RU2809788C2 - Improved immunoglobulin variable domains - Google Patents

Abstract

FIELD: biotechnology; medicine.

SUBSTANCE: immunoglobulin heavy chain single variable domain (ISVD) is a VHH domain, a humanized VHH domain, or an overblown VH domain that is directed against TNF, in which (i) position 112 is either K or Q; or (ii) position 110 is either K or Q and position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is either K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)–(v). The polypeptide has reduced binding to pre-existing antibodies present in samples from subjects suffering from SLE, compared to a polypeptide containing VHH, humanized VHH or overblown VH without amino acid residues (i) 112 K or Q; (ii) 110 K or Q and 11 V; (iii) 89T; (iv) 89L and 110 K or Q; or (v) 11B and 89L; where the positions of amino acid residues are designated by Kabat numbering.

EFFECT: invention can be used in a pharmaceutical composition directed against TNF.

24 cl, 31 dwg, 37 tbl, 15 ex

Description

Field of technology to which the invention relates

The present invention relates to improved immunoglobulin heavy chain variable domains.

In particular, the invention relates to improved immunoglobulin heavy chain variable domains which either have an exposed C-terminal region or end (as described below, also see WO 12/175741) or are used (or intended to be used) in applications where they have an exposed C-terminal region or end (again as described below). Some preferred, but not limited to, examples of these are single immunoglobulin variable domains (which are also referred to herein as “ISV” or “ISVD”), such as nanobodies (including _VHH , humanized _VHH , and camelized _VH , such as camelized human _VH ), (single domain) antibodies that are _VH domains or derived from _VH domains, and dAbs that are _VH domains or derived from _VH domains. Some preferred, but not limited to, examples of the latter are V _H domains that are used (or intended to be used) in single chain Fv (scFv) or diabodies.

The invention also relates to proteins, polypeptides and other constructs, molecules or chemical compounds containing or essentially consisting of (one or more) improved immunoglobulin heavy chain variable domains of the invention as described herein; methods for expressing/producing improved immunoglobulin heavy chain variable domains of the invention and/or expressing/producing proteins, polypeptides and other constructs, molecules or chemical compounds containing them; compositions and products (such as pharmaceutical compositions and products) containing improved immunoglobulin heavy chain variable domains of the invention and/or proteins, polypeptides and other constructs, molecules or chemical compounds containing them; sequences of nucleotides and nucleic acids encoding the improved variable domains of the heavy chain of the immunoglobulin according to the invention and/or encoding proteins or polypeptides containing them; and the use (in particular, therapeutic, prophylactic and diagnostic use) of the improved immunoglobulin heavy chain variable domains of the invention and proteins, polypeptides and other constructs, molecules or chemical compounds containing them.

Other aspects, embodiments, advantages, applications and uses of the present invention will become apparent from the following description.

State of the art

In this application, amino acid residues/positions in the variable domain of the immunoglobulin heavy chain will be designated by Kabat numbering. For convenience, in FIG. 1 is a table listing some of the amino acid positions that will be specifically mentioned here and their numbering according to some alternative numbering systems such as AHo and IMGT. Note: for the present description and claims, the Kabat numbering is decisive; other numbering systems are for reference only).

In addition, in the invention, an immunoglobulin variable domain is said to have an “exposed C-terminal end or region” if it is not linked or linked to a constant domain (such as a C _H 1 domain). We refer to the works presented here from the prior art.

In particular, as described in WO 12/175741, the C-terminal region (as this term is also used here) is part of a putative epitope on ISV, which also includes, among other residues, the amino acid residue at position 14 (and the amino acid residues near it in the amino acid sequence, such as positions 11, 13 and 15), and may also include the amino acid residue at position 83 (and amino acid residues near it in the amino acid sequence, such as positions 82, 82a, 82b and 84) and/or an amino acid residue at position 108 (and amino acid residues nearby in the amino acid sequence, such as position 107). As in WO 12/17574, this putative epitope is also collectively referred to herein as the “C-terminal region”, which C-terminal region is intended to at least include the C-terminal sequence VTVSS (i.e., each of positions 109, 110, 111, 112 and 113) and an amino acid residue at position 14, and may also contain amino acid residues at positions 83 and 108, and possibly amino acid residues at positions 13, 15, 82b, 83, 84 and 107.

As a result of studies of single-chain Fvs or “scFvs” (which are constructs containing immunoglobulin variable domains that, like ISVDs, are not associated with constant domains) in this area, it has been described that the C-terminus of the immunoglobulin variable domain contains a hydrophobic region that In conventional full-length antibodies, it is embedded in the interface between the variable domain and the constant domain, but becomes accessible to solvents when the variable domain is not associated with the constant domain (for example, see Nieba et al., Protein Engineering, 10, 435-444 (1997) and Harmsen et al., Molecular Immunology (2000), 579-590).

It is also well known that epitopes that are normally buried in protein structure (also known as “neoepitopes” or “cryptic epitopes”) can trigger the immune system as soon as they become exposed to solvents, for example due to degradation, misfolding or aggregation of this protein. For example, in the case of the buried hydrophobic portions of biomolecules (so-called “hyppos”), it has been proposed that they form part of a general damage-associated molecular template that leads to an innate immune response once the hyppos are exposed to solvents (for example, see Seong and Matzinger, Nature Reviews 2004, 469), and various examples of previously buried hydrophobic sites causing immune responses have been described (for example, see David et al., JBC, 2001, 6370-6377; Matsuura et al., International Immunology, 2000, 1183-1192; Rasheed et al., Life Sciences 79 (2000), 2320-2328). More generally, it is also known that hydrophobic amino acids tend to be part of B cell epitopes (eg, see WO 11/07586, page 10; and Kolaskar, FEBS 276, 172-174 (1990)). Thus, it has been described that the hydrophobic region at the C-terminus of the heavy chain variable domain (as described in Nieba et al. and Harmsen et al., supra) can form B cell epitopes that can generate and/or interact with ( emerging and/or pre-existing) anti-drug antibodies (WO 11/07586). For this reason, it has been proposed to mutate certain amino acid residues comprising the C-termini of the variable domains to reduce hydrophobicity and/or remove B cell epitopes. For example, Nieba et al. proposed to mutate positions 11, 14, 41, 84, 87 and/or 89 in the V _H region (Kabat numbering), and in WO 11/07586 proposed to mutate positions 99, 101 and/or 148 (AHo numbering) of the V _L domain or provisions 12, 97, 98, 99, 103 and/or 144 of the V _H domain (again according to AHo - these provisions correspond to provisions 11, 83, 84, 85, 89 and 103 according to Kabat). Similarly, Harmsen et al. proposed to mutate positions 12 and 101 (IMGT numbering; these are positions 11 and 89 according to Kabat) to compensate for the absence of the C _H 1 domain; and they also identified a specific subfamily of V _HH (termed "V _HH 4") containing amino acids that are suitable candidates for substitution at these positions.

It has also been described (for example, see WO 12/175741 and the references given in the following paragraphs) that biological samples taken from humans may contain (pre-existing) proteins or factors that are capable of binding to the exposed C-terminal region or end an immunoglobulin variable domain (eg, the C-terminal region or end of the ISVD or the _VH or _VL domain in scFvs or diabodies).

For example, WO 2013/024059 states that “anti- _VH autoantibodies are already present in serum from some healthy naïve human subjects, which can bind both anti- _VH domain antibodies and _VHH molecules, as well as anti- _VL autoantibodies (e.g. anti-V-kappa (VK)), which can bind _VL molecules,” and that “preexisting ADAs that bind anti- _VH dAbs are similar to anti-hinge antibodies in that they bind IgG fragments but do not bind the same sequences located in situ on intact IgG.”

In Holland et al., J. Clin. Immunol. 2013, 33(7):1192-203 described that the blood of approximately half of normal healthy people contains varying levels of a new class of anti-IgG autoantibodies that can bind to the framework sequences of fully human anti-V _H domain antibodies (which Holland et al. also refer to as “HAVH autoantibodies”). Holland et al. also note that these autoantibodies are primarily of the IgG isotype, exhibit relatively high affinity (about ¹⁰⁻¹⁰ M) for _VH sequences, and the free C-terminus appears to be important for the binding of these HAVH autoantibodies to _VH domains.

Issues regarding pre-existing antibodies against biotherapeutic molecules reacting with biotherapeutics and their regulatory effects in general are also discussed in Xue et al., AAPS J. 2013, 15(3):852-5.

The foregoing prior art also addresses methods in which the sequence of an immunoglobulin variable domain can be modified to prevent or reduce binding of such preexisting antibodies/factors to the variable domains. In this regard, WO 2011/07586 proposes to make one or more mutations in the amino acid sequence of a variable domain at certain specific positions of this domain (these positions are exposed). WO 12/175741 describes that the binding of such pre-existing antibodies/factors can be reduced by adding several amino acid residues (even just one alanine residue) to the C-terminal region of the V _H domain and/or by introducing one or more specific substitutions or deletions in The C-terminal region of the variable domain, which is described in WO 12/175741 as comprising at least the C-terminal amino acid sequence VTVSS and the amino acid residue at position 14 (with respect to this position, WO 12/175741 states that the presence of an alanine residue provides reduced binding pre-existing antibodies compared to the presence of the “human” amino acid residue proline), and possibly also amino acid residues at positions 108 and 83 and amino acid residues close to these positions (WO 2013/024059 says basically the same as WO 12 /175741).

For example, in studies conducted by applicant/assignee that led to the filing of WO 12/175741, it was found that adding just one alanine residue to the C-terminal region or end of the exposed _VH domain generally prevents/eliminates (almost completely ) binding of pre-existing antibodies/factors present in samples taken from most subjects (for example, see page 62, lines 20-25, and line 30 on page 57 to line 3 on page 58 in WO 12/175741 ); these data were confirmed by additional results obtained by the applicant/assignee after filing WO 12/175741 when the C-terminal alanine substitution from WO 12/175741 was applied to other nanobodies (data not shown).

Additionally, WO 12/175741, as well as applicant/assignee WO 12/175400, applied the C-terminal extensions described in WO 12/175741 to certain serum albumin binding nanobodies (for example, see WO 12/175741 : SEQ ID NOs: 37, 51-53 and 55-64 and the designs presented in SEQ ID NOs: 41, 43 and 44; and WO 12/175400: SEQ ID NOs: 6-11).

In fig. 9 in WO 12/175741 also shows two albumin binding sequences which are used as reference sequences below in the Experimental Section. This is the sequence of SEQ ID NO: 37 in FIG. 9 in WO 12/175741 (which is also given here as “standard B”, this sequence is shown here as SEQ ID NO: 45) and “SEQ ID NO: 37 without added C-terminal amino acid residues” in FIG. 9 in WO 12/175741 (which is also given here as “Standard A”, this sequence is given in SEQ ID NO: 44). Standard A and Standard B are derived from the sequence of the humanized anti-albumin nanobody “Alb-8”, which is given as SEQ ID NO: 62 in WO 06/122787 (and also given here as “Alb-11”), but, compared to the sequence Alb-11, standard A contains an N-terminal His tag, and standard B contains an N-terminal His tag and a C-terminal alanine residue. Standard A, Standard B and Alb-8/Alb-11 contain the CDRs given in SEQ ID NOs: 41-43, respectively.

Other examples of nanobodies and other single immunoglobulin variable domains having C-terminal extensions and/or mutations in the C-terminal region can be found, for example, in the following prior art: WO 06/129843 (for example, see SEQ ID NOs : 4, 6, 8 and 10); WO 03/035695 (for example, see some of the sequences given on pages 61-64); Vu et al., Molecular Immunology, 1121-1131, 1997 (for example, see some of the sequences shown in FIG. 2); WO 11/003622 (for example, see the sequences given in SEQ ID NOs: 10-27); WO 09/058383 (for example, see the sequence TAR2h-10-27 mentioned on page 51); WO 10/042815 (for example, see SEQ ID NOs: 1, 17, 27 and 30); and WO 04/044204 (for example, see SEQ ID NOs: 31, 35, 37, 47 and 49).

Some of the references herein also provide examples of ISVD sequences in which the last C-terminal amino acid of the ISVD is an amino acid other than serine (S), for example, because the serine at position 113 has been replaced by a different amino acid, and/or because the serine at position 113 was removed and a C-terminal amino acid was added (in practice, the end result in terms of the C-terminal amino acid sequence would be the same).

Some of the references herein also provide examples of nanobodies and other immunoglobulin single variable domains in which the amino acid at position 112 is not serine. For example, WO 12/175741 describes nanobodies in which the amino acid at position 112 is glycine (G); in Vu et al. (above) describes nanobodies in which position 112 is alanine (A) or isoleucine (I); WO 13/024059 provides a replacement for S112A; and WO 08/020079, cited below, introduces the S112F substitution and generally states that the nanobodies described therein may contain a limited number of amino acid residues added to the C-terminal region of the amino acid sequence of the nanobody.

In the studies leading to the present invention, after it was determined that the introduction of a C-terminal extension (which may be as little as a single C-terminal alanine residue, again see WO 12/175741, Example 3) into the C- the terminal region or end of the nanobody essentially prevents/eliminates the binding of pre-existing antibodies/factors in most test subjects/patient samples, it was investigated whether samples obtained from test subjects (healthy volunteers and/or patients suffering from disease or disease) would contain (other) pre-existing antibodies or factors that can bind to the exposed C-terminal region of a nanobody (or other _VH domain) even in the presence of a C-terminal extension. In doing so, the present inventors have discovered that although there is virtually no detectable binding of such preexisting antibodies to the C-terminal extension V _H domain in the blood or serum of healthy volunteers or in the blood or serum obtained from patients suffering from one of a number of different diseases ( including some inflammatory diseases or autoimmune diseases - data not shown), but in some blood or serum samples obtained from some (but not all) subjects suffering from certain severe (auto)immune diseases (such as systemic lupus erythematosus; abbreviated as “SLE”) , contain some pre-existing antibodies/factors that can bind to nanobodies even when these nanobodies contain a C-terminal extension.

The essence of the invention

So, in general, it is an object of the present invention to provide improved immunoglobulin heavy chain variable domains (in particular, improved heavy chain ISVDs, more preferably improved nanobodies) which, when they have an exposed C-terminal region or end, will be less likely to bind to pre-existing antibodies/factors such as those found in blood or serum samples obtained from test subjects.

In particular, it is an object of the present invention to provide improved immunoglobulin heavy chain variable domains which, when they have an exposed C-terminal region or end, will be less likely to bind to pre-existing antibodies/factors (again of the type found in blood or serum obtained from test subjects) which can still bind to the exposed C-terminal region or end of the heavy chain variable domain even when the domain contains a C-terminal extension (for example, as described in WO 12/175741, WO 13 /024059 and other prior art works cited here).

As already noted, such pre-existing antibodies that can bind to the heavy chain variable domain with a C-terminal extension have been discovered by the present inventors in blood or serum samples obtained from subjects suffering from certain (auto)immune diseases in which the immune system is compromised strong impact/activated (SLE type).

Thus, it is more preferably an object of the present invention to provide improved immunoglobulin heavy chain variable domains (in particular, improved heavy chain ISVDs, more preferably improved nanobodies) which, when they have an exposed C-terminal region or end, will be less likely to bind to pre-existing antibodies/factors of the type found in blood or serum samples obtained from subjects suffering from certain (auto)immune diseases in which the immune system is severely affected/activated (such as SLE).

Even more preferably, it is an object of the present invention to provide improved immunoglobulin heavy chain variable domains (in particular, improved heavy chain ISVDs, more preferably improved nanobodies) which, when they have an exposed C-terminal region or tail, will be less likely to bind to such pre-existing antibodies/factors that are found in blood or serum samples obtained from subjects suffering from certain (auto)immune diseases, which can still bind to the exposed C-terminal region or the end of the heavy chain variable domain and when this domain contains C -end extension.

Now it appears that the binding of preexisting antibodies/factors to the C-terminal exposed heavy chain variable domain can be (further) reduced by mutation of the serine at position 112 (Kabat numbering) to lysine (K) or glutamine (Q). In particular, it appears that such a S112K or S112Q mutation can (further) reduce or virtually prevent/eliminate the binding of such pre-existing antibodies/factors that can bind to a heavy chain variable domain containing a C-terminal extension (but without the S112K or S112Q mutation ), such as those pre-existing antibodies/factors found in the blood or serum of subjects suffering from severe autoimmune diseases such as SLE).

It also appears that the introduction of certain mutations described here (in particular the following mutation L11V in combination with V89L, and optionally also in combination with T110K) can improve or help to (further) improve the solubility of such single immunoglobulin variable domains as ISVDs in general and in particular disclosed in the present description (data not provided).

Thus, in a first aspect, the present invention relates to immunoglobulin heavy chain variable domains ( _VH domains) in which the amino acid residue at position 112 (Kabat numbering) is a lysine residue (K) or a glutamine residue (Q). Such immunoglobulin heavy chain variable domains are also referred to herein as “V _H domains of the invention.” And when the V _H domain of the invention is a single immunoglobulin variable domain (which is preferred), it is also referred to herein as “ISVD of the invention.” Likewise, when the _VH domain of the invention is a nanobody (even more preferably), it is also referred to herein as a “nanobody of the invention”.

Generally, the V _H domains of the invention have a C-terminal end or region exposed and/or are found in proteins, polypeptides, compounds, entities or constructs in which they have a C-terminal end or region exposed, and/or are intended for use, in which they have an exposed C-terminal region (eg, for use in proteins, polypeptides, compounds, objects or constructs in which they must form a C-terminal end or region).

In one aspect of the invention, the V _H domain of the invention is a single immunoglobulin (heavy chain) variable domain, which means a heavy chain variable domain that can form a functional antigen binding site without interacting with the V _L domain. For example, the _VH domain of the invention may be a nanobody (including _VHH , humanized _VHH and camellized _VH such as human camellized _VH ), a (single domain) antibody that is a _VH domain or derived from a _VH domain, or a dAb , which is a _VH domain or derived from a _VH domain. The _VH domain of the invention is preferably a nanobody (eg, a _VHH domain, a humanized _VHH domain, or a Camelized _VH domain such as a human Camelized _VH domain).

In accordance with another aspect of the invention, the V _H domain of the invention may be a heavy chain variable domain that, in the protein, polypeptide, entity or construct in which it is found, actually requires interaction with the V _L domain to form an antigen binding site and does have or form an exposed C-terminal end or region. For example, the V _H domain in accordance with this aspect of the invention may be a V _H domain that is found and/or used in scFvs and/or diabodies.

In accordance with a more specific aspect of the invention, the V _H domain of the invention has a C-terminal sequence (Kabat positions 109-113), which is represented by VTVKS (SEQ ID NO: 1) or VTVQS (SEQ ID NO: 2), or a sequence which differs in one amino acid (i.e. at one of positions 109, 110, 111 or 113) from the sequence VTVKS and/or VTVQS and also contains lysine (K) or glutamine (Q) at position 112.

Additionally, as described below, in one particularly preferred aspect of the invention, the V _H domain of the invention also contains a C-terminal extension (for example, as described in WO 12/175741 and/or WO 13/024059) at the C-terminus (i.e. that is, it binds to a serine residue at the end of a VTVKS, VTVQS or similar motif), particularly a C-terminal extension as defined below. However, as also described below, it is also possible that VTVKS, VTVQS or a similar motif forms the C-terminal end of the V _H domain (although this is generally less preferred) or that the V _H domain of the invention joins at the C-terminal end (optionally via a suitable linker) with a different amino acid sequence, moiety, domain or binding block. For example, when the V _H domain of the invention is an ISVD, the V _H domain may be C-terminally connected to another ISVD, optionally via a linker (and the other ISVD may also be a V _H domain of the invention).

In general, as is well known for immunoglobulin variable domains in general, the V _H domains of the invention should contain 4 framework regions (FW1, FW2, FW3 and FW4) and 3 CDR regions (CDR1, CDR2 and CDR3). As with variable domains in general, the sequences of the CDR regions will depend on the antigen/target to which the V _H domains of the invention have been prepared and/or to which they are intended to bind. The framework regions can generally be any suitable framework regions for V _H domains (although position 112 and/or position 89 should be as described below). If the V _H domain of the invention is an ISVD, then the V _H domain must have framework sequences that are suitable for an ISVD (optionally in combination with one or more of the CDR regions). For example, if the _VH domain of the invention is a nanobody, then the framework regions will generally contain a suitable number of characteristic _VHH residues (for which reference is made, for example, to WO 08/020079 and certain other applicant/assignee patent applications cited herein) .

