] <210> 272

[3676] <211> 58

[3677] <212> PROTEIN

[3678] <213> Artificial sequence

[3679] <220>

[3680] <223> Modified bacterial sequence

[3681] <400> 272

[3682] Ala Glu Ala Lys Tyr Ala Lys Glu Met Arg Asn Ala Tyr Trp Glu Ile

[3683] 1 5 10 15

[3684] Ala Leu Leu Pro Asn Leu Thr Asn Gln Gln Lys Arg Ala Phe Ile Arg

[3685] 20 25 30

[3686] Lys Leu Tyr Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3687] 35 40 45

[3688] Lys Lys Leu Asn Asp Ser Gln Ala Pro Lys

[3689] 50 55

[3690] <210> 273

[3691] <211> 58

[3692] <212> PROTEIN

[3693] <213> Artificial sequence

[3694] <220>

[3695] <223> Modified bacterial sequence

[3696] <400> 273

[3697] Ala Glu Ala Lys Tyr Ala Lys Glu Met Arg Asn Ala Tyr Trp Glu Ile

[3698] 1 5 10 15

[3699] Ala Leu Leu Pro Asn Leu Thr Asn Gln Gln Lys Arg Ala Phe Ile Arg

[3700] 20 25 30

[3701] Lys Leu Tyr Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3702] 35 40 45

[3703] Lys Lys Leu Ser Glu Ser Gln Ala Pro Lys

[3704] 50 55

[3705] <210> 274

[3706] <211> 58

[3707] <212> PROTEIN

[3708] <213> Artificial sequence

[3709] <220>

[3710] <223> Modified bacterial sequence

[3711] <400> 274

[3712] Ala Glu Ala Lys Tyr Ala Lys Glu Met Arg Asn Ala Tyr Trp Glu Ile

[3713] 1 5 10 15

[3714] Ala Leu Leu Pro Asn Leu Thr Asn Gln Gln Lys Arg Ala Phe Ile Arg

[3715] 20 25 30

[3716] Lys Leu Tyr Arg Gln Pro Glu Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3717] 35 40 45

[3718] Lys Lys Leu Ser Glu Ser Gln Ala Pro Lys

[3719] 50 55

[3720] <210> 275

[3721] <211> 58

[3722] <212> PROTEIN

[3723] <213> Artificial sequence

[3724] <220>

[3725] <223> Modified bacterial sequence

[3726] <400> 275

[3727] Ala Glu Ala Lys Tyr Ala Lys Glu Leu Ile Glu Ala Ala Ala Glu Ile

[3728] 1 5 10 15

[3729] Asp Ala Leu Pro Asn Leu Thr Arg Arg Gln Trp Asn Ala Phe Ile Lys

[3730] 20 25 30

[3731] Lys Leu Val Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3732] 35 40 45

[3733] Lys Lys Leu Asn Asp Ser Gln Ala Pro Lys

[3734] 50 55

[3735] <210> 276

[3736] <211> 58

[3737] <212> PROTEIN

[3738] <213> Artificial sequence

[3739] <220>

[3740] <223> Modified bacterial sequence

[3741] <400> 276

[3742] Ala Glu Ala Lys Tyr Ala Lys Glu Leu Ile Glu Ala Ala Ala Glu Ile

[3743] 1 5 10 15

[3744] Asp Ala Leu Pro Asn Leu Thr Arg Arg Gln Trp Asn Ala Phe Ile Lys

[3745] 20 25 30

[3746] Lys Leu Val Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3747] 35 40 45

[3748] Lys Lys Leu Ser Glu Ser Gln Ala Pro Lys

[3749] 50 55

[3750] <210> 277

[3751] <211> 58

[3752] <212> PROTEIN

[3753] <213> Artificial sequence

[3754] <220>

[3755] <223> Modified bacterial sequence

[3756] <400> 277

[3757] Ala Glu Ala Lys Tyr Ala Lys Glu Leu Ile Glu Ala Ala Ala Glu Ile

[3758] 1 5 10 15

[3759] Asp Ala Leu Pro Asn Leu Thr Arg Arg Gln Trp Asn Ala Phe Ile Lys

[3760] 20 25 30

[3761] Lys Leu Val Arg Gln Pro Glu Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3762] 35 40 45