Thus, for example, when the _VH domains of the invention are nanobodies, the nanobodies of the invention may contain one or more “characteristic residues” that are characteristic of _VHH /nanobodies (e.g., at positions 11, 37, 44, 45, 47, 83 , 84, 103, 104 and/or 108; for example, see tables A-3 and A-5 to A-8 in WO 08/020079); one or more other amino acid residues that may be present in V _HH /nanobodies (such as one or more humanizing substitutions that are known per se for V _HH and nanobodies; refer, for example, to WO 08/020079, again see previously mentioned tables A-3 and A-5 to A-8), and/or one or more other suitable amino acid residues or substitutions for V _HH /nanobodies; or any suitable combinations of such amino acid residues/substitutions.

Nanobodies of the invention having a K or Q at position 112 (with or without a C-terminal extension) preferably at position 11 contain an amino acid that is selected from L (this amino acid residue is most often found in V _HH ), E, K , M, S, V, W and Y; more preferably from L, E, K, V and Y and even more preferably from L, K and V (with V being the most preferred). For example, and without limitation, compared to the leucine residue that is most commonly found in V _HH , they may contain the L11K or L11V mutation. For example, but without limitation, they may also contain the Q108L mutation (a well-known humanizing substitution for V _HH /nanobodies). Other amino acid residues that may be present (again, without limitation, for example, other amino acid residues that naturally occur at that position in human _VH or _VHH may also be present at these positions) are represented by, for example, one or several of alanine (A) at position 14 (this amino acid residue is very common in natural V _HH ), proline at position 14 (this is the most common amino acid at this position in human V _H domains), and mutations proposed by Harmsen et al. (particularly those proposed by Harmsen et al. based on the V _HH class V _HH 4 sequence, such as V89M or V89T), and/or (other) mutations at positions proposed by Nieba (for example, in one or more from provisions 11, 87 and/or 89, see Nieba, page 437, right column). Another suitable mutation is, for example, T110K or T110Q. And also: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) given in table. A-6 in WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), then is one of those amino acid residues most commonly found at this position in humans or llamas, more preferably it may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 in WO 08/020079 for position 42, in particular it may be (or selected from) glycine (G) or glutamic acid (E), and/or (iii) position 87 may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 in WO 08/020079 for position 87, in particular it may be (or is selected from) threonine (T) or alanine (A).

In accordance with a more specific aspect of the invention, the _VH domain of the invention (as described below) has a framework region 4 (FW4) sequence, which is represented by:

a) one of the FW4 sequences according to SEQ ID NOs: 3-20, given below in table. 1:

Table 1. FW4 sequences

WGQGTQVTVKS (SEQ ID NO:3) WGKGTLVTVKS (SEQ ID NO:4) RGQGTRVTVKS (SEQ ID NO:5) WGLGTQVTISS (SEQ ID NO:6) GSQGTQVTVKS (SEQ ID NO:7) LRGGTQVTVKS (SEQ ID NO:8) RGQGTLVTVKS (SEQ ID NO:9) RSRGIQVTVKS (SEQ ID NO:10) WGKGTQVTVKS (SEQ ID NO:11) WGQGTQVTVQS (SEQ ID NO:12) WGKGTLVTVQS (SEQ ID NO:13) RGQGTRVTVQS (SEQ ID NO:14) WGLGTQVTISS (SEQ ID NO:15) GSQGTQVTVQS (SEQ ID NO:16) LRGGTQVTVQS (SEQ ID NO:17) RGQGTLVTVQS (SEQ ID NO:18) RSRGIQVTVQS (SEQ ID NO:19) WGKGTQVTVQS (SEQ ID NO:20)

or

b) a sequence that has no more than 3, preferably no more than 2 amino acid differences from at least one of the FW4 sequences of SEQ ID Nos 3-20, in which (i) an amino acid residue at a position corresponding to position 112 in the Kabat numbering, represented by K or Q; and (ii) the amino acid residue at the position corresponding to position 103 in the Kabat numbering, preferably represented by W or R; (iii) the amino acid residue at the position corresponding to position 104 in the Kabat numbering is preferably represented by G; (iv) the amino acid residue at the position corresponding to position 106 in the Kabat numbering is preferably represented by G; (v) the amino acid residue at the position corresponding to position 107 in the Kabat numbering is preferably represented by T; (vi) the amino acid residue at the position corresponding to position 108 in the Kabat numbering is preferably Q or L (and in humanized nanobodies it is preferably L); (vii) the amino acid residue at the position corresponding to position 109 in the Kabat numbering is preferably represented by V; (viii) the amino acid residue at the position corresponding to position 110 in the Kabat numbering is preferably represented by T (or it may be K or Q); (ix) the amino acid residue at the position corresponding to position 111 in the Kabat numbering is preferably represented by V. Below in the table. 2 provides some non-limiting examples of amino acid residues that may be present at various positions (numbered according to Kabat) in such FW4 sequences.

Table 2. Examples of amino acid residues that may be present in the FW4 sequences of the V _H domains of the invention

Pos. Amino acid residues 103 W, R, G, S, K, A, M, Y, L, F, T, N, V, Q, P, E, C; preferably W 104 G, A, S, T, D, P, N, E, C, L; preferably G 105 Q, K, H, R, P, E, L, T, N, S, V, A, M, G 106 G, R, E 107 T, Q, I, A, S, N, R, V, D 108 Q, L, R, P, E, K, S, T, M, A, H; preferably Q or L 109 V, I, L 110 T, S, N, A, I, F, K, Q 111 V, I, A 112 K or Q (according to invention) 113 S, T, A, L, P, F, E, V

Preferably, the _VH domain of the invention has a framework region 4 (FW4) sequence, which is represented by:

a) WGQGTQVTVKS (SEQ ID NO: 3) or WGQGTQVTVQS (SEQ ID NO: 12); or

b) a sequence that has no more than 3, preferably no more than 2 amino acid differences (such as only one amino acid difference) from SEQ ID NO: 3 and/or SEQ ID NO: 12, in which (i) an amino acid residue in the position corresponding to position 112 in the Kabat numbering is represented by K or Q; and (ii) the amino acid residue at the position corresponding to position 103 in the Kabat numbering, preferably represented by W or R; (iii) the amino acid residue at the position corresponding to position 104 in the Kabat numbering is preferably represented by G; (iv) the amino acid residue at the position corresponding to position 106 in the Kabat numbering is preferably represented by G; (v) the amino acid residue at the position corresponding to position 107 in the Kabat numbering is preferably represented by T; (vi) the amino acid residue at the position corresponding to position 108 in the Kabat numbering is preferably Q or L (and in humanized nanobodies it is preferably L); (vii) the amino acid residue at the position corresponding to position 109 in the Kabat numbering is preferably represented by V; (viii) the amino acid residue at the position corresponding to position 110 in the Kabat numbering is preferably represented by T (or it may be K or Q); (ix) the amino acid residue at the position corresponding to position 111 in the Kabat numbering is preferably represented by V. Again in the table. 2 provides some non-limiting examples of amino acid residues that may be present at various positions (numbered according to Kabat) in such FW4 sequences.

As described below, in accordance with a preferred aspect of the invention, V _H domains of the invention containing such an FW4 sequence as described above preferably also contain a C-terminal extension (as described below). However, also as described below, it is also possible that the FW4 sequence forms the C-terminal end of a V _H domain (although this is generally less preferred) or that the V _H domain of the invention is joined at the C-terminal end (optionally via a suitable linker) to another amino acid sequence, grouping, domain or linking block. For example, when the V _H domain of the invention is an ISVD, the V _H domain may be C-terminally connected to another ISVD, optionally via a linker (and the other ISVD may also be a V _H domain of the invention).

As stated herein, in accordance with a preferred, but not limiting, aspect of the invention, the V _H domains of the invention contain a C-terminal extension, such as the C-terminal extension described in WO 12/175741 and/or WO 13/024059, in features as described in WO 12/175741.

Thus, in accordance with this aspect, the V _H domain of the invention is an immunoglobulin heavy chain variable domain (V _H domain) in which: (i) the amino acid residue at position 112 (Kabat numbering) is not a serine residue, but is preferably represented by either a lysine residue (K) or a glutamine residue (Q); and (ii) connects at the C-terminal end (i.e., the amino acid residue at the position corresponding to position 113 in the Kabat numbering) with another amino acid sequence (i.e., the “C-terminal extension”), which includes from 1 up to 5 amino acid residues (such as 1, 2, 3, 4 or 5, preferably 1, 2 or 3, and most preferably only 1 or 2, such as only 1), each independently selected from suitable amino acid residues, and preferably each is independently selected from naturally occurring amino acids, and even more preferably each is independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I) (although, as can be seen from the data presented in WO 12/17574, other amino acid residues such as serine, proline, threonine and/or lysine can also be used in the C-terminal extension).

In particular, in accordance with this aspect of the invention, the V _H domain of the invention preferably has a C-terminal sequence, which is represented by VTVKS(X) _n (SEQ ID NO:21) or VTVQS(X) _n (SEQ ID NO:22) or the same amino acid sequence in which at the positions of the VTVKS motif or VTVQS motif there is a difference in one amino acid from the VTVKS and/or VTVQS sequence, but retains lysine (K) or glutamine (Q) at position 112, while (i) amino acid residues of the motif VTVKS or VTVQS (or a motif similar to VTVKS or VTVQS) corresponds to positions 109-113 of the _VH domain by Kabat numbering; (ii) n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (preferably 1 or 2, such as 1); and (iii) each X is an amino acid residue (preferably naturally occurring) that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I).

More preferably, in accordance with this aspect of the invention, the V _H domain of the invention as the FW4 sequence may have one of the FW4 sequences of SEQ ID NOs 3-20 (or an amino acid sequence that has no more than 3, preferably no more than 2 amino acid differences from at least one of the FW4 sequences of SEQ ID NOs 3-20, wherein the amino acid residue at the position corresponding to Kabat numbering position 112 is K or Q), in which the FW4 sequence is joined at the C-terminal end to the C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (preferably 1 or 2, such as 1); and each X represents an amino acid residue (preferably naturally occurring) that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) .

Accordingly, in this aspect of the invention, the V _H domain of the invention may have at its C-terminal end:

a) one of the amino acid sequences shown as SEQ ID NOs 23-40 in table. 3:

Table 3. FW4 sequences with C-terminal extension

WGQGTQVTVKS(X) _n (SEQ ID NO:23) WGKGTLVTVKS(X) _n (SEQ ID NO:24) RGQGTRVTVKS(X) _n (SEQ ID NO:25) WGLGTQVTISS(X) _n (SEQ ID NO:26) GSQGTQVTVKS(X) _n (SEQ ID NO:27) LRGGTQVTVKS(X) _n (SEQ ID NO:28) RGQGTLVTVKS(X) _n (SEQ ID NO:29) RSRGIQVTVKS(X) _n (SEQ ID NO:30) WGKGTQVTVKS(X) _n (SEQ ID NO:31) WGQGTQVTVQS(X) _n (SEQ ID NO:32) WGKGTLVTVQS(X) _n (SEQ ID NO:33) RGQGTRVTVQS(X) _n (SEQ ID NO:34) WGLGTQVTISS(X) _n (SEQ ID NO:35) GSQGTQVTVQS(X) _n (SEQ ID NO:36) LRGGTQVTVQS(X) _n (SEQ ID NO:37) RGQGTLVTVQS(X) _n (SEQ ID NO:38) RSRGIQVTVQS(X) _n (SEQ ID NO:39) WGKGTQVTVQS(X) _n (SEQ ID NO:40)

wherein (i) the amino acid residues of the FW4 sequences that precede the (X) _n in the C-terminal extension of SEQ ID NOs: 23-40 correspond to the amino acid positions in the FW4 V _H domain (i.e., positions 103-113 in Kabat numbering ); (ii) n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (preferably 1 or 2, such as 1); and (iii) each X represents an amino acid residue (preferably naturally occurring) which is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I); or

b) an amino acid sequence having no more than 3, preferably no more than 2 amino acid differences from at least one of the amino acid sequences of SEQ ID NOs 23-40 (and these amino acid differences occur at positions corresponding to the amino acid positions in the FW4 domain _VH , i.e., to positions 103-113 according to Kabat numbering, without taking into account any differences in amino acids within the C-terminal extension (X) _n ), with: (i) an amino acid residue at a position corresponding to position 112 according to Kabat numbering , represented by K or Q; (ii) n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (preferably 1 or 2, such as 1); and (iii) each X represents an amino acid residue (preferably naturally occurring) which is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I). Again, in addition to points (i)-(iii) given in the previous sentence, in the following amino acid sequence: (iv) the amino acid residue at the position corresponding to position 103 in the Kabat numbering is preferably represented by W or R; (v) the amino acid residue at the position corresponding to position 104 in the Kabat numbering is preferably represented by G; (vi) the amino acid residue at the position corresponding to position 106 in the Kabat numbering is preferably represented by G; (vii) the amino acid residue at the position corresponding to position 107 in the Kabat numbering is preferably represented by T; (viii) the amino acid residue at the position corresponding to position 108 in the Kabat numbering is preferably Q or L (and in humanized nanobodies it is preferably L); (ix) the amino acid residue at the position corresponding to position 109 in the Kabat numbering is preferably represented by V; (x) the amino acid residue at the position corresponding to position 110 in the Kabat numbering is preferably represented by T (or it may be K or Q); (xi) the amino acid residue at the position corresponding to position 111 in the Kabat numbering is preferably represented by V; again we refer to the table. 2 regarding such amino acid residues that may be present at each position.

Preferably, in accordance with this aspect of the invention, the V _H domain of the invention may have at its C-terminal end:

a) an amino acid sequence represented by WGQGTQVTVKS(X) _n (SEQ ID NO:23) or WGQGTQVTVQS(X) _n (SEQ ID NO:32), where n is 1-10, preferably 1-5, such as 1, 2 , 3, 4 or 5 (preferably 1 or 2, somehow 1); and each X represents an amino acid residue (preferably naturally occurring) that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) ; or

b) an amino acid sequence having no more than 3, preferably no more than 2 amino acid differences from at least one of the amino acid sequences WGQGTQVTVKS(X) _n (SEQ ID NO:23) and WGQGTQVTVQS(X) _n (SEQ ID NO:32) (and these differences in amino acids occur at positions corresponding to amino acid positions in the FW4 domain V _H , i.e., at positions 103-113 according to Kabat numbering, without taking into account any differences in amino acids within the C-terminal extension (X) _n ), wherein: (i) the amino acid residue at the position corresponding to position 112 in the Kabat numbering is represented by K or Q; (ii) n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (preferably 1 or 2, such as 1); and (iii) each X represents an amino acid residue (preferably naturally occurring) which is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I). Again, with respect to such amino acid sequences, paragraphs (vi)-(xi) described in the previous paragraphs are preferably also applicable.

Also, as noted herein, the V _H domains of the invention may contain other amino acid residues or substitutions that are known per se for V _H domains and especially for ISVDs (more preferably nanobodies) at appropriate positions. Some non-limiting examples can be given which include, for example, one or more “characteristic residues” that are characteristic of V _HH /nanobodies (including, for example, leucine (L) at position 11), other amino acid residues that are commonly found in V _HH (such as alanine (A) at position 14), humanizing substitutions known per se for V _HH /nanobodies (such as Q108L and A14P), one or more of the mutations proposed by Harmsen (such as V89M or V89T) and/or in provisions proposed by Nieba (for example, 11, 87 or 89); or any suitable combination thereof; and/or, for example, mutations T110K, T110Q or V89L.

When a _VH domain of the invention contains a C-terminal extension (X) _n , according to some preferred but non-limiting examples of such extensions, X and n may be:

a) n = 1 and X = Ala;

b) n = 2 and each X = Ala;

c) n = 3 and each X = Ala;

d) n = 2 and at least one X = Ala (and the remaining amino acid residues X are independently selected from naturally occurring amino acids, but preferably they are independently selected from Val, Leu and/or Ile);

e) n = 3 and at least one X = Ala (and the remaining amino acid residues X are independently selected from naturally occurring amino acids, but preferably they are independently selected from Val, Leu and/or Ile);

f) n = 3 and at least two X = Ala (and the remaining amino acid residues X are independently selected from naturally occurring amino acids, but preferably they are independently selected from Val, Leu and/or Ile);

g) n = 1 and X = Gly;

h) n = 2 and each X = Gly;

i) n = 3 and each X = Gly;

j) n = 2 and at least one X = Gly (and the remaining amino acid residues X are independently selected from naturally occurring amino acids, but preferably they are independently selected from Val, Leu and/or Ile);

k) n = 3 and at least one X = Gly (and the remaining amino acid residues X are independently selected from naturally occurring amino acids, but preferably they are independently selected from Val, Leu and/or Ile);

l) n = 3 and at least two X = Gly (and the remaining amino acid residues X are independently selected from naturally occurring amino acids, but preferably they are independently selected from Val, Leu and/or Ile);

m) n = 2 and each X = Ala or Gly;

n) n = 3 and each X = Ala or Gly;

o) n = 3 and at least one X = Ala or Gly (and the remaining amino acid residues X are independently selected from naturally occurring amino acids, but preferably they are independently selected from Val, Leu and/or Ile);

p) n = 3 and at least two X = Ala or Gly (and the remaining amino acid residues X are independently selected from naturally occurring amino acids, but preferably they are independently selected from Val, Leu and/or Ile);

wherein items (a), (b), (c), (g), (h), (i), (m) and (n) are particularly preferred, with n = 1 or 2 being preferred, and Items where n = 1 are especially preferred.

It should also be noted that preferably the C-terminal extension in the V _H domain of the invention does not contain a (free) cysteine residue (unless the cysteine residue is used or intended for further functionalization, for example, for PEGylation).

In addition, the preferences given on pages 35-41 of WO 12/175741 for C-terminal extensions used in accordance with WO 12/175741 (which are also preferred C-terminal extensions when used in the _VH domains of the present invention) , are also applicable to C-terminal extensions used in the V _H domains of the invention, and these preferences according to WO 12/175741 are also incorporated herein by reference.

Preferably, when the V _H domain of the invention contains a C-terminal extension (X) _n , n is 1, 2 or 3 and each X is Ala or Gly. More preferably, each X is Ala and n = 1 or 2, preferably 1.

When the V _H domains of the invention contain a C-terminal extension, they are typically located at (and often form) the C-terminal end of the protein, polypeptide, compound, construct or other chemical entity in which they are found. Again, such a protein, polypeptide, compound, construct or other chemical entity may contain one or more other V _H domains of the invention (ie, not at the C-terminus); in such a case, such other V _H domains of the invention must contain a lysine (K) or glutamine (Q) at position 112 (and be as described below), but must not contain C-terminal extensions (instead, they may join ( optionally via one or more suitable linkers) at the C-termini with one or more other amino acid sequences, moieties, binding domains or binding blocks present in a protein, polypeptide, compound, construct or other chemical entity such as the V _H domain of the invention with a C- terminal extension at the C-terminal end)).

Because the V _H domains of the invention (and proteins, polypeptides, compounds, constructs and other chemical entities containing them, as described below) are particularly suitable (and intended for) pharmaceutical use (such as the prevention, treatment and/or diagnosis of diseases and disorders in individuals in need thereof), they preferably have a high degree of sequence homology in the framework regions with the human _VH domain framework sequences. In particular, the _VH domains of the invention preferably have an overall degree of sequence identity (when determined as described below, taking into account only the framework regions and not the CDRs, and excluding substitution at position 112 and C-terminal extensions, if any is) with at least one human gametic sequence (type DP-47, DP-51 or DP-29) by at least 80%, preferably at least 85%, such as 90% or more. More preferably, the V _H domains of the invention preferably have an overall degree of sequence identity (when determined as described below, taking into account only the framework regions and not the CDRs, and also excluding substitution at position 112 and C-terminal extensions, if any is) at least 80%, preferably at least 85%, such as 90% or more with at least one of the following human gamete sequences: DP-47, DP-51 and/or DP-29.

As described below, in accordance with one aspect of the invention, the V _H domain of the invention may be a heavy chain variable domain that, in the protein, polypeptide, or construct in which it is located, interacts/associates (or is designed to interact/associate) with the domain V _L to form an antigen binding site in which at least the V _H domain has an exposed C-terminal end or region. For example, the V _H domain in accordance with this aspect of the invention may be a V _H domain that is present and/or used in scFvs and/or diabodies where it will bind to the V _L domain to form an antigen binding site.

However, in accordance with a preferred aspect of the invention, the _VH domain of the invention is a single variable domain (heavy chain) of an immunoglobulin, i.e. “ISVD”, which means a heavy chain variable domain that can form a functional antigen binding site without interaction with the V _L domain. For example, the _VH domain of the invention may be a nanobody (including _VHH , humanized _VHH and camellized _VH such as human camellized _VH ), a (single domain) antibody that is a _VH domain or derived from a _VH domain, or a dAb , which is a _VH domain or derived from a _VH domain. The _VH domain of the invention is preferably a nanobody (more preferably a _VHH domain, a humanized _VHH domain, or a Camelized _VH domain such as a human Camelized _VH domain).

In this description:

- the term “nanobody” generally corresponds to the definition in WO 08/020079 or WO 09/138519, and in a particular aspect generally means V _HH , humanized V _HH or camellized V _H such as human camellized V _H or sequence optimized V _HH (as -those, for example, optimized for chemical stability and/or solubility, maximum overlap with known human framework regions and maximum expression). It should be noted that the terms nanobody or nanobodies are registered trademarks of Ablynx NV and may therefore be referred to as nanobody ^® and/or nanobodies ^® ;

- the term “ISVD” (or “ISV”) is used herein in its broadest sense and also covers “ISVD-based biologics” and, when the ISVD is a nanobody, “nanobody-based biologics.” “ISVD-based biologics” are defined herein as proteins, polypeptides, or other biologicals that contain or are substantially composed of at least one (such as one, two, or three) ISVDs. Similarly, “nanobody-based biologics” are defined herein as proteins, polypeptides, or other biologicals that contain or are substantially composed of at least one (such as one, two, or three) nanobodies. As with the term “ISVD,” whenever the term “ISVD-based biologics” is used, it should be understood that the ISVD-based biologic is preferably a nanobody-based biologic. In the context of the present invention, both “ISVD-based biologics” and “nanobody-based biologics” may be, for example, monovalent, bivalent (or multivalent), bispecific (or multispecific), and biparatope (or multiparatope) ISVD constructs or constructs nanobodies, respectively. In addition, ISVD-based or nanobody-based biologics, for example, along with one or more (such as one, two or three) ISVDs or nanobodies, may optionally also contain one or more (such as one or two) other additional therapeutic molecules and/or one or more (such as one or two) other moieties that affect the pharmacokinetic or pharmacodynamic properties of ISVD-based or nanobody-based biologics (such as half-life). Suitable examples of such additional therapeutic or other molecules will be known to those skilled in the art, for example they may generally include any therapeutically active proteins, polypeptides or other binding domains or binding blocks, as well as, for example, modifications such as those described on page 149 -152 WO 09/138159. ISVD-based biologics or nanobody-based biologics are preferably therapeutic or intended for use as therapeutics (including prophylaxis and diagnostics) and for this purpose they preferably contain at least one ISVD against a corresponding therapeutic target (such as RANK -L, vWF, IgE, RSV, CXCR4, IL-23 or other interleukins, etc.). For some specific but non-limiting examples of such ISVD-based or nanobody-based biological products, reference is made to Examples 8-18, as well as, for example, to various applications from Ablynx N.V. (such as, but not limited to, WO 2004/062551, WO 2006/122825, WO 2008/020079 and WO 2009/068627), and also, for example (and without limitation), applications such as WO 06 /038027, WO 06/059108, WO 07/063308, WO 07/063311, WO 07/066016 and WO 07/085814. In addition, as described below, the ISVDs or nanobodies described herein may be directed against a (human) serum protein such as serum albumin (human), and such ISVDs or nanobodies may also have therapeutic uses, particularly in and/or to prolong the half-life therapeutic molecules and compounds (such as in or for the ISV-based biologics described herein). Reference is made, for example, to WO 2004/041865, WO 2006/122787 and WO 2012/175400, which generally describe the use of serum albumin binding nanobodies to prolong the half-life. In addition, in this specification, unless expressly stated otherwise, all terms used have the meanings given in WO 09/138519 (or the prior art cited in WO 09/13851) or WO 08/020079 (or the prior art prior art given in WO 08/020079). In addition, if a method or technique is not specifically described herein, it may be performed as described in WO 09/138519 (or the prior art work given in WO 09/138519) or WO 08/020079 (or the prior art work). prior art given in WO 08/020079).

In addition, when used in the present specification or claims, the following terms have the same meanings as given in and/or, if applicable, which can be defined as described on pages 62-75 in WO 09/138519: “agonist ”, “antagonist”, “inverse agonist”, “non-polar, uncharged amino acid residue”, “polar uncharged amino acid residue”, “polar, charged amino acid residue”, “sequence identity”, “exactly the same” and “amino acid differences” (when talking about sequence comparison of two amino acid sequences), “(in) practically isolated (form)”, “domain”, “binding domain”, “antigenic determinant”, “epitope”, “against” or “directed against” (antigen), “specificity” and “half-life”. In addition, the terms “modulatory” and “modulate”, “interaction site”, “specific to”, “cross-blocking”, “cross-blocking” and “cross-blocking” and “virtually independent of pH” are consistent with the definitions (and/or may be defined as described) on pages 74-79 in WO 10/130832 from the applicant. In addition, when referring to the constructs, compounds, proteins or polypeptides of the invention, terms such as “monovalent”, “bivalent” (or “multivalent”), “bispecific” (or “multispecific”) and “biparatopic” (or “multiparatopic”) ") may have the meanings given in WO 09/138519, WO 10/130832 or WO 08/020079.

The term “half-life” as applied to ISVDs, nanobodies, ISVD-based biologics, nanobody-based biologics, or any other amino acid sequences, compounds, or polypeptides provided herein may be generally defined as described in paragraph o) on page 57 in WO 08/020079 and, as stated therein, refers to the time required for the in vivo serum concentration of an amino acid sequence, compound or polypeptide to decrease by 50%, for example due to degradation of the sequence or compound and/or clearance or sequestration of the sequence or connections by natural mechanisms. The half-life of an amino acid sequence, compound or polypeptide of the invention in vivo can be determined by any known method per se, for example, using a pharmacokinetic analysis. Suitable methods will be known to those skilled in the art and may be, for example, those described in point o) on page 57 of WO 08/020079. Also in paragraph o) on page 57 of WO 08/020079 it is stated that the half-life can be expressed using parameters such as t _½ -alpha, t _½ -beta and area under the curve (AUC). In this regard, it should be noted that the term “half-life” as used herein specifically refers to _t½ -beta or terminal half-life (whereby _t½ -alpha and/or AUC or both may be excluded from consideration). Let us refer, for example, to the “Experimental Part” below, as well as to standard reference books, such as Kenneth A et al., Chemical Stability of Pharmaceuticals: A Handbook for Pharmacists; and Peters et al., Pharmacokinetic Analysis: A Practical Approach (1996). We also refer to “Pharmacokinetics”, M Gibaldi & D Perron, published by Marcel Dekker, 2nd Rev. edition (1982). Likewise, the terms “increased half-life” or “increased half-life” also correspond to the definitions in paragraph o) on page 57 of WO 08/020079 and in particular refer to an increase in t _½ -beta, with an increase in t _½ -alpha and /or AUC or both or without it.

If a term is not specifically defined here, it has its usual meaning in the art, which should be known to those skilled in the art. Let us refer, for example,
to standard reference books such as Sambrook et al., “Molecular Cloning: A Laboratory Manual” (2nd Ed.), Vols. 1-3, Cold Spring Harbor Laboratory Press (1989); F. Ausubel et al., eds., “Current Protocols in Molecular Biology,” Green Publishing & Wiley Interscience, New York (1987); Lewin, “Genes II”, John Wiley & Sons, New York, NY (1985); Old et al., “Principles of Gene Manipulation: An Introduction to Genetic Engineering,” 2nd edition, University of California Press, Berkeley, CA (1981); Roitt et al., “Immunology” (6th Ed.), Mosby/Elsevier, Edinburgh (2001); Roitt et al., “Roitt's Essential Immunology”, 10th Ed., Blackwell Publishing, UK (2001); and Janeway et al., “Immunobiology” (6th Ed.), Garland Science Publishing/Churchill Livingstone, New York (2005), as well as general work in the field cited here.

In addition, as already stated, the amino acid residues of the nanobodies are numbered in accordance with the general numbering for V _H domains set forth by Kabat et al. (“Sequence of proteins of immunological interest”, US Public Health Services, NIH Bethesda, MD, Publication No. 91), and in relation to camel V _HH domains in the article by Riechmann and Muyldermans, J. Immunol. Methods 2000 Jun 23, 240 (1-2): 185-195; or given here. According to this numbering, FR1 in nanobodies includes amino acid residues at positions 1-30, CDR1 in nanobodies includes amino acid residues in positions 31-35, FR2 in nanobodies includes amino acids in positions 36-49, CDR2 in nanobodies includes amino acid residues in positions 50-65 FR3 in nanobodies includes amino acid residues at positions 66-94, CDR3 in nanobodies includes amino acid residues in positions 95-102, and FR4 in nanobodies includes amino acid residues in positions 103-113. [In this regard, it should be noted that, as is well known in the art for V _H domains and for V _HH domains, the total number of amino acid residues in each of the CDRs may vary and may not correspond to the total number of amino acid residues indicated by Kabat numbering ( that is, one or more Kabat numbering positions may not be occupied in the actual sequence, or the actual sequence may contain more amino acid residues than the number allowed by Kabat numbering). This means that, in general, the Kabat numbering may not correspond to the actual numbering of amino acid residues in the actual sequence. However, in general we can say that in accordance with the Kabat numbering and regardless of the number of amino acid residues in the CDRs, position 1 according to the Kabat numbering corresponds to the beginning of FR1 and vice versa, position 36 according to the Kabat numbering corresponds to the beginning of FR2 and vice versa, position 66 according to the Kabat numbering corresponds to the beginning FR3 and vice versa, and position 103 according to Kabat numbering corresponds to the beginning of FR4 and vice versa].

Alternative methods for numbering amino acid residues of V _H domains, which can also be applied in a similar manner to camel V _HH domains and to nanobodies, is the method described by Chothia et al. (Nature 342, 877-883 (1989)), the so-called “AbM definition” and the so-called “contact definition”. However, in the present description, aspects and figures, Kabat numbering will be used, and for VHH domains, Riechmann and Muyldermans numbering will be used unless otherwise noted.

It should also be noted that the figures and sequence listing, "Experimental Part" and examples are provided only to further illustrate the invention and should in no way be interpreted or taken as limiting the scope of the invention and/or the appended claims unless expressly stated otherwise.

The V _H domains of the invention can be directed against any suitable or desired antigen or target, including any pharmaceutically and/or therapeutically relevant targets as described herein.

In accordance with one particular aspect of the invention, the V _H domains of the invention are directed against whey protein, in particular human whey protein. In accordance with a preferred aspect, when the V _H domain of the invention is directed against a whey protein, it is directed against serum albumin, in particular human serum albumin. Thus, the invention also provides such V _H domains of the invention (as defined herein, including the preferences given for V _H domains of the invention) that can specifically bind to whey protein, in particular human whey protein, and preferably can specifically bind to whey protein. albumin, more preferably human serum albumin. Again, such V _H domains are ISVDs (as described above), more preferably nanobodies.

For example, the anti-serum albumin _VH domain of the invention may be one of the anti-serum albumin (human) nanobodies that are described in WO 2004/041865, especially WO 2006/122787 and WO 2012/175400 (all applications from the applicant/assignee ), in which the amino acid at position 112 is replaced by a K or a Q and which optionally contains a C-terminal extension as described herein (and may also, for example, contain one or more other specific amino acid residue substitutions described herein, such as 11L, L11V, L11K, 14A, P14A, 14P, A14P, 89T, V89T, 89L, V89L, 108L, Q108L, 110Q, T110Q, 110K and/or T110K; although usually an additional replacement at position 110 is often not necessary if position 112 is K or Q, while position 110 is preferably T). It is further contemplated that the present invention is also applicable to other heavy chain ISVDs that bind serum albumin, such as those described in WO 03/035694, WO 04/003019, WO 05/118642, WO 06/059106, WO 08/ 096158, WO 09/121804, WO 10/108937 or US 2013/0129727, i.e. by introducing the appropriate substitutions described herein (i.e., at least one of S112K, S112Q, and/or V89T, and optionally one or more other amino acid residue substitutions described herein, such as L11V), and optionally (and usually preferably as set forth herein) adding a C-terminal extension (as described below).

Some preferred, but not limited to, examples of such serum albumin binding nanobodies of the invention are humanized variants of the amino acid sequence SEQ ID NO: 52 in WO 2006/122787 (referred to as “Alb-1” in WO 2006/122787) in which the amino acid at the position 112 is replaced by K or by Q (and which optionally contain a C-terminal extension as described herein), such as the humanized variants of Alb-1 given in SEQ ID NOs: 57-64 in WO 2006/122787 (in each case with the S112K substitution or S112Q and optionally with a C-terminal extension), or humanized variants of Alb-1 given in SEQ ID NOs: 3-11 WO 2012/175400 (again, in each case with the replacement of S112K or S112Q), of which SEQ ID NOs 3, 4 and 5 may optionally contain a C-terminal extension, and SEQ ID NOs 6-11 do contain a C-terminal extension (again, such variants may contain one or more other specific amino acid residue substitutions listed herein, such as - then 11L, L11V, L11K, 14A, P14A, 14P, A14P, 89T, V89T, 89L, V89L, 108L, Q108L, 110Q, T110Q, 110K and/or T110K; although usually the additional substitution at position 110 is often not required if position 112 is K or Q, with position 110 preferably being T). In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

Thus, in a further aspect, the invention relates to nanobodies of the invention (as defined herein) that can bind (in particular, specifically bind) to serum albumin (especially human serum albumin), in which:

- CDR1 has the amino acid sequence SFGMS (SEQ ID NO:41);

- CDR2 has the amino acid sequence SISGSGSDTLYADSVKG (SEQ ID NO:42);

- CDR3 has the amino acid sequence GGSLSR (SEQ ID NO:43);

- the amino acid residue at position 112 is represented by K or Q;

and which optionally contain at the C-terminal end a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as something 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I) (again, such a C-terminal extension is preferably as described below, and again, such a nanobody, for example, may also contain one or more other specific amino acid residue substitutions listed herein, such as 11L, L11V, L11K , 14A, P14A, 14P, A14P, 89T, V89T, 89L, V89L, 108L, Q108L, 110Q, T110Q, 110K and/or T110K; although usually an additional replacement at position 110 is often not necessary if position 112 is K or Q, with T being preferably at position 110). In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

In a preferred aspect, the invention relates to nanobodies of the invention (as defined herein) that can bind (in particular, specifically bind)
with serum albumin (especially human serum albumin), which are humanized versions of SEQ ID NO: 52 of WO 2006/122787, in which:

- CDR1 has the amino acid sequence SFGMS (SEQ ID NO:41);

- CDR2 has the amino acid sequence SISGSGSDTLYADSVKG (SEQ ID NO:42);

- CDR3 has the amino acid sequence GGSLSR (SEQ ID NO:43);

- the amino acid residue at position 112 is represented by K or Q;

which optionally contain at the C-terminal end a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (again, such a C-terminal extension is preferably as described below, and again, such a nanobody, for example, may also contain one or more other specific amino acid residue substitutions listed herein, such as 11L, L11V, L11K , 14A, P14A, 14P, A14P, 89T, V89T, 89L, V89L, 108L, Q108L, 110Q, T110Q, 110K and/or T110K; although usually an additional replacement at position 110 is often not necessary if position 112 is K or Q, with T being preferably at position 110). In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

In a preferred aspect, the invention relates to nanobodies of the invention (as defined herein) that can bind (in particular, specifically bind) serum albumin (especially human serum albumin) that is at least 80%, preferably at least 85% %, more preferably at least 90%, such as at least 95% identical in sequence to at least one of Alb-1 (SEQ ID NO: 52, WO 2006/122787), Alb-8 (SEQ ID NO: 46, here) and/or Alb-23 (SEQ ID NO: 61, here) (taking into account both framework sequences and CDRs, but excluding the C-terminal extension), in which the amino acid residue at position 112 is K or Q and which optionally contain at the C-terminal end a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2 , somehow 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (again, such a C-terminal extension is preferably as described below, and again, such a nanobody, for example, may also contain one or more other specific amino acid residue substitutions listed herein, such as 11L, L11V, L11K , 14A, P14A, 14P, A14P, 89T, V89T, 89L, V89L, 108L, Q108L, 110Q, T110Q, 110K and/or T110K; although usually an additional replacement at position 110 is often not necessary if position 112 is K or Q, with position 110 preferably being T). In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

Such nanobodies of the invention are again preferably humanized variants of Alb-1 (but with S112K or S112Q substitution), and more preferably contain at least one, preferably any two, and more preferably all three of the CDR1, CDR2 and/or CDR3 given in SEQ ID NOs 41-43, respectively.

In accordance with one particular aspect, any serum albumin binding nanobody of the invention may also contain amino acid residues characteristic of Alb-23 and variants thereof, as described in WO 12/175400 (i.e., the GP amino acid motif at positions 44 and 45, amino acid motif SKN at positions 74-76 and preferably G at position 16, and optionally R at position 83).

Some preferred, but non-limiting, examples of nanobodies of the invention directed against human serum albumin are given in table. 4 and Example 20.

In another aspect, the invention relates to V _H domains, in particular ISVDs, more preferably nanobodies, which:

a) the FW4 sequence is one of the following FW4 sequences:

Table 5. FW4 sequences

SSQGTLVTVKS (SEQ ID NO:99) SSQGTLVTVQS (SEQ ID NO:100) SSQGTLVKVSS (SEQ ID NO:101) SSQGTLVQVSS (SEQ ID NO:102) SSQGTLVTVKS(X) _n (SEQ ID NO:103) SSQGTLVTVQS(X) _n (SEQ ID NO:104) SSQGTLVKVSS(X) _n (SEQ ID NO:105) SSQGTLVQVSS(X) _n (SEQ ID NO:106)

wherein (i) the amino acid residues of the FW4 sequences that precede the C-terminal extension of the (X) _n in SEQ ID NOs: 23-40 correspond to the amino acid positions in the FW4 V _H domain (i.e., positions 103-113 in Kabat numbering) ; (ii) n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and (iii) each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L), and isoleucine (I); or

c) the amino acid sequence has no more than 3, preferably no more than 2 amino acid differences from at least one of the amino acid sequences of SEQ ID NOs: 99-106, and these amino acid differences occur at positions corresponding to the amino acid positions in the FW4 domain _VH , those. to positions 103-113 in Kabat numbering, without regard to any amino acid differences within the C-terminal extension (X) _n , wherein: (i) if the amino acid residue at the position corresponding to position 112 in Kabat numbering is represented by K or Q, the amino acid differences are at amino acid positions other than 112, and the amino acid residue at position 89 of the V _H domain is preferably selected from V, T and L (most preferably V); (ii) if the amino acid residue at the position corresponding to position 110 in the Kabat numbering is represented by K or Q, then these amino acid differences occur at amino acid positions other than 110, and at position 89 of the V _H domain is L; (iii) n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and (iv) each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L), and isoleucine (I). Again, in addition to points (i)-(iv) given in the previous sentence, in the following amino acid sequence: (v) the amino acid residue at the position corresponding to position 103 in the Kabat numbering is preferably represented by S; (vi) the amino acid residue at the position corresponding to position 104 in the Kabat numbering is preferably represented by S; (vii) the amino acid residue at the position corresponding to position 106 in the Kabat numbering is preferably represented by G; (viii) the amino acid residue at the position corresponding to position 107 in the Kabat numbering is preferably represented by T; (ix) the amino acid residue at the position corresponding to position 108 in the Kabat numbering is preferably Q or L (and in humanized nanobodies it is preferably L); (x) the amino acid residue at the position corresponding to position 109 in the Kabat numbering is preferably represented by V; again we refer to the table. 2 regarding such amino acid residues that may be present at each position.