[3763] Lys Lys Leu Ser Glu Ser Gln Ala Pro Lys

[3764] 50 55

[3765] <210> 278

[3766] <211> 58

[3767] <212> PROTEIN

[3768] <213> Artificial sequence

[3769] <220>

[3770] <223> Modified bacterial sequence

[3771] <400> 278

[3772] Ala Glu Ala Lys Tyr Ala Lys Glu Gln Asp Ala Ala Ala His Glu Ile

[3773] 1 5 10 15

[3774] Arg Trp Leu Pro Asn Leu Thr Phe Asp Gln Arg Val Ala Phe Ile His

[3775] 20 25 30

[3776] Lys Leu Ala Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3777] 35 40 45

[3778] Lys Lys Leu Asn Asp Ser Gln Ala Pro Lys

[3779] 50 55

[3780] <210> 279

[3781] <211> 58

[3782] <212> PROTEIN

[3783] <213> Artificial sequence

[3784] <220>

[3785] <223> Modified bacterial sequence

[3786] <400> 279

[3787] Ala Glu Ala Lys Tyr Ala Lys Glu Gln Asp Ala Ala Ala His Glu Ile

[3788] 1 5 10 15

[3789] Arg Trp Leu Pro Asn Leu Thr Phe Asp Gln Arg Val Ala Phe Ile His

[3790] 20 25 30

[3791] Lys Leu Ala Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3792] 35 40 45

[3793] Lys Lys Leu Ser Glu Ser Gln Ala Pro Lys

[3794] 50 55

[3795] <210> 280

[3796] <211> 58

[3797] <212> PROTEIN

[3798] <213> Artificial sequence

[3799] <220>

[3800] <223> Modified bacterial sequence

[3801] <400> 280

[3802] Ala Glu Ala Lys Tyr Ala Lys Glu Gln Asp Ala Ala Ala His Glu Ile

[3803] 1 5 10 15

[3804] Arg Trp Leu Pro Asn Leu Thr Phe Asp Gln Arg Val Ala Phe Ile His

[3805] 20 25 30

[3806] Lys Leu Ala Arg Gln Pro Glu Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3807] 35 40 45

[3808] Lys Lys Leu Ser Glu Ser Gln Ala Pro Lys

[3809] 50 55

[3810] <210> 281

[3811] <211> 58

[3812] <212> PROTEIN

[3813] <213> Artificial sequence

[3814] <220>

[3815] <223> Modified bacterial sequence

[3816] <400> 281

[3817] Ala Glu Ala Lys Tyr Ala Lys Glu Asn Leu Phe Ala Gly Trp Glu Ile

[3818] 1 5 10 15

[3819] Ser Asp Leu Pro Asn Leu Thr Asp Tyr Gln Arg Asn Ala Phe Ile Tyr

[3820] 20 25 30

[3821] Lys Leu Trp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3822] 35 40 45

[3823] Lys Lys Leu Asn Asp Ser Gln Ala Pro Lys

[3824] 50 55

[3825] <210> 282

[3826] <211> 58

[3827] <212> PROTEIN

[3828] <213> Artificial sequence

[3829] <220>

[3830] <223> Modified bacterial sequence

[3831] <400> 282

[3832] Ala Glu Ala Lys Tyr Ala Lys Glu Asn Leu Phe Ala Gly Trp Glu Ile

[3833] 1 5 10 15

[3834] Ser Asp Leu Pro Asn Leu Thr Asp Tyr Gln Arg Asn Ala Phe Ile Tyr

[3835] 20 25 30

[3836] Lys Leu Trp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3837] 35 40 45

[3838] Lys Lys Leu Ser Glu Ser Gln Ala Pro Lys

[3839] 50 55

[3840] <210> 283

[3841] <211> 58

[3842] <212> PROTEIN

[3843] <213> Artificial sequence

[3844] <220>

[3845] <223> Modified bacterial sequence

[3846] <400> 283

[3847] Ala Glu Ala Lys Tyr Ala Lys Glu Asn Leu Phe Ala Gly Trp Glu Ile

[3848] 1 5 10 15

[3849] Ser Asp Leu Pro Asn Leu Thr Asp Tyr Gln Arg Asn Ala Phe Ile Tyr

[3850] 20 25 30

[3851] Lys Leu Trp Arg Gln Pro Glu Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3852] 35 40 45