Moreover, in such V _H domains according to the invention: (a) the amino acid residue at position 11 is L, V or K (more preferably V); the amino acid residue at position 14 is preferably A or P; the amino acid residue at position 41 is preferably A or P. Moreover, such V _H domains of the invention are preferably ISVDs, and more preferably nanobodies; and they can be directed against human serum albumin (in which case they preferably have CDR1, CDR2 and CDR3, respectively, corresponding to SEQ ID NOs 41, 42 and 43, respectively). Additionally, when such V _H domains are ISVDs or anti-human serum albumin nanobodies, they may also be as described herein for anti-human serum albumin nanobodies of the invention.

The V _H domains of the invention that are directed against serum albumin (in particular the serum albumin binding ISVDs of the invention) can be used to increase the half-life of therapeutically active compounds, (poly)peptides, proteins, binding domains, binding blocks or other therapeutically active substances or molecules, substantially as described in WO 2004/041865, WO 2006/122787 and/or WO 2012/175400 for the use of serum albumin binding nanobodies disclosed in these references (i.e., with appropriate attachment of serum albumin binding ISVD to proteins, polypeptides, compounds or other substances, optionally through a suitable linker (for example, WO 12/175400 on pages 12 and 13 provides some examples of how suitable fusion proteins can be constructed).

In another aspect, the invention relates to immunoglobulin heavy chain variable domains (V _H domains), in which the amino acid residue at position 89 (Kabat numbering) is threonine (T), and the amino acid residue at position 112 is a serine (S), lysine (K) residue ) or a glutamine residue (Q). Such immunoglobulin heavy chain variable domains ( _VH domains) with a T at position 89 are also encompassed by the term “ _VH domains of the invention,” which is used herein in the broadest sense, and may also be as described herein for _VH domains of the invention containing a K or Q at position 112. Accordingly, such immunoglobulin heavy chain variable domains ( _VH domains) may contain a C-terminal extension as described below (including the stated preferences for such C-terminal extensions); they may be ISVDs and in particular nanobodies, as described below.

Again, if such a V _H domain of the invention has an exposed C-terminal region (for example, because it forms the C-terminal end of the protein, polypeptide or other construct in which it is found), then preferably it contains a C-terminal extension ( see data presented in Table C below).

In addition, nanobodies of the invention in which position 89 is represented by a T (i.e., with or without a C-terminal extension) preferably contain an amino acid at position 11 that is selected from L (this amino acid residue is most often found in V _HH ) , E, K, M, S, V, W and Y; more preferably from L, E, K, V and Y and even more preferably from L, K and V (with V being most preferably). For example, they may contain an L11K or L11V substitution, and also, for example, a P14A or A14P substitution, a Q108L substitution, and/or a T110K, T110Q, S112K, and/or S112Q substitution (although it is common to have one or two additional substitutions at position 110 and/or or 112 is often not required if T is at position 89, while T is preferably at position 110, and S is preferably at position 112).

In particular, the immunoglobulin heavy chain variable domain ( _VH domain) of the invention according to this particular aspect contains a T at position 89 (Kabat) and the C-terminal end is one of VTVSS (SEQ ID NO: 77), VTVSS( X) _n (SEQ ID NO: 78), VTVKS (SEQ ID NO: l), VTVKS(X) _n (SEQ ID NO: 21), VTVQS (SEQ ID NO: 2), VTVQS(X) _n (SEQ ID NO: 22), VKVSS (SEQ ID NO: 95), VKVSS(X) _n (SEQ ID NO: 97), VQVSS (SEQ ID NO: 96), VQVSS(X) _n (SEQ ID NO: 98), VZVZS (SEQ ID NO: 107, wherein each amino acid residue Z is independently K or Q) or VZVZS(X) _n (SEQ ID NO: 108, wherein each amino acid residue Z is independently K or Q), and preferably one of VTVKS (SEQ ID NO: l), VTVQS (SEQ ID NO: 2), VTVSS (SEQ ID NO: 77), VTVKS(X) _n (SEQ ID NO: 21), VTVQS(X) _n (SEQ ID NO: 22 ) or VTVSS(X) _n (SEQ ID NO: 78), more preferably either VTVSS (SEQ ID NO: 77) or VTVSS(X) _n (SEQ ID NO: 78), where n and X are as described here for V _H domains of the invention having a Q or K at position 112 (and the C-terminal extension is preferably as described here for V _H domains of the invention having a Q or K at position 112). In addition, as in the case of V _H domains of the invention, which have a Q or K at position 112, when such a V _H domain with a T at position 89 is a nanobody, then at position 11 there is preferably leucine (L), at position 14, in particular, may be alanine (A) or proline (P), and at position 108, in particular, may be Q or L (and in humanized nanobodies this is preferably L); wherein such nanobodies with T at position 89 may contain one or more characteristic residues and/or be suitably humanized. In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

Such a _VH domain of the invention with a T at position 89 may again be a nanobody to serum albumin, as already described herein. For example, such a serum albumin binding nanobody may have one of the sequences of SEQ ID NOs: 46-75, but with a T at position 89; or another serum albumin binding nanobody with a T at position 89 that is at least 80%, preferably at least 85%, more preferably at least 90%, somehow at least 95% identical in sequence with at least one of Alb-1 (SEQ ID NO: 52, WO 2006/122787), Alb-8 (SEQ ID NO: 46, here) and/or Alb-23 (SEQ ID NO:61, here) (taking taking into account both framework sequences and CDRs, but excluding C-terminal extension). Some other examples of such nanobodies with T at position 89 are provided in SEQ ID NOs: 78-91 (these are other variants of Alb-1/Alb-8 or Alb-23 with T at position 89 and S at position 112).

More generally, the anti-serum albumin _VH domain of this aspect of the invention may be one of the anti-serum albumin (human) nanobodies that are described in WO 2004/041865 and in particular in WO 2006/122787 and WO 2012/175400 (all these are applications from the applicant/assignee) in which the amino acid at position 89 is threonine (T) and which optionally contains a C-terminal extension as described herein (and may also, for example, contain one or more other specific amino acid residue substitutions listed here, such as 11L, L11V, L11K, 14A, P14A, 14P, A14P, 108L, Q108L, 110K, T110K, 110Q, T110Q, S112K and/or S112Q; although it is common to have additional substitutions at positions 110 and/or 112 and is not required if position 89 is T, position 110 is preferably T, and position 112 is preferably S). In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A). Moreover, it is contemplated that the present invention is also applicable to other heavy chain ISVDs that bind serum albumin, such as those described in WO 03/035694, WO 04/003019, WO 05/118642, WO 06/059106, WO 08/ 096158, WO 09/121804, WO 10/108937 or US 2013/0129727, i.e. by appropriately introducing a threonine (T) at position 89 and optionally one or more other amino acid residue substitutions described herein, and optionally (and generally preferably as set forth herein) the addition of a C-terminal extension (also as described herein).

Some preferred, but not limited to, examples of such serum albumin binding nanobodies of the invention are humanized variants of the amino acid sequence SEQ ID NO: 52 in WO 2006/122787 (referred to as “Alb-1” in WO 2006/122787) in which the amino acid at the position 89 represents T (and which optionally contain a C-terminal extension as described herein), such as the humanized Alb-1 variants set forth in SEQ ID NOs: 57-64 in WO 2006/122787 (in each case with the substitution V89T and optionally with C -terminal extension), or humanized variants of Alb-1 given in SEQ ID NOs: 3-11 in WO 2012/175400 (again, in each case with a V89T substitution), of which SEQ ID NOs 3, 4 and 5 may optionally contain a C-terminal extension, and SEQ ID NOs 6-11 do contain a C-terminal extension (again, such variants may contain one or more of the other specific amino acid residue substitutions listed here, such as 11L, L11V, L11K, 14A, P14A, 14P, A14P, 108L, Q108L, 110K, T110K, 110Q, T110Q, 112Q, 112K, S112K and/or S112Q; although usually additional substitutions at positions 110 and/or 112 are often not required if position 89 is T, position 110 is preferably T, and position 112 is preferably S). In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

Thus, in a further aspect, the invention relates to nanobodies of the invention (as defined herein) that can bind (in particular, specifically bind)
with serum albumin (especially human serum albumin), in which:

- CDR1 has the amino acid sequence SFGMS (SEQ ID NO:41);

- CDR2 has the amino acid sequence SISGSGSDTLYADSVKG (SEQ ID NO:42);

- CDR3 has the amino acid sequence GGSLSR (SEQ ID NO:43);

- the amino acid residue at position 89 is represented by T;

which optionally contain at the C-terminal end a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (again, such a C-terminal extension is preferably as described below, and again, such a nanobody, for example, may also contain one or more other specific amino acid residue substitutions listed herein, such as 11L, L11V, L11K . position 89 is T, while position 110 is preferably T, and position 112 is preferably S). In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

In a preferred aspect, the invention relates to nanobodies of the invention (as defined herein) that can bind (in particular, specifically bind)
with serum albumin (especially human serum albumin), which are humanized versions of SEQ ID NO: 52 of WO 2006/122787, in which:

- CDR1 has the amino acid sequence SFGMS (SEQ ID NO:41);

- CDR2 has the amino acid sequence SISGSGSDTLYADSVKG (SEQ ID NO:42);

- CDR3 has the amino acid sequence GGSLSR (SEQ ID NO:43);

- the amino acid residue at position 89 is represented by T;

which optionally contain at the C-terminal end a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (again, such a C-terminal extension is preferably as described below, and again, such a nanobody, for example, may also contain one or more other specific amino acid residue substitutions listed herein, such as 11L, L11V, L11K . position 89 is T, while position 110 is preferably T, and position 112 is preferably S). In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

In a preferred aspect, the invention relates to nanobodies of the invention (as defined herein) that can bind (in particular, specifically bind)
with serum albumin (especially human serum albumin) that are at least 80%, preferably at least 85%, more preferably at least 90%, such as at least 95% identical in sequence although with one of Alb-1 (SEQ ID NO: 52 in WO 2006/122787), Alb-8 (SEQ ID NO: 46, here) and/or Alb-23 (SEQ ID NO: 61, here) (taking into account attention to both framework sequences and CDRs, but without taking into account the C-terminal extension), in which the amino acid residue at position 89 is T; which optionally contain at the C-terminal end a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (again, such a C-terminal extension is preferably as already described herein, and again, such a nanobody, for example, may also contain one or more other specific amino acid residue substitutions set forth herein, such as 11L, L11V, L11K, 14A, P14A, 14P, A14P, 108L, Q108L, 110K, T110K, 110Q, T110Q, 112Q, 112K, S112K and/or S112Q; although additional substitutions at positions 110 and/or 112 are often not required if position 89 is T, position 110 is preferably T, and position 112 is preferably S). In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

In accordance with one particular aspect, such serum albumin binding nanobodies of the invention with a T at position 89 may also contain amino acid residues characteristic of Alb-23 and variants thereof, as described in WO 12/175400 (i.e., the GP amino acid motif in positions 44 and 45, the amino acid motif SKN at positions 74-76 and preferably G at position 16, and optionally R at position 83).

Like the _VH domains of the invention containing a Q or K at position 112, the _VH domains of the invention containing a T at position 89 (optionally together with a Q or K at position 112 and/or together with a C-terminal extension) exhibit a decrease binding of pre-existing antibodies, in particular those pre-existing antibodies (for example, those found in samples from SLE patients) that are capable of binding to V _H domains and nanobodies in the presence of a C-terminal extension.

In a further aspect, the invention relates to immunoglobulin heavy chain variable domains ( _VH domains) in which the amino acid residue at position 89 (Kabat numbering) is leucine (L) and the amino acid residue at position 110 is a lysine residue (K) or a glutamine residue ( Q). Such immunoglobulin heavy chain variable domains ( _VH domains) with L at position 89 and K or Q at position 110 are also encompassed by the term “ _VH domains of the invention”, which is used herein in the broadest sense, and may also be as described here for other V _H domains of the invention (ie those containing a K or Q at position 112 or containing a T at position 89). Accordingly, such immunoglobulin heavy chain variable domains ( _VH domains) may comprise a C-terminal extension as described below (including the stated preferences for such C-terminal extensions); they may be ISVDs and in particular nanobodies, as described below.

Again, if such a V _H domain of the invention has an exposed C-terminal region (for example, because it forms the C-terminal end of the protein, polypeptide or other construct in which it is found), then preferably it contains a C-terminal extension ( see data presented in Table C below).

In addition, nanobodies of the invention in which position 89 is L and position 110 is K or Q (i.e., with or without a C-terminal extension) preferably contain an amino acid at position 11 that is selected from L (this amino acid residue most often found in V _HH ), E, K, M, S, V, W and Y; more preferably from L, E, K, V and Y and even more preferably from L, K and V (with V being most preferably). For example, they may contain the L11K or L11V substitution, and also, for example, the P14A or A14P substitution and/or the Q108L substitution (they may also contain the S112K and/or S112Q mutation (although usually the additional substitution at position 112 is often not required, if there is an L at position 89, and a K or Q at position 110, with an S preferably at position 112) In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. residues human V _H 3 and/or camelid V _HH residues) given in Table A-6 of WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), that is, from among those amino acid residues most often found at this position in humans or llamas, and more preferably it may be proline (P) or alanine (A ); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) given in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

Additionally, in one aspect, such V _H domains of the invention in which 89 is L and 110 is K or Q have the amino acid residue at position 112 being serine (S). More preferably, the C-terminal end of such V _H domains may be (and preferably is) one of VKVSS (SEQ ID NO: 95), VQVSS (SEQ ID NO: 96), VKVSS(X) _n (SEQ ID NO: 97 ) or VQVSS(X) _n (SEQ ID NO: 98), where n and X are as described herein for the V _H domains of the invention in which position 112 is Q or K (and the C-terminal extension is preferably also as described here for the V _H domains of the invention in which position 112 is represented by Q or K). Moreover, as with V _H domains of the invention having a Q or K at position 112 or a T at position 89, when such a V _H domain with an L at position 89 and a K or Q at position 110 is a nanobody, then at position 11 there is preferably leucine (L), at position 14, in particular, there may be alanine (A) or proline (P), and at position 108, in particular, there may be Q or L (and in humanized nanobodies, preferably L ); wherein such a nanobody with L at position 89 and K or Q at position 110 may contain one or more residues characteristic of nanobodies and/or be suitably humanized. In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

Such a V _H domain of the invention with L at position 89 and K or Q at position 110 may again be a nanobody to serum albumin, as already described herein. For example, such a serum albumin binding nanobody may have one of the sequences of SEQ ID NOs: 46-75, but with an L at position 89 and a K or Q at position 110; or another serum albumin binding nanobody with an L at position 89 and a K or Q at position 110 that is at least 80%, preferably at least 85%, more preferably at least 90%, such as at least at least 95% identical in sequence to at least one of Alb-1 (SEQ ID NO: 52, WO 2006/122787), Alb-8 (SEQ ID NO: 46, here) and/or Alb-23 (SEQ ID NO :61, here) (taking into account both framework sequences and CDRs, but excluding C-terminal extension).

More generally, the anti-serum albumin _VH domain of this aspect of the invention may be one of the anti-serum albumin (human) nanobodies that are described in WO 2004/041865 and in particular in WO 2006/122787 and WO 2012/175400 (all these are applications from the applicant/assignee) wherein the amino acid at position 89 is leucine (L) and the amino acid residue at position 110 is K or Q, and which optionally contains a C-terminal extension as described herein (and also, for example, may contain one or more other specific amino acid residue substitutions listed here, such as 11L, L11V, L11K, 14A, P14A, 14P, A14P, 108L and/or Q108L; as well as S112K or S112Q, although it is common to have an additional substitution at position 112 is often not required if position 89 is L, and position 110 is K or Q, while position 112 is preferably S). Moreover, it is contemplated that the present invention is also applicable to other heavy chain ISVDs that bind serum albumin, such as those described in WO 03/035694, WO 04/003019, WO 05/118642, WO 06/059106, WO 08/ 096158, WO 09/121804, WO 10/108937 or US 2013/0129727, i.e. with the appropriate introduction of leucine (L) at position 89 and K or Q at position 110, and optionally one or more other amino acid residue substitutions described herein, and optionally (and generally preferably, as set forth herein) the addition of a C-terminal extension (also as described here). In such anti-serum albumin V _H domains, the amino acid at position 112 is preferably S, and in such V _H domains, the C-terminal end is preferably one of SEQ ID NOs: 95-98. In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

Some preferred, but not limited to, examples of such serum albumin binding nanobodies of the invention are humanized variants of the amino acid sequence SEQ ID NO: 52 of WO 2006/122787 (referred to as “Alb-1” in WO 2006/122787) in which the amino acid at the position 89 is L, and the amino acid residue at position 110 is K or Q (and which optionally contain a C-terminal extension as described herein), such as the humanized Alb-1 variants set forth in SEQ ID NOs: 57-64 in WO 2006/122787 (in each case with a V89L substitution and a T110Q or T110K substitution and optionally with a C-terminal extension), or the humanized Alb-1 variants given in SEQ ID NOs: 3-11 in WO 2012/175400 (again, in each case with substitution V89L and substitution T110Q or T110K), of which SEQ ID NOs 3, 4 and 5 may optionally contain a C-terminal extension, and SEQ ID NOs 6-11 do contain a C-terminal extension (again, such variants may contain one or more other specific amino acid residue substitutions set forth herein, such as 11L, L11V, L11K, 14A, P14A, 14P, A14P, 108L and/or Q108L; and S112K or S112Q, although usually an additional substitution at position 112 is often not necessary if position 89 is L, and position 110 is K or Q, with position 112 preferably containing S). In such anti-serum albumin V _H domains, the amino acid at position 112 is preferably S, and in such V _H domains, the C-terminal end is preferably one of SEQ ID NOs: 95-98. In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

Thus, in a further aspect, the invention relates to nanobodies of the invention (as defined herein) that can bind (in particular, specifically bind)
with serum albumin (especially human serum albumin), in which:

- CDR1 has the amino acid sequence SFGMS (SEQ ID NO:41);

- CDR2 has the amino acid sequence SISGSGSDTLYADSVKG (SEQ ID NO:42);

- CDR3 has the amino acid sequence GGSLSR (SEQ ID NO:43);

- the amino acid residue at position 89 is represented by L;

- the amino acid residue at position 110 is represented by K or Q;

which optionally contain at the C-terminal end a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (again, such a C-terminal extension is preferably as described herein, and again, such a nanobody, for example, may also contain one or more other specific amino acid residue substitutions set forth herein, such as 11L, L11V, L11K , 14A, P14A, 14P, A14P, 108L and/or Q108L; and S112K or S112Q, although usually an additional replacement at position 112 is often not necessary if position 89 is L, and position 110 is K or Q, in this case, S) is preferably located at position 112. In such anti-serum albumin V _H domains, the amino acid at position 112 is preferably S, and in such V _H domains, the C-terminal end is preferably one of SEQ ID NOs: 95-98. In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

In a preferred aspect, the invention relates to nanobodies of the invention (as defined herein) that can bind (in particular, specifically bind)
with serum albumin (especially human serum albumin), which are humanized versions of SEQ ID NO: 52 of WO 2006/122787, in which:

- CDR1 has the amino acid sequence SFGMS (SEQ ID NO:41);

- CDR2 has the amino acid sequence SISGSGSDTLYADSVKG (SEQ ID NO:42);

- CDR3 has the amino acid sequence GGSLSR (SEQ ID NO:43);

- the amino acid residue at position 89 is represented by L;

- the amino acid residue at position 110 is represented by K or Q;

which optionally contain at the C-terminal end a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (again, such a C-terminal extension is preferably as described herein, and again, such a nanobody, for example, may also contain one or more other specific amino acid residue substitutions set forth herein, such as 11L, L11V, L11K , 14A, P14A, 14P, A14P, 108L and/or Q108L; and S112K or S112Q, although usually an additional replacement at position 112 is often not necessary if position 89 is L, and position 110 is K or Q, in this case, S) is preferably located at position 112. In such anti-serum albumin V _H domains, the amino acid at position 112 is preferably S, and in such V _H domains, the C-terminal end is preferably one of SEQ ID NOs: 95-98. In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

In a preferred aspect, the invention relates to nanobodies of the invention (as defined herein) that can bind (in particular, specifically bind)
with serum albumin (especially human serum albumin) that are at least 80%, preferably at least 85%, more preferably at least 90%, such as at least 95% identical in sequence although with one of Alb-1 (SEQ ID NO: 52, WO 2006/122787), Alb-8 (SEQ ID NO: 46, here) and/or Alb-23 (SEQ ID NO: 61, here) (taking into account attention to both framework sequences and CDRs, but without regard to the C-terminal extension), in which the amino acid residue at position 89 is L and the amino acid residue at position 110 is K or Q, and which optionally contain at the C-terminal end a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (again, such a C-terminal extension is preferably as described herein, and again, such a nanobody may also, for example, contain one or more other specific amino acid residue substitutions set forth herein, such as 11L, L11V, L11K , 14A, P14A, 14P, A14P, 108L and/or Q108L; and S112K or S112Q, although usually an additional replacement at position 112 is often not necessary if position 89 is L, and position 110 is K or Q, in this case, S) is preferably located at position 112. Such nanobodies of the invention are again preferably humanized variants of Alb-1 (but with V89L and T110K or T110Q replaced), and more preferably contain at least one, preferably any two, and more preferably all three of CDR1, CDR2 and/or CDR3 given in SEQ ID NOs 41-43, respectively. In such anti-serum albumin V _H domains, the amino acid at position 112 is preferably S, and in such V _H domains, the C-terminal end is preferably one of SEQ ID NOs: 95-98. In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

In accordance with one particular aspect, any serum albumin binding nanobody of the invention with an L at position 89 and a K or Q at position 110 may also contain amino acid residues characteristic of Alb-23 and variants thereof, as described in WO 12/175400 (t i.e. amino acid motif GP at positions 44 and 45, amino acid motif SKN at positions 74-76 and preferably G at position 16, and optionally R at position 83). In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

Like inventive _VH domains containing a Q or K at position 112 or containing a T at position 89, inventive _VH domains containing an L at position 89 and a K or Q at position 110 exhibit reduced binding of preexisting antibodies, in particular such pre-existing antibodies (for example, those found in samples from SLE patients) that are capable of binding to V _H domains and nanobodies in the presence of a C-terminal extension.

Some non-limiting examples of V _H domains of the invention containing L at position 89 and K at position 110 (as well as V at position 11) are shown in FIG. 2 as SEQ ID NOs: 123-136. These _VH domains that bind to human serum albumin contain the CDR regions specified herein for the preferred _VH domains of the invention that bind to serum albumin.

In a further aspect, the invention relates to immunoglobulin heavy chain variable domains ( _VH domains) in which the amino acid residue at position 89 (Kabat numbering) is leucine (L) and the amino acid residue at position 11 is valine (V). Such immunoglobulin heavy chain variable domains ( _VH domains) with L at position 89 and V at position 11 are also encompassed by the term “ _VH domains of the invention”, which is used herein in the broadest sense, and may also be as described herein for other V _H domains of the invention (i.e., containing a K or Q at position 112, containing a T at position 89, or containing an L at position 89 and a K or Q at position 110; although V _H domains in accordance with this aspect have an amino acid residue position 89 must be L, the amino acid residue at position 11 must be V, and the amino acid residues at positions 110 and 112, respectively, can be any amino acid residue suitable for these positions). Accordingly, such immunoglobulin heavy chain variable domains ( _VH domains) may comprise a C-terminal extension as already described herein (including the stated preferences for such C-terminal extensions); they may be ISVDs and in particular nanobodies, as described here.

Again, if such a V _H domain of the invention has an exposed C-terminal region (for example, because it forms the C-terminal end of the protein, polypeptide or other construct in which it is found), then preferably it contains a C-terminal extension ( see data presented in Table C below).

In addition, nanobodies of the invention in which position 89 is L and position 11 is V (i.e., with or without a C-terminal extension): (i) preferably contain an amino acid at position 110 that is selected from T, I, A, K and Q (and preferably T, K and Q, more preferably it may be T); (ii) preferably contain an amino acid at position 112 that is selected from S, F, K and Q (and preferably from S, K and Q, more preferably it may be S); and (iii) may also contain a substitution, such as P14A or A14P and/or a Q108L substitution. In one particular embodiment, for V _H domains in accordance with this aspect of the invention, the amino acid residue at position 110 is T, the amino acid residue at position 112 is S, and the C-terminal end is preferably either VTVSS (SEQ ID NO: 77), or VTVSS(X) _n (SEQ ID NO: 78), where X and n are as defined here for the C-terminal extension of other V _H domains of the invention. In addition, V _H domains in accordance with this aspect of the invention: (i) at position 41 may have, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

Thus, for example, in such V _H domains of the invention in which position 89 is L and 11 is V, the C-terminal end of such V _H domains can be (and preferably is) one of the VTVSS (SEQ ID NO: 77 ), VTVSS(X) _n (SEQ ID NO: 78), VTVKS (SEQ ID NO: l), VTVKS(X) _n (SEQ ID NO: 21), VTVQS (SEQ ID NO: 2), VTVQS(X) _n (SEQ ID NO: 22), VKVSS (SEQ ID NO: 95), VKVSS(X) _n (SEQ ID NO: 97), VQVSS (SEQ ID NO: 96), VQVSS(X) _n (SEQ ID NO: 98), VZVZS (SEQ ID NO: 107, wherein each amino acid residue Z is independently K or Q), or VZVZS(X) _n (SEQ ID NO: 108, wherein each amino acid residue Z is independently K or Q), and preferably one of VTVSS, VKVSS (SEQ ID NO: 95), VQVSS (SEQ ID NO: 96), VKVSS(X) _n (SEQ ID NO:97) or VQVSS(X) _n (SEQ ID NO: 98), more preferably it is either VTVSS (SEQ ID NO: 77) or VTVSS(X) _n (SEQ ID NO: 78), where n and X are as described herein for V _H domains of the invention having a Q at position 112 or K (and the C-terminal extension is preferably as described here for the V _H domains of the invention, which have a Q or K at position 112). In addition, as in the case of V _H domains according to the invention, which have a Q or K at position 112 or a T at position 89, when such a V _H domain with L at position 89 and V at position 11 is a nanobody, then position 11 is preferably leucine (L), position 14, in particular, may be alanine (A) or proline (P), and position 108 may be Q or L (and in humanized nanobodies this is preferably L); wherein such nanobodies with L at position 89 and V at position 11 may contain one or more residues characteristic of nanobodies and/or be suitably humanized. And also: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) given in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

Such a V _H domain of the invention with L at position 89 and V at position 11 may again be a nanobody to serum albumin, as already described herein. For example, such a serum albumin binding nanobody may have one of the sequences of SEQ ID NOs: 46-75, but with L at position 89 and V at position 11; or another serum albumin binding nanobody with an L at position 89 and a V at position 11 that is at least 80%, preferably at least 85%, more preferably at least 90%, such as at least 95% sequence identity to at least one of Alb-1 (SEQ ID NO: 52, WO 2006/122787), Alb-8 (SEQ ID NO: 46, here) and/or Alb-23 (SEQ ID NO:61 , here) (taking into account both framework sequences and CDRs, but excluding C-terminal extension).

More generally, the anti-serum albumin _VH domain of this aspect of the invention may be one of the anti-serum albumin (human) nanobodies that are described in WO 2004/041865 and in particular in WO 2006/122787 and WO 2012/175400 (all these are applications from the applicant/assignee) wherein the amino acid at position 89 is leucine (L) and the amino acid residue at position 11 is V, and which optionally contains a C-terminal extension as described herein (and may also, for example, contain one or more other specific amino acid residue substitutions listed herein, such as 14A, P14A, 14P, A14P, 108L, Q108L, V110K, V110Q, S112K and/or S112Q). Moreover, it is contemplated that the present invention is also applicable to other heavy chain ISVDs that bind serum albumin, such as those described in WO 03/035694, WO 04/003019, WO 05/118642, WO 06/059106, WO 08/ 096158, WO 09/121804, WO 10/108937 or US 2013/0129727, i.e. with the appropriate introduction of leucine (L) at position 89 and valine at position 11, and optionally one or more other amino acid residue substitutions described herein, and optionally (and generally preferably as set forth herein) the addition of a C-terminal extension (also as described Here). In such anti-serum albumin V _H domains, the amino acid at position 112 is preferably S, and in such V _H domains, the C-terminal end is preferably one of SEQ ID NOs: 95-98. In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

Some preferred, but not limited to, examples of such serum albumin binding nanobodies of the invention are humanized variants of the amino acid sequence SEQ ID NO: 52 of WO 2006/122787 (referred to as “Alb-1” in WO 2006/122787) in which the amino acid at the position 89 is L and the amino acid at position 11 is V (and which optionally contain a C-terminal extension as described herein), such as the humanized Alb-1 variants set forth in SEQ ID NOs: 57-64 in WO 2006/122787 (each case with a V89L substitution and an L11V substitution and optionally a C-terminal extension), or the humanized Alb-1 variants given in SEQ ID NOs: 3-11 in WO 2012/175400 (again, in each case with a V89L substitution and an L11V substitution ), of which SEQ ID NOs 3, 4 and 5 may optionally contain a C-terminal extension, and SEQ ID NOs 6-11 do contain a C-terminal extension (again, such variants may contain one or more other specific amino acid substitutions residues given here as 14A, P14A, 14P, A14P, 108L, Q108L, V110K, V110Q, S112K and/or S112Q). In such anti-serum albumin V _H domains, the amino acid at position 112 is preferably S, and in such V _H domains, the C-terminal end is preferably one of SEQ ID NOs: 95-98. In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

Thus, in a further aspect, the invention relates to nanobodies of the invention (as defined herein) that can bind (in particular, specifically bind) to serum albumin (especially human serum albumin), in which:

- CDR1 has the amino acid sequence SFGMS (SEQ ID NO:41);

- CDR2 has the amino acid sequence SISGSGSDTLYADSVKG (SEQ ID NO:42);

- CDR3 has the amino acid sequence GGSLSR (SEQ ID NO:43);

- the amino acid residue at position 89 is represented by L;

- the amino acid residue at position 11 is represented by V;

in this case it is preferable:

- the amino acid residue at position 110 is K, Q or T, more preferably T;

- the amino acid residue at position 112 is K, Q or S, more preferably S;

which optionally contain at the C-terminal end a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (again, such a C-terminal extension is preferably as described herein, and again, such a nanobody, for example, may also contain one or more other specific amino acid residue substitutions set forth herein, such as 14A, P14A, 14P , A14P, 108L, Q108L). Again, in such anti-serum albumin V _H domains with L at position 89 and V at position 11, the amino acid at position 110 is preferably T and the amino acid at position 112 is preferably S, and also in such V _H domains the C-terminal end is preferred represented by one of SEQ ID NOs: 95-98. In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

In a preferred aspect, the invention relates to nanobodies of the invention (as defined herein) that can bind (in particular, specifically bind)
with serum albumin (especially human serum albumin), which are humanized versions of SEQ ID NO: 52 of WO 2006/122787, in which:

- CDR1 has the amino acid sequence SFGMS (SEQ ID NO:41);

- CDR2 has the amino acid sequence SISGSGSDTLYADSVKG (SEQ ID NO:42);

- CDR3 has the amino acid sequence GGSLSR (SEQ ID NO:43);

- the amino acid residue at position 89 is represented by L;

- the amino acid residue at position 11 is represented by V;

and also preferably:

- the amino acid residue at position 110 is K, Q or T, more preferably T;

- the amino acid residue at position 112 is K, Q or S, more preferably S;

which optionally contain at the C-terminal end a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (again, such a C-terminal extension is preferably as described herein, and again, such a nanobody, for example, may also contain one or more other specific amino acid residue substitutions set forth herein, such as 11L, L11V, L11K , 14A, P14A, 14P, A14P, 108L and/or Q108L). Again, in such anti-serum albumin V _H domains with L at position 89 and V at position 11, the amino acid at position 110 is preferably T and the amino acid at position 112 is preferably S, and also in such V _H domains the C-terminal end is preferred represented by one of SEQ ID NOs: 95-98. In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

In a preferred aspect, the invention relates to nanobodies of the invention (as defined herein) that can bind (in particular, specifically bind)
with serum albumin (especially human serum albumin) that are at least 80%, preferably at least 85%, more preferably at least 90%, such as at least 95% identical in sequence although with one of Alb-1 (SEQ ID NO: 52, WO 2006/122787), Alb-8 (SEQ ID NO: 46, here) and/or Alb-23 (SEQ ID NO: 61, here) (taking into account attention to both framework sequences and CDRs, but without regard to the C-terminal extension) in which the amino acid residue at position 89 is L and the amino acid residue at position 11 is V, and which optionally contain at the C-terminal end a C-terminal extension ( X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (again, such a C-terminal extension is preferably as described herein, and again, such a nanobody may also, for example, contain one or more other specific amino acid residue substitutions set forth herein, such as 14A, P14A, 14P , A14P, 108L, Q108L, T110K, T110Q, S112K and/or S112Q). Such nanobodies of the invention are again preferably humanized variants of Alb-1 (but with V89L and L11V replaced), and more preferably contain at least one, preferably any two, and more preferably all three of CDR1, CDR2 and/or CDR3 given in SEQ ID NOs 41-43, respectively. In such anti-serum albumin V _H domains, the amino acid at position 112 is preferably S, and in such V _H domains, the C-terminal end is preferably one of SEQ ID NOs: 95-98. In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

In accordance with one particular aspect, any serum albumin binding nanobody of the invention with an L at position 89 and a V at position 11 may also contain amino acid residues characteristic of Alb-23 and variants thereof, as described in WO 12/175400 (i.e. amino acid motif GP at positions 44 and 45, amino acid motif SKN at positions 74-76 and preferably G at position 16, and optionally R at position 83). In addition: (i) at position 41 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

Like V _H domains of the invention containing a Q or K at position 112 or containing a T at position 89, V _H domains of the invention containing an L at position 89 and a V at position 11 exhibit reduced binding of preexisting antibodies, in particular such preexisting antibodies antibodies (for example, those found in samples from SLE patients) that are able to bind to V _H domains and nanobodies in the presence of a C-terminal extension. And it should also be noted with respect to the V _H domains of the invention, which have an L at position 89 and a V at position 11, that these substitutions occur with a certain frequency in human V _H domains (see Table A-5 in WO 08/ 020079 for position 11 and Table A-7 in WO 08/020079 for position 89).

Some non-limiting examples of V _H domains of the invention containing V at position 11 and L at position 89 are shown in FIG. 2 as SEQ ID NOs: 109-136. In these V _H domains, the sequences shown in SEQ ID NOs: 123-136, along with the L11V and V89L mutations, also contain the T110K mutation. These _VH domains that bind to human serum albumin contain the CDR regions specified herein for the preferred _VH domains of the invention that bind to serum albumin.

In a further aspect, the invention relates to _VH domains (in particular ISVD _VH domains, more preferably nanobody _VH domains) in which:

- the amino acid residue at position 11 is represented by V;

- the amino acid residue at position 14 is A or P;

- the amino acid residue at position 41 is A or P;

- the amino acid residue at position 89 is represented by L;

- the amino acid residue at position 108 is represented by Q or L;

- the amino acid residue at position 110 is T, K or Q; And

- the amino acid residue at position 112 is S, K or Q;

wherein such _VH domains optionally contain a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (and the C-terminal extension is preferably as described herein). In addition: (i) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (ii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A). Preferably, for V _H domains according to this aspect, the amino acid residue at position 110 is T and the amino acid residue at position 112 is S. Again, as with other V _H domains of the invention, such V _H domains can be directed against any suitable target ( in particular, a therapeutically relevant target). In accordance with one particular aspect, such V _H domains are directed against serum albumin.

In a further aspect, the invention relates to _VH domains (in particular ISVD _VH domains, more preferably nanobody _VH domains) in which:

- the amino acid residue at position 11 is L, V or K;

- the amino acid residue at position 14 is A or P;

- the amino acid residue at position 41 is A or P;

- the amino acid residue at position 89 is T, V or L;

- the amino acid residue at position 108 is represented by Q or L;

- the amino acid residue at position 110 is T, K or Q; And

- the amino acid residue at position 112 is S, K or Q;

wherein either (i) the amino acid residue at position 112 is K or Q; and/or (ii) the amino acid residue at position 89 is T; and/or (iii) the amino acid residue at position 89 is L and the amino acid residue at position 110 is K or Q; and (iv) in each of cases (i)-(iii), the amino acid at position 11 is preferably V;

wherein such _VH domains optionally contain a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (and the C-terminal extension is preferably as described herein). In addition: (i) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (ii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A). Another aspect of the invention relates to _VH domains (in particular, ISVD _VH domains, more preferably nanobody _VH domains) which are as described in this paragraph, wherein the amino acid residue at position 11 is V, and the amino acid residue at position 110 is K or Q (whereas amino acid residues at positions 14, 41, 89, 108 and 112 may be as indicated in the bulleted list above, amino acid residues at positions 42 and 87 may be, for example, such as described in this paragraph, and the _VH domain may optionally contain a C-terminal extension (X) _n as described in this paragraph).

In a further aspect, the invention relates to _VH domains (in particular ISVD _VH domains, more preferably nanobody _VH domains) in which:

- the amino acid residue at position 11 is L, V or K;

- the amino acid residue at position 14 is A or P;

- the amino acid residue at position 41 is A or P;

- the amino acid residue at position 89 is T, V or L;

- the amino acid residue at position 108 is represented by Q or L;

- the amino acid residue at position 110 is T, K or Q; And

- the amino acid residue at position 112 is S, K or Q;

wherein either (i) the amino acid residue at position 112 is K or Q, at position 89 is T, V or L (preferably V), and the amino acid residue at position 110 is T, K or Q (preferably T); and/or (ii) the amino acid residue at position 89 is T, the amino acid residue at position 112 is S, K or Q (preferably S), and the amino acid residue at position 110 is T, K or Q (preferably T); and/or (iii) the amino acid residue at position 89 is L, the amino acid residue at position 110 is K or Q, and the amino acid residue at position 112 is S, K or Q (preferably S); and (iv) in each of cases (i)-(iii), the amino acid at position 11 is preferably V;

wherein such _VH domains optionally contain a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (and the C-terminal extension is preferably as described herein). In addition: (i) at position 42 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (ii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A). Another aspect of the invention relates to _VH domains (in particular, ISVD _VH domains, more preferably nanobody _VH domains) which are as described in this paragraph, wherein the amino acid residue at position 11 is V, and the amino acid residue at position 110 is K or Q (whereas amino acid residues at positions 14, 41, 89, 108 and 112 may be as indicated in the bulleted list above, amino acid residues at positions 42 and 87 may be, for example, such as described in this paragraph, and the _VH domain may optionally contain a C-terminal extension (X) _n as described in this paragraph).

In a further aspect, the invention relates to _VH domains (in particular ISVD _VH domains, more preferably nanobody _VH domains) in which:

- the amino acid residue at position 11 is L, V or K;

- the amino acid residue at position 14 is A or P;

- the amino acid residue at position 41 is A or P;

- the amino acid residue at position 89 is T, V or L;

- the amino acid residue at position 108 is represented by Q or L;

- the amino acid residue at position 110 is T, K or Q; And

- the amino acid residue at position 112 is S, K or Q;

wherein either (i) the amino acid residue at position 112 is K or Q; or (ii) the amino acid residue at position 89 is T; or (iii) the amino acid residue at position 89 is L and the amino acid residue at position 110 is K or Q; and (iv) in each of cases (i)-(iii), the amino acid at position 11 is preferably V;

wherein such _VH domains optionally contain a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (and the C-terminal extension is preferably as described herein). In addition: (i) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (ii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A). Another aspect of the invention relates to _VH domains (in particular, ISVD _VH domains, more preferably nanobody _VH domains) which are as described in this paragraph, wherein the amino acid residue at position 11 is V, and the amino acid residue at position 110 is K or Q (whereas amino acid residues at positions 14, 41, 89, 108 and 112 may be as indicated in the bulleted list above, amino acid residues at positions 42 and 87 may be, for example, such as described in this paragraph, and the _VH domain may optionally contain a C-terminal extension (X) _n as described in this paragraph).