[3853] Lys Lys Leu Ser Glu Ser Gln Ala Pro Lys

[3854] 50 55

[3855] <210> 284

[3856] <211> 58

[3857] <212> PROTEIN

[3858] <213> Artificial sequence

[3859] <220>

[3860] <223> Modified bacterial sequence

[3861] <400> 284

[3862] Ala Glu Ala Lys Tyr Ala Lys Glu Asn Leu Phe Ala Gly Trp Glu Ile

[3863] 1 5 10 15

[3864] Ser Asp Leu Pro Asn Leu Thr Asp Tyr Gln Arg Asn Ala Phe Ile Tyr

[3865] 20 25 30

[3866] Lys Leu Trp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3867] 35 40 45

[3868] Lys Lys Leu Asn Glu Ser Gln Ala Pro Lys

[3869] 50 55

[3870] <210> 285

[3871] <211> 58

[3872] <212> PROTEIN

[3873] <213> Artificial sequence

[3874] <220>

[3875] <223> Modified bacterial sequence

[3876] <400> 285

[3877] Ala Glu Ala Lys Tyr Ala Lys Glu Asn Leu Phe Ala Gly Trp Glu Ile

[3878] 1 5 10 15

[3879] Ser Asp Leu Pro Asn Leu Thr Asp Tyr Gln Arg Asn Ala Phe Ile Tyr

[3880] 20 25 30

[3881] Lys Leu Trp Arg Gln Pro Glu Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3882] 35 40 45

[3883] Lys Lys Leu Asn Glu Ser Gln Ala Pro Lys

[3884] 50 55

[3885] <210> 286

[3886] <211> 58

[3887] <212> PROTEIN

[3888] <213> Artificial sequence

[3889] <220>

[3890] <223> Modified bacterial sequence

[3891] <400> 286

[3892] Ala Glu Ala Lys Tyr Ala Lys Glu Asn Leu Phe Ala Gly Trp Glu Ile

[3893] 1 5 10 15

[3894] Ser Asp Leu Pro Asn Leu Thr Asp Tyr Gln Arg Asn Ala Phe Ile Tyr

[3895] 20 25 30

[3896] Lys Leu Trp Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3897] 35 40 45

[3898] Lys Lys Leu Ser Asp Ser Gln Ala Pro Lys

[3899] 50 55

[3900] <210> 287

[3901] <211> 58

[3902] <212> PROTEIN

[3903] <213> Artificial sequence

[3904] <220>

[3905] <223> Modified bacterial sequence

[3906] <400> 287

[3907] Ala Glu Ala Lys Tyr Ala Lys Glu Asn Leu Phe Ala Gly Trp Glu Ile

[3908] 1 5 10 15

[3909] Ser Asp Leu Pro Asn Leu Thr Asp Tyr Gln Arg Asn Ala Phe Ile Tyr

[3910] 20 25 30

[3911] Lys Leu Trp Arg Gln Pro Glu Gln Ser Ser Glu Leu Leu Ser Glu Ala

[3912] 35 40 45

[3913] Lys Lys Leu Ser Asp Ser Gln Ala Pro Lys

[3914] 50 55

[3915] <---

Claims

1. A polynucleotide encoding a polypeptide capable of binding human complement component 5 (C5), wherein the polypeptide comprises the amino acid sequence [BM]-[L2]-QSX 42 X 43 LLX 46 EAKKLX 52 X 53 X 54 Q where, independently of each other, [BM] is a C5-binding motif containing the amino acid sequence EX9X 10 X 11 AX 13 X 14 EIDX 18 LPNLX 23 X 24 X 25 QWX 28 AFIX 32 X 33 LX 35 ; where, independently of each other, X9 is selected from H, Q, S, T and V; X 10 selected from I, L, M and V; X 11 selected from A, D, E, H, K, L, N, Q, R, S, T and Y; X 13 selected from N and W; X 14 selected from A, D, E, H, N, Q, R, S and T; X 18selected from A, E, G, H, K, L, Q, R, S, T and Y; X 23 selected from N and T; X 24 selected from I, L and V; X 25 selected from A, D, E, H, K, N, Q, R, S and T; X 28 selected from I, L and V; X 32 selected from D, E, G, H, N, S and T; X 33 selected from K and S; X 35 selected from A, D, E, H, N, Q, S, T and Y; [L2] selected from DDPS and RQPE; X 42 represents S; X 43 represents E; X 46 represents S; X 52 X 53 X 54 represents SES, ESS, NES or SDS.