In a further aspect, the invention relates to _VH domains (in particular ISVD _VH domains, more preferably nanobody _VH domains) in which:

- the amino acid residue at position 11 is L, V or K;

- the amino acid residue at position 14 is A or P;

- the amino acid residue at position 41 is A or P;

- the amino acid residue at position 89 is T, V or L;

- the amino acid residue at position 108 is represented by Q or L;

- the amino acid residue at position 110 is T, K or Q; And

- the amino acid residue at position 112 is S, K or Q;

wherein either (i) the amino acid residue at position 112 is K or Q, at position 89 is T, V or L (preferably V), and the amino acid residue at position 110 is T, K or Q (preferably T); or (ii) the amino acid residue at position 89 is T, the amino acid residue at position 112 is S, K or Q (preferably S), and the amino acid residue at position 110 is T, K or Q (preferably T); or (iii) the amino acid residue at position 89 is L, the amino acid residue at position 110 is K or Q, and the amino acid residue at position 112 is S, K or Q (preferably S); and (iv) in each of cases (i)-(iii), the amino acid at position 11 is preferably V;

wherein such _VH domains optionally contain a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (and the C-terminal extension is preferably as described herein). In addition: (i) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (ii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A). Another aspect of the invention relates to _VH domains (in particular, ISVD _VH domains, more preferably nanobody _VH domains) which are as described in this paragraph, wherein the amino acid residue at position 11 is V, and the amino acid residue at position 110 is K or Q (whereas amino acid residues at positions 14, 41, 89, 108 and 112 may be as indicated in the bulleted list above, amino acid residues at positions 42 and 87 may be, for example, such as described in this paragraph, and the _VH domain may optionally contain a C-terminal extension (X) _n as described in this paragraph).

In a further aspect, the invention relates to _VH domains (in particular ISVD _VH domains, more preferably nanobody _VH domains) in which:

- the amino acid residue at position 11 is L, V or K;

- the amino acid residue at position 14 is A or P;

- the amino acid residue at position 41 is A or P;

- the amino acid residue at position 89 is T, V or L;

- the amino acid residue at position 108 is represented by Q or L;

- the amino acid residue at position 110 is T, K or Q; And

- the amino acid residue at position 112 is S, K or Q;

wherein either (i) the amino acid residue at position 112 is K or Q, at position 89 is V, and the amino acid residue at position 110 is T; or (ii) the amino acid residue at position 89 is T, the amino acid residue at position 112 is S, and the amino acid residue at position 110 is T; or (iii) the amino acid residue at position 89 is L, the amino acid residue at position 110 is K or Q, and the amino acid residue at position 112 is S (preferably S); and (iv) in each of cases (i)-(iii), the amino acid at position 11 is preferably V;

wherein such _VH domains optionally contain a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (and the C-terminal extension is preferably as described herein). In addition: (i) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (ii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A). Another aspect of the invention relates to _VH domains (in particular, ISVD _VH domains, more preferably nanobody _VH domains) which are as described in this paragraph, wherein the amino acid residue at position 11 is V, and the amino acid residue at position 110 is K or Q (whereas amino acid residues at positions 14, 41, 89, 108 and 112 may be as indicated in the bulleted list above, amino acid residues at positions 42 and 87 may be, for example, such as described in this paragraph, and the _VH domain may optionally contain a C-terminal extension (X) _n as described in this paragraph).

In a further aspect, the invention relates to _VH domains (in particular ISVD _VH domains, more preferably nanobody _VH domains) in which:

- the amino acid residue at position 11 is L, V or K;

- the amino acid residue at position 14 is A or P;

- the amino acid residue at position 41 is A or P;

- the amino acid residue at position 89 is T, V or L;

- the amino acid residue at position 108 is represented by Q or L;

- the amino acid residue at position 110 is T, K or Q; And

- the amino acid residue at position 112 is S, K or Q;

wherein either (i) the amino acid residue at position 112 is K or Q; and/or (ii) the amino acid residue at position 89 is T; and/or (iii) the amino acid residue at position 89 is L and the amino acid residue at position 110 is K or Q; and (iv) in each of cases (i)-(iii), the amino acid at position 11 is preferably V;

wherein such _VH domains optionally contain a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (and the C-terminal extension is preferably as described herein). In addition: (i) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (ii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A). Another aspect of the invention relates to _VH domains (in particular, ISVD _VH domains, more preferably nanobody _VH domains) which are as described in this paragraph, wherein the amino acid residue at position 11 is V, and the amino acid residue at position 110 is K or Q (whereas amino acid residues at positions 14, 41, 89, 108 and 112 may be as indicated in the bulleted list above, amino acid residues at positions 42 and 87 may be, for example, such as described in this paragraph, and the _VH domain may optionally contain a C-terminal extension (X) _n as described in this paragraph).

In a further aspect, the invention relates to _VH domains (in particular ISVD _VH domains, more preferably nanobody _VH domains) in which:

- the amino acid residue at position 11 is L, V or K;

- the amino acid residue at position 14 is A or P;

- the amino acid residue at position 41 is A or P;

- the amino acid residue at position 89 is T, V or L;

- the amino acid residue at position 108 is represented by Q or L;

- the amino acid residue at position 110 is T, K or Q; And

- the amino acid residue at position 112 is S, K or Q;

wherein either (i) the amino acid residue at position 112 is K or Q, at position 89 is T, V or L (preferably V), and the amino acid residue at position 110 is T, K or Q (preferably T); and/or (ii) the amino acid residue at position 89 is T, the amino acid residue at position 112 is S, K or Q (preferably S), and the amino acid residue at position 110 is T, K or Q (preferably T); and/or (iii) the amino acid residue at position 89 is L, the amino acid residue at position 110 is K or Q, and the amino acid residue at position 112 is S, K or Q (preferably S); and (iv) in each of cases (i)-(iii), the amino acid at position 11 is preferably V;

wherein such _VH domains optionally contain a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (and the C-terminal extension is preferably as described herein). In addition: (i) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (ii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A). Another aspect of the invention relates to _VH domains (in particular, ISVD _VH domains, more preferably nanobody _VH domains) which are as described in this paragraph, wherein the amino acid residue at position 11 is V, and the amino acid residue at position 110 is K or Q (whereas amino acid residues at positions 14, 41, 89, 108 and 112 may be as indicated in the bulleted list above, amino acid residues at positions 42 and 87 may be, for example, such as described in this paragraph, and the _VH domain may optionally contain a C-terminal extension (X) _n as described in this paragraph).

In a further aspect, the invention relates to _VH domains (in particular ISVD _VH domains, more preferably nanobody _VH domains) in which:

- the amino acid residue at position 11 is L, V or K;

- the amino acid residue at position 14 is A or P;

- the amino acid residue at position 41 is A or P;

- the amino acid residue at position 89 is T, V or L;

- the amino acid residue at position 108 is represented by Q or L;

- the amino acid residue at position 110 is T, K or Q; And

- the amino acid residue at position 112 is S, K or Q;

wherein either (i) the amino acid residue at position 112 is K or Q; or (ii) the amino acid residue at position 89 is T; or (iii) the amino acid residue at position 89 is L and the amino acid residue at position 110 is K or Q; and (iv) in each of cases (i)-(iii), the amino acid at position 11 is preferably V;

wherein such _VH domains optionally contain a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (and the C-terminal extension is preferably as described herein). In addition: (i) at position 42 there may be, for example, one of the amino acid residues (i.e. human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (ii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A). Another aspect of the invention relates to _VH domains (in particular, ISVD _VH domains, more preferably nanobody _VH domains) which are as described in this paragraph, wherein the amino acid residue at position 11 is V, and the amino acid residue at position 110 is K or Q (whereas amino acid residues at positions 14, 41, 89, 108 and 112 may be as indicated in the bulleted list above, amino acid residues at positions 42 and 87 may be, for example, such as described in this paragraph, and the _VH domain may optionally contain a C-terminal extension (X) _n as described in this paragraph).

In a further aspect, the invention relates to _VH domains (in particular ISVD _VH domains, more preferably nanobody _VH domains) in which:

- the amino acid residue at position 11 is L, V or K;

- the amino acid residue at position 14 is A or P;

- the amino acid residue at position 41 is A or P;

- the amino acid residue at position 89 is T, V or L;

- the amino acid residue at position 108 is represented by Q or L;

- the amino acid residue at position 110 is T, K or Q; And

- the amino acid residue at position 112 is S, K or Q;

wherein either (i) the amino acid residue at position 112 is K or Q, at position 89 is T, V or L (preferably V), and the amino acid residue at position 110 is T, K or Q (preferably T); or (ii) the amino acid residue at position 89 is T, the amino acid residue at position 112 is S, K or Q (preferably S), and the amino acid residue at position 110 is T, K or Q (preferably T); or (iii) the amino acid residue at position 89 is L, the amino acid residue at position 110 is K or Q, and the amino acid residue at position 112 is S, K or Q (preferably S); and (iv) in each of cases (i)-(iii), the amino acid at position 11 is preferably V;

wherein such _VH domains optionally contain a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (and the C-terminal extension is preferably as described herein). In addition: (i) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (ii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A). Another aspect of the invention relates to _VH domains (in particular, ISVD _VH domains, more preferably nanobody _VH domains) which are as described in this paragraph, wherein the amino acid residue at position 11 is V, and the amino acid residue at position 110 is K or Q (whereas amino acid residues at positions 14, 41, 89, 108 and 112 may be as indicated in the bulleted list above, amino acid residues at positions 42 and 87 may be, for example, such as described in this paragraph, and the _VH domain may optionally contain a C-terminal extension (X) _n as described in this paragraph).

In a further aspect, the invention relates to _VH domains (in particular ISVD _VH domains, more preferably nanobody _VH domains) in which:

- the amino acid residue at position 11 is L, V or K;

- the amino acid residue at position 14 is A or P;

- the amino acid residue at position 41 is A or P;

- the amino acid residue at position 89 is T, V or L;

- the amino acid residue at position 108 is represented by Q or L;

- the amino acid residue at position 110 is T, K or Q; And

- the amino acid residue at position 112 is S, K or Q;

wherein either (i) the amino acid residue at position 112 is K or Q, at position 89 is V, and the amino acid residue at position 110 is T; or (ii) the amino acid residue at position 89 is T, the amino acid residue at position 112 is S, and the amino acid residue at position 110 is T; or (iii) the amino acid residue at position 89 is L, the amino acid residue at position 110 is K or Q, and the amino acid residue at position 112 is S (preferably S); and (iv) in each of cases (i)-(iii), the amino acid at position 11 is preferably V;

wherein such _VH domains optionally contain a C-terminal extension (X) _n , where n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as then 1); and each X represents a (preferably naturally occurring) amino acid residue that is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I) (and the C-terminal extension is preferably as described herein). In addition: (i) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (ii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A). Another aspect of the invention relates to _VH domains (in particular, ISVD _VH domains, more preferably nanobody _VH domains) which are as described in this paragraph, wherein the amino acid residue at position 11 is V, and the amino acid residue at position 110 is K or Q (whereas amino acid residues at positions 14, 41, 89, 108 and 112 may be as indicated in the bulleted list above, amino acid residues at positions 42 and 87 may be, for example, such as described in this paragraph, and the _VH domain may optionally contain a C-terminal extension (X) _n as described in this paragraph).

Again, in the _VH domains of the invention, as defined herein, amino acid residues at positions not expressly defined herein may be any amino acid residues that are suitable at such positions for _VH domains, in particular for ISVD, more preferably for nanobodies (including humanized _VHH domains). Let us again refer to the works of the prior art cited here, such as, for example, table. A-3 and A-5 to A-8 in WO 08/020079. Preferably, in each case, the amino acid residue at position 11 is L or V, more preferably V. In addition: (i) position 41 may, for example, be one of the amino acid residues (i.e. human V _H 3 residues and/ or remains of camelid V _HH ), given in Table. A-6 WO 08/020079 for position 41, in particular it may be (or selected from) proline (P), serine (S), threonine (T), alanine (A) or leucine (L), i.e. from among those amino acid residues most commonly found at this position in humans or llamas, and more preferably may be proline (P) or alanine (A); and/or (ii) at position 42 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) listed in table. A-6 WO 08/020079 for position 42, in particular it may be (or be selected from) glycine (G) or glutamic acid (E); and/or (iii) at position 87 there may be, for example, one of the amino acid residues (i.e., human V _H 3 residues and/or camel V _HH residues) given in table. A-7 WO 08/020079 for position 87, in particular it can be (or is selected from) threonine (T) or alanine (A).

In addition, such V _H domains of the invention can be directed against any suitable target, especially a therapeutic target. In one aspect, they are directed against a human serum protein such as human serum albumin.

The invention also relates to proteins, polypeptides, constructs, compounds or other chemical substances containing at least one V _H domain of the invention (collectively these are also referred to herein as “compounds of the invention”).

As described below, in accordance with one particular aspect, the compounds of the invention have the V _H domain of the invention located at/forming their C-terminal end. In such a case, the V _H domain of the invention forming/located at the C-terminal end of the compound of the invention preferably has a C-terminal extension as described herein.

Also as described below, the compounds of the invention may be scFvs, diabodies or other proteins, polypeptides or constructs in which one or more V _H domains of the invention are linked to one or more V _L domains to form one or more functional antigen binding sites.

However, in accordance with a preferred aspect of the invention, the V _H domains of the invention are ISVDs, and the compounds of the invention are proteins, polypeptides, constructs, compounds or other chemical entities containing or substantially consisting of at least one ISVD of the invention and optionally one or more other amino acid sequences, moieties, binding domains or binding blocks (suitably linked to each other, optionally through one or more linkers). In particular, such compounds of the invention may contain or consist essentially of one or more ISVDs, at least one of which is an ISVD of the invention. Such compounds of the invention may in particular have the ISVD of the invention at the C-terminal end, in which case the ISVD of the invention preferably also has a C-terminal extension as described herein. Additionally, if such a compound of the invention contains two or more ISVDs, then those two or more or substantially all of the ISVDs may be ISVDs of the invention (i.e., each may have at least one of the following amino acid residue substitutions: 112K, 112Q, S112K, S112Q, 89T and/or V89T, or a combination of V89L with T110K or T110Q; and optionally one or more of the other replacements provided herein for the ISVD of the invention, such as L11V). In addition, for such compounds of the invention, the ISVDs of the invention are preferably represented by nanobodies of the invention, and all or substantially all of the ISVDs in the compound of the invention may be (and preferably are) nanobodies (in particular, nanobodies of the invention, i.e., each may have at least at least one of the following amino acid residue substitutions: 112K, 112Q, S112K, S112Q, 89T and/or V89T, or a combination of V89L with T110K or T110Q; and optionally one or more of the other substitutions provided herein for the nanobodies of the invention, such as L11V ). Examples of such compounds of the invention will be apparent to those skilled in the art from the following description.

Some non-limiting examples of proteins, polypeptides, constructs, compounds or other chemical entities containing one or more ISVDs (including at least one ISVD of the invention) are multivalent, multispecific (such as bispecific) or multiparatopic (such as biparatopic ) constructs containing two or more ISVDs connected directly or through one or more suitable linkers. Again, these ISVDs are preferably nanobodies. For some non-limiting examples of such structures and general information on how such structures can be obtained (particularly based on nanobodies), reference is made, for example, to Conrath et al., JBC 276, 10(9), 7346 (2001) , as well as the review article Muyldermans, Reviews in Mol. Biotechnol., 74: 27 (2001).

For example, such a compound of the invention containing two or more ISVDs (of which at least one is an ISVD of the invention) may be a bivalent, trivalent, tetravalent or pentavalent construct, and/or may be a monospecific, bispecific, trispecific construct, and/or may be a biparatopic or triparatopic design. Let us again refer to the prior art work presented here on IVSD-based and nanobody-based biological products. In addition, such a compound of the invention may have an increased half-life when functionalized and/or when included in the construct with a molecule or binding block that increases the half-life of the construct. Examples of such functionalization, molecules or binding blocks will be known to those skilled in the art and may be, for example, as described herein, they may include, for example, PEGylation, fusion to serum albumin, or fusion to a peptide or binding block that can bind to serum a protein such as serum albumin. Such serum albumin binding peptide or binding domain may be any suitable serum albumin binding peptide or binding domain capable of increasing the half-life of the construct (compared to the same construct without the serum albumin binding peptide or binding domain), in particular it may be binding serum albumin peptides as described in Applicant's WO 2008/068280 (especially WO 2009/127691 and unpublished application USA 61/301,819, both from Applicant), or serum albumin-binding ISVs (such as serum albumin-binding nanobodies, e.g. Alb -1 or humanized variants of Alb-1 such as Alb-8, for which we refer, for example, to WO 06/122787), or ISVD according to the invention, directed against a (human) serum protein such as human serum albumin (as already described here) . In general, any extended half-life compound of the invention will preferably have a half-life (as defined herein) in humans of at least 1 day, preferably at least 3 days, more preferably at least 7 days, such as at least 10 days.

When a compound of the invention contains at least one (and preferably one) ISVD of the invention (in particular a nanobody of the invention) that is directed against a (human) serum protein, in particular against (human) serum albumin, the compound of the invention will typically additionally contains one or more other therapeutically active amino acid sequences, binding domains or binding units (ie, directed against a therapeutically relevant target, pathway or mechanism), and the ISVD of the invention will work to increase its half-life (and the overall compound). Again, such additional therapeutically active molecules are preferably ISVDs (more preferably nanobodies), which may be IVSDs of the invention (more preferably nanobodies of the invention). For such compounds of the invention, the ISVD of the invention, which is directed against human serum albumin, may again be at or form the C-terminal end of the compound, in which case it may (and preferably does) contain a C-terminal extension as described herein. When a compound of the invention contains an ISVD of the invention that is directed against serum albumin (human), the compound must have a half-life (as defined herein) of at least 1 day, preferably at least 3 days, more preferably at least in 7 days, somehow at least 10 days in those people to whom it is administered. Some non-limiting examples of ISVDs of the invention against human serum albumin that can be used for this purpose are also described here.

In one aspect, all ISVDs or nanobodies present in a given compound of the invention are ISVDs of the invention (meaning that they contain substitutions of amino acid residues that are characteristic of the V _H domains of the invention as defined herein, i.e., at least 112K or Q, or at least 89T, or at least 89L combined with 110K or 110Q). When all ISVDs of a compound of the invention are represented by ISVDs of the invention, they may contain the same substitutions (eg, one may have the S112K or S112Q substitution, and another may have the V89L mutation combined with T110K or T110Q). In addition, typically only the ISVD at the C-terminal end of a compound of the invention contains a C-terminal extension (since the others will need to connect at the C-terminal end to another ISVD present in that compound).

Thus, in a further aspect, the invention relates to proteins, polypeptides or other compounds or molecules containing or essentially consisting of ISVDs of the invention (as already described herein).

The invention also relates to proteins, polypeptides or other compounds or molecules containing at least one ISVD of the invention and at least one other therapeutic molecule or substance (which is connected directly or through a suitable linker).

The invention also relates to proteins, polypeptides or other compounds or molecules containing at least one ISVD of the invention directed against (human) serum protein (and preferably against human serum albumin), and at least one other therapeutic molecule or substance (which connects directly or through a suitable linker).

The invention also relates to proteins, polypeptides or other compounds or molecules containing at least two (such as 2, 3 or 4) single immunoglobulin variable domains (connected directly or through a suitable linker), of which at least one is represented by the ISVD of the invention . In this aspect: (i) the ISVDs present may be the same or different; and when they are different, they may be directed against the same target (for example, they may have different sequences and/or be directed against different epitopes on the same target) or against two or more different targets (i.e. the resulting protein, polypeptide, other compound or molecule will be a bi- or multispecific construct); and/or (ii) the ISVD located at the C-terminal end of the protein, polypeptide or other compound or molecule may or may not be an ISVD of the invention (but preferably is); and/or (iii) when the ISVD of the invention is at the C-terminal end of a protein, polypeptide or other compound or molecule, it preferably contains a C-terminal extension as described herein; and/or (iv) substantially all of the ISVDs present in a protein, polypeptide or other compound or molecule may be ISVDs of the invention. In addition, when the ISVDs are directed against different targets (of which at least one is a therapeutic target), in accordance with a further aspect, at least one of the ISVDs present may be directed against a (human) serum protein such as human serum albumin (wherein this The ISVD may or may not be an inventive ISVD; and when it is an inventive ISVD, it is preferably an anti-human serum albumin nanobody, which is already described herein).

The invention also relates to such proteins, polypeptides or other compounds or molecules that contain or essentially consist of two single immunoglobulin variable domains (connected directly or through a suitable linker).

The invention also relates to such proteins, polypeptides or other compounds or molecules that contain or are substantially composed of three single immunoglobulin variable domains (connected directly or through a suitable linker).

The invention also relates to such proteins, polypeptides or other compounds or molecules that contain or are substantially composed of four single immunoglobulin variable domains (connected directly or through a suitable linker).

The invention also relates to such proteins, polypeptides or other compounds or molecules that further comprise at least one moiety, one binding domain or binding block that imparts an increased half-life to the protein, polypeptide, other compound or molecule (i.e., compared to with a corresponding protein, polypeptide, other compound or molecule without such moiety, binding domain or binding block). In a more specific aspect, the at least one moiety, binding domain, or binding block that imparts an increased half-life to the protein, polypeptide, other compound, or molecule is an immunoglobulin single variable domain, more preferably such an immunoglobulin single variable domain, which is directed against a serum protein (such as serum albumin), preferably against a human serum protein (such as human serum albumin); which, as described here, in particular can be the ISVD according to the invention. Such an anti-whey protein ISVD may be at the N-terminal end of the protein, polypeptide, other compound or molecule, at the C-terminal end, or (if the protein, polypeptide or other compound or molecule contains more than two ISVDs) in the middle of the molecule.

The invention also relates to such proteins, polypeptides or other compounds or molecules which contain or consist essentially of:

- two single immunoglobulin variable domains (connected directly or through a suitable linker), i.e. (this) one single immunoglobulin variable domain (nanobody type) conferring an increased half-life, and one other immunoglobulin variable domain (nanobody type) which, in particular, can be directed against a therapeutic target;

- three single immunoglobulin variable domains (connected directly or through a suitable linker), i.e. (of this) one single immunoglobulin variable domain (a type of nanobody) conferring an increased half-life, and two other single immunoglobulin variable domains (such as two other nanobodies), which, in particular, can be directed against a therapeutic target (these two other single immunoglobulin variable domains may be directed against the same target, against two different targets, or against two different epitopes on the same target); or

- four single immunoglobulin variable domains (connected directly or through a suitable linker), i.e. (of this) one single immunoglobulin variable domain (a type of nanobody) conferring an increased half-life, and three other single immunoglobulin variable domains (such as three other nanobodies), which, in particular, can be directed against a therapeutic target (these three other single immunoglobulin variable domains may be directed against the same target, against two or three different targets, and/or against two or three different epitopes on the same target).

Again, for such proteins, polypeptides or other compounds or molecules: (i) the ISVDs present may be the same or different; and when they are different, they may be directed against the same target (for example, they may have different sequences and/or be directed against different epitopes on the same target) or against two or more different targets (i.e. the resulting protein, polypeptide, other compound or molecule will be a bi- or multispecific construct); and/or (ii) the ISVD located at the C-terminal end of the protein, polypeptide or other compound or molecule may or may not be an ISVD of the invention (but preferably is); and/or (iii) when the ISVD of the invention is at the C-terminal end of a protein, polypeptide or other compound or molecule, it preferably contains a C-terminal extension as described herein; and/or (iv) substantially all of the ISVDs present in a protein, polypeptide or other compound or molecule may be ISVDs of the invention.

The invention also relates to methods for expressing/producing/obtaining the V _H domains of the invention and the compounds of the invention (which are already described herein). For example, the V _H domain of the invention can be expressed/obtained by expressing the nucleic acid encoding it in a suitable host organism. Reference is made, for example, to WO 08/020079 (as well as certain other applicant/assignee patent applications cited herein), which outline suitable methods and techniques for expressing/producing nanobodies that can also be suitably used to express/ obtaining nanobodies according to the invention. Methods for expressing V _H domains of the invention other than nanobodies will also be apparent to those skilled in the art from the description and prior art cited herein. The compounds of the invention may conveniently be prepared by appropriately linking (usually via covalent bonds) one or more _VH domains of the invention to one or more other amino acid residues (and/or other groups or moieties) that are optionally required to be present in the final compound of the invention through one or more linkers or spacers. On the other hand, if the compound of the invention is a protein or polypeptide, it can be produced by suitable expression of the nucleic acid encoding it in a suitable host organism. Again, reference is made, for example, to the general methods described in WO 08/020079 and several other applicant/assignee patent applications cited herein.

The invention also relates to nucleotide and/or nucleic acid sequences encoding V _H domains of the invention or compounds of the invention. Such nucleic acids may be in the form of a plasmid or vector. Again, we refer, for example, to WO 08/020079 and some other patent applications cited here from the applicant/assignee.

The invention also relates to compositions containing at least one V _H domain of the invention, a compound of the invention, or a nucleic acid encoding one or the other.

The invention also relates to pharmaceutical compositions containing ISVs (preferably therapeutic ISVs) or proteins or polypeptides containing at least one ISV (and preferably at least one therapeutic ISV), wherein the ISV, protein or polypeptide is as already described herein ( i.e., it is an ISV, protein, or polypeptide in accordance with one or more of the aspects described herein, in particular, in accordance with one or more aspects described in the preceding pages, and more preferably, it is an ISV, protein, or polypeptide that has a C -terminal end/sequence in accordance with one or more of the aspects described herein), as well as at least one suitable carrier, diluent or excipient (i.e. suitable for pharmaceutical use) and optionally one or more other biologically active substances. Such compositions, carriers, diluents or excipients, for example, may be as described in WO 08/020079 for pharmaceutical compositions containing nanobodies or proteins or polypeptides containing at least one nanobody (as already stated, in accordance with the present invention, the ISV is also preferably a nanobody).

The invention also relates to ISVs, or proteins or polypeptides containing at least one ISV, for use in the therapy of diseases in humans (for example, in patients in need of such therapy), wherein the ISV, protein or polypeptide is as already described herein (i.e. i.e. it is an ISV, protein or polypeptide in accordance with one or more of the aspects described herein, in particular in accordance with one or more aspects described on the previous pages, and more preferably it is an ISV, protein or polypeptide that has a C- terminal end/sequence in accordance with one or more of the aspects described herein).

The invention also relates to the use of ISVs or proteins or polypeptides containing at least one ISV in the preparation of pharmaceutical compositions, wherein the ISV, protein or polypeptide is as already described herein (i.e. it is an ISV, protein or polypeptide in accordance with one or more of the aspects described herein, particularly in accordance with one or more of the aspects described in the preceding pages; and more preferably, it is an ISV, protein or polypeptide that has a C-terminal end/sequence in accordance with one or more of the described aspects here).

The invention also relates to a method of treatment that includes administering to a human (eg, a patient in need of such treatment) an ISV or a protein or polypeptide comprising at least one ISV in the preparation of a pharmaceutical composition, wherein the ISV, protein or polypeptide is as already described here (i.e., it is an ISV, protein, or polypeptide in accordance with one or more aspects described herein, particularly in accordance with one or more aspects described on the preceding pages; and more preferably, it is an ISV, protein, or polypeptide that has a C-terminal end/sequence in accordance with one or more of the aspects described herein); or a pharmaceutical composition (as described above) containing at least one such ISV, protein or polypeptide.

With respect to the foregoing, it should be understood that the therapeutic use of the ISVs, proteins and polypeptides described herein is a very important aspect of the invention, since such therapeutic use (or clinical development of such ISVs, proteins and polypeptides for such therapeutic use) may involve the use of ADA assays for determining whether a given ISV, protein or polypeptide is immunogenic (ie, can cause ADA when administered to humans). In this regard, it should also be understood that concerns about possible immunogenicity should be considered in particular when the therapeutic agent is administered for a long time (several weeks, months or years) and/or has a half-life (preferably expressed as t _½ -beta) in the human body for at least 3 days, somehow at least one week and up to 10 days or more.

Thus, in accordance with one specific aspect, the invention relates to ISVs, proteins, polypeptides, compounds or molecules of the invention as described herein (or pharmaceutical compositions thereof) that are intended for the treatment of chronic diseases in humans, and/or such ISVs, proteins , polypeptides as described herein must be present in the bloodstream of individuals (i.e., at a pharmacologically active level) to whom they are administered (i.e., at a therapeutically active dose) for at least one week, preferably at least two weeks, somehow at least a month; and/or such ISVs, proteins, polypeptides as described herein have a half-life (preferably expressed as t _½ -beta) in the human body of at least 3 days, such as at least one week, and up to 10 days or more; and/or such ISVs, proteins, polypeptides or pharmaceutical compositions as described herein are intended for administration to a human in two or more doses that are administered over at least 3 days, such as at least one week, for example , at least two weeks or at least one month or even more (ie at least 3 months, at least 6 months or at least one year) or are administered chronically.

In addition, as will be clear to those skilled in the art from the foregoing description, the improvements made to the _VH domains described herein and the resulting improved _VH domains will find particular use in proteins, polypeptides or other compounds or molecules intended for administration to such humans (in in particular, patients) whose blood/serum contains (or is suspected of containing) pre-existing antibodies of a type that - in accordance with the present invention - is found in samples obtained from patients with SLE, i.e. pre-existing antibodies that can bind to the C-terminal region of the V _H domain even in the presence of a C-terminal extension, as described here. In particular, the _VH domain improvements described herein and the resulting improved _VH domains will find particular use in proteins, polypeptides, or other compounds or molecules intended for the treatment or prevention of diseases or disorders in such patients. These can be any disease or disorder, but preferably those diseases or disorders that lead to and/or are associated with the presence or appearance of such pre-existing antibodies (SLE is one example, but it is expected that other severe (auto)immune diseases may also lead to the appearance of such pre-existing antibodies). This can be easily determined by testing samples obtained from the relevant patient population for the presence of such pre-existing antibodies, in essentially the same way as the testing performed on samples from SLE patients in the Experimental Section below.

Thus, in accordance with one specific aspect, the invention relates to ISVs, proteins, polypeptides, compounds or molecules of the invention as described herein (or pharmaceutical compositions thereof) that are intended for administration to humans whose blood contains pre-existing antibodies that can bind to exposed C-terminal portion of the V _H domain even when the V _H domain contains a C-terminal extension as described herein (or when the C-terminal end of the V _H domain is linked to another protein or polypeptide, such as another ISV, optionally via a suitable linker).

In particular, the invention relates to ISVs, proteins, polypeptides, compounds or molecules of the invention as described herein (or pharmaceutical compositions thereof) for use in the treatment of diseases or disorders in humans whose blood contains pre-existing antibodies that can bind to exposed C -terminal portion of the V _H domain even when the V _H domain contains a C-terminal extension as described herein (or when the C-terminal end of the V _H domain is linked to another protein or polypeptide, such as another ISV, optionally through a suitable linker). These may be any diseases or disorders, but preferably those diseases or disorders that lead to, cause or are otherwise associated with the presence of such pre-existing antibodies in the blood of such patients, such as SLE or other (severe) autoimmune diseases.

Thus, in accordance with one specific aspect, the invention relates to ISVs, proteins, polypeptides, compounds or molecules of the invention, as described herein (or pharmaceutical compositions thereof), for use in the treatment of diseases or disorders in humans/patients, such diseases or disorders that lead to, cause or are otherwise associated with the presence of such pre-existing antibodies in the blood of such persons/patients that can bind to the exposed C-terminal region of the V _H domain even when the V _H domain contains a C-terminal extension, as described here (or when the C-terminal end of the V _H domain is connected to another protein or polypeptide, such as another ISV, optionally through a suitable linker). For example, such ISVs, proteins, polypeptides, compounds or molecules of the invention as described herein (or pharmaceutical compositions thereof) for use in the treatment of SLE or other severe (auto)immune diseases in humans/patients.

As will be appreciated by those skilled in the art, when proteins, polypeptides, compounds or molecules are intended for the prevention or treatment of such diseases or disorders, they must contain at least one (such as one, two, three or four) block or molecule binding domain or a substance that is therapeutically active against a relevant disease or disorder (eg, directed against a target or pathway that is therapeutically significant for the relevant disease or disorder). Again, such binding domains or binding blocks may be, for example, (other) ISVDs, and in one aspect they are preferably the V _H domains or ISVDs of the invention. Another general example of such a protein, polypeptide, compound or molecule is a protein, polypeptide, compound or molecule in which the one or more therapeutic domains, binding blocks or molecules or substances may not be ISVDs (but, for example, originate from another backbone) but contain a _VH domain of the invention that prolongs their half-life (such as serum albumin binders as described herein).

In a further aspect, the V _H domains, ISVDs or compounds of the invention (as described herein) are directed to the Kv1.3 ion channel. Some preferred, but not limited to, examples of such _VH domains, ISVDs or compounds are set forth in Example 7, with the anti-Kv1.3 _VH domains described in this example (as well as compounds of the invention containing them), as well as specific compounds of the invention against Kv1.3 described in this example constitute additional aspects of the present invention.

For example, and without limitation, a compound of the invention directed against Kv1.3 may contain or consist essentially of a single _VH domain, and preferably a nanobody of the invention directed against Kv1.3, or may contain or consist mainly of at least of at least two (such as two or three) _VH domains, and preferably nanobodies of the invention directed against Kv1.3. When such a polypeptide contains two or more V _H domains of the invention against Kv1.3, these V _H domains may be the same or different, and when different, they may be directed against the same epitope on Kv1.3 or subunits on Kv1.3 or against various epitopes or subunits.

Again, as generally described herein for the compounds of the invention, such compounds typically may contain one or more linkers, may contain a C-terminal extension (i.e., as already described herein), and may also contain one or more additional linking units or binding domains (or other amino acid sequences or parts of molecules), such as an additional ISVD directed against a target other than Kv1.3. For example, and without limitation, the compounds of the invention may (also) contain a binding domain or binding block providing an extended half-life, such as an ISVD against a serum protein such as serum albumin (e.g., an anti-human serum albumin nanobody such as an anti-serum albumin nanobody of the invention person).

In further aspects, the invention relates to (synthetic) libraries of immunoglobulin variable domain sequences that are as described herein (ie, contain the amino acid residues/mutations/substitutions that are described herein). Such libraries typically contain at least 100 different sequences, such as at least 1000 different sequences, preferably more than 10 ⁵ different sequences, more preferably more than 10 ⁶ , such as 10 ⁸ to 10 ¹⁰ or more different sequences (which in the broadest sense, means that there is at least one amino acid difference between sequences), which all typically have (virtually) the same framework sequences (and they contain the amino acid residues/mutations specified here), but different CDRs (meaning that each a sequence in the library has at least “one amino acid difference” in at least one of the CDRs compared to other sequences in the library)).

Synthetic libraries of immunoglobulin variable domain sequences (for example, based on human _VH sequences or camel _VHH sequences) and methods for their preparation/construction (including libraries based on a given backbone and/or containing one or more specific amino acid residues/mutations in the framework regions ), are well known in the art. We refer, for example, to Tanha et al., J. Biol. Chem., Vol. 276, pp. 24774-24780, 2001; Bond et al., J. Mol. Biol. (2003) 332, 643-655; Mandrup et al., PLOS One, October 2013, Volume 8, Issue 10, e76834; Goldman et al., Anal. Chem., 2006, 78, 8245-8255; Hussak et al., Protein Engineering, Design & Selection vol. 25 no. 6 pp. 313-318, 2012; and Chen et al., Methods Mol. Biol., 2009, 525, 81. The methods described therein (and similar methods known per se) can be suitably used or adapted to create libraries of single immunoglobulin variable domains of the invention.

The ISVDs contained in such libraries may accordingly contain any suitable CDRs from any suitable source, such as CDRs derived from the immune repertoire of naïve mammals (eg camel or human sequences), CDRs derived from the immune repertoire of animals (eg e.g. camels) that have been appropriately immunized with the antigen; completely synthetic CDR repertoires; or repertoires obtained by methods such as mutagenesis (eg, random mutagenesis or site-directed mutagenesis). Such libraries can also be prepared, for example, by affinity maturation techniques known per se.

The framework regions of the ISVDs contained in such libraries may suitably be derived from any suitable starting sequence/backbone, for example, based on a backbone that was derived from a starting V _H sequence (such as a human V _H sequence) or a starting nanobody sequence (such as V _HH sequence or humanized V _H sequence). Also, the library may contain ISVDs derived from two or more different sources or based on two or more different backbones (eg, because the library was obtained by combining two or more libraries obtained from different sources or based on different backbones).

In addition, the libraries (ISVDs contained therein) can be in the form of proteins or in the form of DNA or RNA encoding the corresponding ISVDs. For example, the libraries may be in the form of an expression library suitable for screening and/or selection methods, and may be, for example, in a form suitable for display methods, such as a phage display library, a yeast display library or a ribosomal display library .

So, in general terms, the invention also relates to libraries (as described herein) containing the V _H domains of the invention (as already described herein). Preferably, in accordance with one particular aspect of such libraries, all V _H domains therein have the same (or substantially the same) framework sequences, but different CDR sequences (again, as noted, this means that each of the individual V _H domains in the library has at least one amino acid difference in at least one CDR compared to the other V _H domains in the library).

In one aspect, such libraries of the invention are libraries of ISVDs of the invention (as already described herein, including libraries of suitable nucleic acids encoding these ISVDs) in which:

- the amino acid residue at position 11 is L, V or K;

- the amino acid residue at position 14 is A or P;

- the amino acid residue at position 41 is A or P;

- the amino acid residue at position 89 is T, V or L;

- the amino acid residue at position 108 is represented by Q or L;

- the amino acid residue at position 110 is T, K or Q; And

- the amino acid residue at position 112 is S, K or Q;

wherein either (i) the amino acid residue at position 112 is K or Q; and/or (ii) the amino acid residue at position 89 is T; and/or (iii) the amino acid residue at position 89 is L and the amino acid residue at position 110 is K or Q; and (iv) in each of cases (i)-(iii), the amino acid at position 11 is preferably V. Optionally, ISVDs found in such a library may also contain a C-terminal extension (as already described herein for the _VH domains of the invention) and/or respectively contain a suitable tag (such as histidine tags).

In another aspect, such libraries of the invention are libraries of ISVDs of the invention (as already described herein, including libraries of suitable nucleic acids encoding these ISVDs) in which:

- the amino acid residue at position 11 is represented by V;

- the amino acid residue at position 14 is A or P;

- the amino acid residue at position 41 is A or P;

- the amino acid residue at position 89 is represented by L;

- the amino acid residue at position 108 is represented by Q or L;

- the amino acid residue at position 110 is T, K or Q; And

- the amino acid residue at position 112 is S, K or Q.

Optionally, the ISVDs found in such a library may also contain a C-terminal extension (as already described here for the _VH domains of the invention) and/or suitably contain a suitable tag (such as histidine tags).

The libraries of the invention may be used for any suitable purpose known per se. For example, they may, for example, be used for screening and/or selection purposes (or as part of a screening and/or selection process), used for/as part of affinity maturation methods or other processes designed to produce improved _VH domains, or , for example, to scan for alanine. In practice, as a rule, the size, design and other features of the library must be adapted to its purpose, which is the responsibility of specialists.

The invention will now be described in more detail using the following non-limiting preferred aspects, examples and figures.

Brief description of the figures

In fig. 1 is a table listing some of the amino acid positions that are specifically reported here and numbering them according to some alternative numbering systems (such as AHo and IMGT).