2. The polynucleotide according to claim 1, wherein the polypeptide comprises an amino acid sequence AEAKYAK-[BM]-[L2]-QSX 42 X 43 LLX 46 EAKKLX 52 X 53 X 54 QAP where, independently of each other, [BM], [L2], X 42 , X43 , X 46 , X 52 , X 53 and X 54 such as defined in paragraph 1.

3. A polynucleotide according to claim 1 or 2, where X 52 X 53 X 54 represents SES.

4. A polynucleotide according to claim 1 or 2, where X 52 X 53 X 54 represents ESS.

5. A polynucleotide according to claim 1 or 2, where X 52 X 53 X 54 represents NES.

6. A polynucleotide according to claim 1 or 2, where X 52 X 53 X 54 is SDS.

7. A polynucleotide according to any one of claims 1 to 6, wherein said polypeptide comprises an amino acid sequence AEAKYAKEX9X 10 X 11 AX 13 X 14 EIDX 18 LPNLX 23 X 24 X 25 QWX 28 AFIX 32 X 33 LX 35 -[L2]-QSX 42 X 43 LLX 46 EAKKLX 52 X 53 X 54 QAP; where, independently of each other, X9 is selected from H, Q, S, T and V; X 10 selected from I, L, M and V; X 11 selected from A, D, E, H, K, L, N, Q, R, S, T and Y; X 13 selected from N and W; X 14 selected from A, D, E, H, N, Q, R, S and T; X 18 selected from A, E, G, H, K, L, Q, R, S, T and Y; X 23 selected from N and T; X 24 selected from I, L and V; X 25 selected from A, D, E, H, K, N, Q, R, S and T; X 28 selected from I, L and V; X 32 selected from D, E, G, H, N, S and T; X 33 selected from K and S; X 35 selected from A, D, E, H, N, Q, S, T and Y; [L2] selected from DDPS and RQPE; X 42 represents S; X 43 represents E; X 46 represents S; X 52 X 53 X 54represents SES, ESS, NES or SDS.

8. A polynucleotide according to any one of claims 1 to 7, wherein at least one of the following conditions is met: X9 represents V, X 10 represents L, X 11 represents E, X 13 represents W, X 14 represents D, X 18 represents R, X 23 represents T, X 24 represents I, X 25 represents E, X 28 represents L, X 32 represents N, X 33 represents K, X 35 represents D, [L2] is a DDPS, X 42 represents S, X 43 represents E, X 46 represents S, X 54 represents S.

9. The polynucleotide of any one of claims 1 to 8, wherein [BM] comprises an amino acid sequence selected from the group consisting of positions 1 to 28 of any of the sequences SEQ ID NO: 1 to 248.

10. The polynucleotide according to claim 9, wherein [BM] comprises the amino acid sequence from positions 1-28 of the sequence SEQ ID NO:

1.

11. A polynucleotide according to any one of claims 1 to 10, wherein the polypeptide comprises the amino acid sequence SEQ ID NO:

260.

12. The polynucleotide according to any one of claims 1 to 10, wherein the polypeptide comprises the amino acid sequence SEQ ID NO:

265.

13. The polynucleotide according to any one of claims 1 to 10, wherein the polypeptide comprises the amino acid sequence SEQ ID NO:

266.

14. The polynucleotide according to any one of claims 1 to 10, wherein the polypeptide comprises the amino acid sequence SEQ ID NO:

267.

15. The polynucleotide of any one of claims 1 to 10, wherein the polypeptide comprises the amino acid sequence SEQ ID NO:

261.

16. The polynucleotide of any one of claims 1 to 10, wherein the polypeptide comprises the amino acid sequence SEQ ID NO:

263.

17. The polynucleotide of any one of claims 1 to 10, wherein the polypeptide comprises the amino acid sequence SEQ ID NO:

264.

18. The polynucleotide of any one of claims 1 to 10, wherein the polypeptide comprises the amino acid sequence SEQ ID NO:

269.

19. The polynucleotide according to any one of claims 1 to 10, wherein the polypeptide comprises the amino acid sequence SEQ ID NO:

270.

20. An expression vector comprising a polynucleotide according to any of the preceding claims.

21. A host cell for expressing a polypeptide capable of binding human complement component 5 (C5), wherein the host cell comprises the vector of claim 20.

Images