In fig. 2 shows the sequences shown here.

In fig. Figure 3 is a graph of the data obtained in Example 4 by testing 96 serum samples for binding of a representative nanobody with the S112K mutation (standard A + S112K + C-terminal alanine, indicated as (2) in Fig. 3), compared to the control nanobody without the S112K mutation (standard A, SEQ ID NO: 44, indicated as (1) in Fig. 3).

In fig. 4 is a graph of the data obtained in Example 4 by testing 129 serum samples for binding of a representative nanobody with the V89T mutation (standard A + L11V + V89T + C-terminal alanine, indicated as (2) in Fig. 4), compared to control nanobody without the V89T mutation (standard A, SEQ ID NO: 44, indicated as (1) in Fig. 4).

In fig. 5 is a graph of the data obtained in Example 5 by testing 100 serum samples for binding of representative nanobodies with the V89L, T110K and/or T110Q mutations (standard A + L11V + V89L + C-terminal alanine, indicated as (2) in FIG. 5; standard A + L11V + V89L + T110K + C-terminal alanine, which is indicated as (3) in Fig. 5; standard A + L11V + V89L + T110Q + C-terminal alanine, which is indicated as (4) in Fig. 5; 5; standard A + L11V + T87A + V89L + C-terminal alanine, indicated as (5) in Fig. 5), compared to the control nanobody without such mutations (standard A, SEQ ID NO: 44, indicated as (1 ) in Fig. 5).

In fig. 6 is a graph of data obtained in Example 6 by testing 98 serum samples from healthy volunteers for binding of representative trivalent nanobody constructs. Each dot represents data obtained from testing the indicated construct on one of 98 serum samples. Designations: (1) standard X (nanobody A-35GS-nanobody A-35GS-nanobody B); (2) X+C-terminal Ala standard; (3) standard X + L11V + V89L + C-terminal Ala; (4) standard X + L11V + T87A + V89L + C-terminal Ala; (5) standard X + L11V + V89L + T110K + C-terminal Ala; (6) standard X + L11V + V89L + T110Q + C-terminal Ala.

In fig. 7 is a graph of data obtained in Example 6 by testing 30 serum samples from healthy volunteers (samples selected for high titers of preexisting antibodies or the presence of highly binding preexisting antibodies even in the presence of a C-terminal alanine extension) for binding of representative trivalent nanobody constructs . Each dot represents data obtained from testing the indicated construct on one of 30 serum samples. Designations: (1) standard X + C-terminal Ala; (2) standard X + L11V + V89L + C-terminal Ala; (3) standard X + L11V + T87A + V89L + C-terminal Ala; (4) standard X + L11V + V89L + T110K + C-terminal Ala.

In fig. 8 is a graph of data obtained in Example 6 by testing 98 serum samples from healthy volunteers for binding of representative bivalent nanobody constructs. Each dot represents data obtained from testing the indicated construct on one of 98 serum samples. Designations: (1) standard Y (nanobody A-35GS-nanobody B); (2) Y+C-terminal Ala standard; (3) standard Y + L11V + V89L + C-terminal Ala; (4) standard Y + L11V + T87A + V89L + C-terminal Ala; (5) standard Y + L11V + V89L + T110K + C-terminal Ala; (6) standard Y + L11V + V89L + T110Q + C-terminal Ala.

In fig. 9A and 9B show preferred, but not limited to, examples of monovalent nanobodies of the invention (FIG. 9A) and trivalent bispecific extended half-life compounds of the invention (FIG. 9B) against the Kv1.3 ion channel; and in fig. 9C lists some preferred CDRs (Kabat and AbM classification, respectively) for ISVDs against Kv1.3.

In fig. 10 is a graph of data obtained in Example 7 by testing 47 serum samples from people with diabetes for the binding of representative trivalent half-life extended bispecific compounds of the invention against Kv1.3. Each dot represents data obtained from testing the indicated construct on one of 47 serum samples. SEQ ID NOs refer to the corresponding sequences shown in FIG. 9.

In fig. 11 is a graph of data obtained in Example 7 by testing 90 serum samples from healthy volunteers for the binding of representative trivalent half-life extended bispecific compounds of the invention against Kv1.3. Each dot represents data obtained from testing the indicated construct on one of 90 serum samples. SEQ ID NOs refer to the corresponding sequences shown in FIG. 9.

In fig. 12A and 12B depict the CDR regions and amino acid sequences of some preferred, but not limited to, examples of anti-IL-23 nanobodies of the invention based on the reference sequences. See also example 8.

In fig. 13 shows the CDR regions and amino acid sequences of some preferred, but not limited to, examples of anti-OX40-L nanobodies of the invention based on the reference sequence. See also example 9.

In fig. 14 shows the CDR regions and amino acid sequences of some preferred, but not limited to, examples of anti-IgE nanobodies of the invention based on the reference sequence. See also example 10.

In fig. 15A and 15B depict the CDR regions and amino acid sequences of some preferred, but not limited to, examples of anti-CXCR-4 nanobodies of the invention based on the reference sequences. See also example 11.

In fig. 16A and 16B depict the CDR regions and amino acid sequences of some preferred, but not limited to, examples of anti-HER-3 nanobodies of the invention based on the reference sequences. See also example 12.

In fig. 17A and 17B show the CDR regions and amino acid sequences of some preferred, but not limited to, examples of anti-TNF nanobodies of the invention based on these standard sequences. See also examples 13 and 14.

In fig. 18A and 18B show the CDR regions and amino acid sequences of some preferred, but not limited to, examples of anti-c-Met nanobodies of the invention based on these standard sequences. See also example 15.

In fig. 19 shows the CDR regions and amino acid sequences of some preferred, but not limited to, examples of anti-RANK-L nanobodies of the invention based on the reference sequence. See also example 16.

In fig. 20A-20C show the CDR regions and amino acid sequences of some preferred, but not limited to, examples of anti-CXCR-7 nanobodies of the invention based on these standard sequences. See also example 17.

In fig. 21A and 21B depict the CDR regions and amino acid sequences of some preferred, but not limited to, examples of anti-A-beta nanobodies of the invention based on these standard sequences. See also example 18.

In fig. 22 shows the amino acid sequences of some preferred, but not limited to, examples of anti-IL-23 compounds of the invention.

In fig. 23 shows the amino acid sequences of some preferred, but not limited to, examples of the anti-OX40-L compounds of the invention.

In fig. 24 shows the amino acid sequences of some preferred, but not limited to, examples of anti-IgE compounds of the invention.

In fig. 25 shows the amino acid sequences of some preferred, but not limited to, examples of anti-CXCR-4 compounds of the invention.

In fig. 26 shows the amino acid sequences of some preferred, but not limited to, examples of anti-HER-3 compounds of the invention.

In fig. 27 shows the amino acid sequences of some preferred, but not limited to, examples of the anti-TNF compounds of the invention.

In fig. 28A and 28B show the amino acid sequences of some preferred, but not limited to, examples of anti-c-Met compounds of the invention.

In fig. 29 shows the amino acid sequences of some preferred, but not limited to, examples of anti-RANK-L compounds of the invention.

In fig. 30 shows the amino acid sequences of some preferred, but not limited to, examples of anti-A-beta compounds of the invention.

In fig. 31A is a graph of data obtained in Example 19 by testing 92 serum samples from healthy volunteers for the binding of representative trivalent half-life extended bispecific compounds of the invention against A-beta. Each dot represents data obtained from testing the indicated construct on one of 92 serum samples. The numbers correspond to those given in the table. CC-1. And in fig. 31B is a graph of data obtained in Example 19 by testing 92 serum samples from healthy volunteers for binding of the (monovalent) C-terminal nanobodies that are present in the constructs tested in FIG. 31A. Each dot represents data obtained from testing the indicated construct on one of 92 serum samples. The numbers correspond to those given in the table. CC-2.

experimental part

The human samples used in the Experimental Section below were obtained from either commercial sources or human volunteers (after all necessary approvals and approvals have been obtained) and were used in accordance with applicable legal and regulatory requirements (including including those related to medical confidentiality and patient privacy).

In the examples below, the binding of preexisting antibodies present in the samples used (ie, from healthy volunteers, patients with rheumatoid arthritis (RA) and patients with SLE) to the nanobodies of interest was determined on the ProteOn installation as follows.

Binding of preexisting antibodies to human serum albumin (HSA)-coated nanobodies was determined using a ProteOn XPR36 (BioRad Laboratories, Inc.). PBS/Tween (phosphate-buffered saline, pH 7.4, 0.005% Tween 20) was used as a working buffer and experiments were carried out at 25°C. Ligand lanes on the ProteOn GLC sensor chip were activated with EDC/NHS (flow rate 30 μl/min) and HSA was injected at 10 μg/ml in ProteOn acetate buffer pH 4.5 (flow rate 100 μl/min) to obtain the level immobilization at approximately 3200 RU. After immobilization, the surfaces were decontaminated using ethanolamine·HCl (flow rate 30 μL/min). Nanobodies were injected over the surface with HSA for 2 min at 45 μL/min to obtain a nanobody uptake level of approximately 200 RU. Samples containing preexisting antibodies were centrifuged for 2 min at 14,000 rpm, and the supernatant was diluted 1:10 in PBS-Tween 20 (0005%) and injected for 2 min at 45 μl/min, followed by a dissociation step for 400 sec . After each cycle (i.e., before the new nanobody capture and blood sample injection operation), the HSA-coated surfaces were regenerated by injecting HCl (100 mM) for 2 min at 45 μL/min. Sensogram processing and data analysis were performed using ProteOn Manager 3.1.0 (BioRad Laboratories, Inc.). Sensograms showing binding of preexisting antibodies were obtained after double binding by subtracting 1) nanobody-HSA dissociation and 2) nonspecific binding to the control ligand lane. The level of binding of pre-existing antibodies was determined when data recording was set to 125 sec (5 sec after the end of association). The percentage reduction in binding of preexisting antibodies relative to the level of binding of the control nanobody after 125 sec was calculated.

Example 1: S112K Mutation Inhibits Binding of Preexisting Antibodies

The effect of substitution at position 112 on the binding of preexisting antibodies in human samples to nanobodies was determined and compared with the effect of a C-terminal alanine extension as described in WO 12/175741.

Two control compounds (standard A without a C-terminal alanine extension and standard B with a C-terminal alanine extension) and variants of these control compounds with different mutations at position 112 were tested on sera obtained from 6 different RA patients and 8 sera obtained from various healthy people. The binding of preexisting antibodies in samples to the nanobodies under study was measured using a ProteOn installation using the general procedure described above. The results are presented in the table below. A.

As can be seen, of the mutations at position 112 that were tested, the S112 mutation caused a decrease in the binding of preexisting antibodies found in the sera studied, which was comparable to that of the C-terminal alanine extension (even without the C-terminal alanine extension in the S112K variant). Similar results were obtained with three human plasma samples (data not shown).

Example 2. Effect of the S112K mutation on the binding of pre-existing antibodies present in samples from patients with SLE

The same nanobody variants used in Example 1 were tested for binding to preexisting antibodies in 7 serum samples obtained from patients found positive for systemic lupus erythematosus (SLE). Plasma samples from two healthy volunteers were included for comparison.

The binding of preexisting antibodies in the samples to the nanobodies under study was measured using a ProteOn installation using the general procedure described above. The results are presented in the table below. B.

As can be seen from a comparison of the binding data for Standard A and Standard B and the nanobodies of the invention, samples obtained from some SLE patients clearly contain some pre-existing antibodies that can still bind to the nanobodies even in the presence of a C-terminal alanine residue (The C-terminal alanine residue actually prevented/avoided (partially or virtually completely) any binding of pre-existing antibodies present in plasma samples from healthy volunteers)).

It is also seen that the binding of these pre-existing antibodies from SLE samples is greatly reduced by mutations at positions 11 and 112 (and in the case of position 112, especially at S112K).

Example 3: Effect of Combining Framework Mutations and C-Terminal Extensions on the Binding of Preexisting Antibodies Found in Samples from SLE Patients

Four different nanobodies (with defined framework mutations and with or without a C-terminal alanine extension) were tested for binding to preexisting antibodies in 7 serum samples obtained from patients found to be positive for systemic lupus erythematosus (SLE). One plasma sample from a healthy volunteer was included for comparison.

The binding of preexisting antibodies in the samples to the nanobodies under study was measured using a ProteOn installation using the general procedure described above. The results are presented in the table below. C and D.

As can be seen from a comparison of the binding data for standard A and standard B, samples obtained from SLE patients clearly contain some pre-existing antibodies that can still bind to nanobodies even in the presence of a C-terminal alanine residue (C-terminal alanine residue alanine actually prevented/eliminating any binding of pre-existing antibodies present in plasma samples from a healthy volunteer).

It is also seen that the binding of these pre-existing antibodies from SLE samples is greatly reduced by mutations at positions 11 and 112 (and in the case of position 112, especially at S112K).

Example 4. Effect of the V89T mutation on the binding of pre-existing antibodies in samples from patients with SLE

As described here, samples obtained from some SLE patients clearly contain preexisting antibodies/factors that can bind to the exposed C-terminal end of the V _H domain, even in the presence of a C-terminal extension. It was examined whether the V89T mutation could reduce or prevent/eliminate such binding, with or without the presence of a C-terminal extension. The results are also presented below in the table. C and E.

As we can see, the V89T mutation can actually prevent/eliminate the binding of pre-existing antibodies found in samples obtained from SLE patients to the same extent as the S112K mutation. However, as can be seen from a comparison of the data given in table. C and E for nanobodies with the V89T mutation without a C-terminal extension and similar nanobodies with the S112K mutation without a C-terminal extension, the presence of a mutation at position 112 in nanobodies without a C-terminal extension generally reduces the binding of preexisting antibodies in healthy volunteer samples to a greater extent than the V89T mutation (namely, 100%, 85% and 64% in S112K nanobodies versus 9%, 11% and 16% in V89T nanobodies, respectively). For this reason, using a mutation at position 112 (specifically S112K or S112K) will often be preferable to using a mutation at position 89 (such as V89T).

However, also as can be seen from the data in table. C and E, addition of a C-terminal alanine to the V89T nanobody completely prevents/eliminates binding of pre-existing antibodies in samples obtained from a healthy volunteer, and for this reason the combination of the V89T mutation and C-terminal extension as described here would be preferable (i.e. . before using V89T without a C-terminal extension) if the V89T nanobody or V _H domain has or is expected to have an exposed C-terminal region in the protein or polypeptide in which it will be present (for example, because it forms its C-terminal end).

To confirm that the results/data from the tables above are generally applicable, representative nanobodies with the S112K and/or V89T mutations were tested against a test panel of 96 (S112K) and 129 (V89T) human serum samples. Binding was determined on a ProteOn installation according to the method described above.

The results are presented in Fig. 3 and in table. F (representative nanobody with S112K mutation) and FIG. 4 and in table. G (representative nanobody with V89T mutation).

In fig. 3 compared a nanobody with the S112K mutation (standard A + S112 + C-terminal alanine, see Table C above) with a control nanobody (standard A; SEQ ID NO:44). Both the S112K mutation nanobody and standard A were tested on each of the serum samples and the binding level was determined at 125 sec (RU). These data were then plotted in FIG. 3, where each dot represents the level of binding in one sample for either standard A (labeled (1) in Fig. 3) or the S112K mutant (labeled (2) in Fig. 3). The dotted line indicates the binding level of 20 RU.

The same data is also presented digitally in Table. F, which shows - for standard A and mutant S112K, respectively - the total number of samples tested in which the binding level after 125 sec was more than 20 RU, less than 20 RU (i.e. between 0 and 20 RU) and less than 10 RU .

As can be seen from the data presented in Fig. 3 and in table. F, for standard A, more than half of the 96 samples tested had a binding level greater than 20 RU (in some cases reaching 150-200 RU), indicating that pre-existing antibodies present in the sample bind to standard A. In comparison, of the S112K mutant, no samples yielded binding levels greater than 20 RU (and most yielded less than 10 RU), indicating that the S122K mutation was in fact able to reduce/prevent binding of preexisting antibodies in all 96 samples tested.

A similar graph and the same data are presented in Fig. 4 and in table. G, respectively, for a representative nanobody with the V89T mutation (standard A + L11V + V89T + C-terminal alanine; see Table E above) when tested on 129 serum samples and also compared with standard A (denoted as (1) on Fig. 4; the V89T mutant is designated as (2) in Fig. 4). Again, from the graph in FIG. 4 and data in table. G is visible
that, with some exceptions (namely, less than 10% of samples tested had absolute binding values at 125 sec of 100 RU or less), the V89T mutation was able to reduce/prevent binding of preexisting antibodies in most of the 129 samples tested, whereas standard A without The V89T mutation was associated with preexisting antibodies in the majority of samples tested.

Table F. Testing of a representative nanobody with the S112K mutation on 96 serum samples

Nanobody Binding level after 125 sec < 10 RU Binding level after 125 sec < 20 RU Binding level after 125 sec > 20 RU Standard A 34 41 55 Standard A + S112K + V89T + C-terminal alanine 92 96 0

Table G. Testing of mutant nanobodies with V89L and/or T100K/Q mutations on 129 serum samples

Nanobody Binding level after 125 sec < 10 RU Binding level after 125 sec < 20 RU Binding level after 125 sec > 20 RU Standard A 27 40 89 Standard A + L11V + V89T + C-terminal alanine 110 119 10

Example 5. Effect of the V89L mutation in combination with the T110K or T110Q mutation on the binding of pre-existing antibodies in samples from patients with SLE

As described here, samples obtained from some SLE patients clearly contain preexisting antibodies/factors that can bind to the exposed C-terminal end of the V _H domain, even in the presence of a C-terminal extension. We examined whether the V89L and/or T110Q or T110K mutation (or combinations thereof) could reduce or prevent/eliminate such binding, with or without a C-terminal extension. The results are also presented below in table. H and I, which present data from two separate experiments (Table D above also shows data for the invention S112Q mutation combined with the V89L mutation). Nanobodies used in Table. I were also used to obtain the data presented in FIG. 5 and in table. J.

To confirm that the results/data from the tables above are generally applicable, representative nanobodies with the V89L, T110K and/or T110Q mutations were again tested against a test panel of 99 human serum samples. Binding data was also obtained and plotted as indicated in Example 4 for the results and data shown in FIG. 3 and 4 and in table. F and G.

The following nanobodies were tested (numbers correspond to those used in Fig. 5): (1) standard A; (2) standard A + L11V + V89L + C-terminal Ala; (3) standard A + L11V + V89L + T110K + C-terminal Ala; (4) standard A + L11V + V89L + T110Q + C-terminal Ala; (5) standard A + L11V + T87A + V89L + C-terminal Ala. The results are presented in Fig. 5 and in table. I.

As we can see, the introduction of the studied mutations again greatly reduces the number of samples in which pre-existing antibodies are able to bind the nanobodies under study. It can also be seen that, for nanobody (2) in FIG. 5 (standard A + L11V + V89L + C-terminal Ala), some samples still showed binding of pre-existing antibodies after 125 sec at a level of more than 20 RU (but much less than 100 RU). However, when the V89L mutation was combined with the T110K mutation (nanobody (3)) or the T100Q mutation (nanobody (4)), virtually all of the 99 samples tested exhibited binding levels of less than 20RU (in fact less than 10RU, see Table J ).

Table J. Testing of Representative Nanobodies with V89L, T110K and/or T110Q Mutations in 99 Serum Samples

Nanobody Binding level after 125 sec < 10 RU Binding level after 125 sec < 20 RU Binding level after 125 sec > 20 RU Standard A 52 64 35 Standard A + L11V + V89L + C-terminal alanine 94 95 4 Standard A + L11V + V89L + T110K + C-terminal Ala 99 99 0 Standard A + L11V + V89L + T110Q + C-terminal Ala 99 99 0 Standard A + L11V + T87A + V89L + C-terminal Ala 99 99 0

Example 6: Testing Multivalent Constructs for Binding of Pre-Existing Antibodies

Multivalent constructs based on the following nanobodies were obtained:

Nanobody A (directed against therapeutic target):

EVQLVESGGGLVQPGGSLRLSCAASGRTFNNYAMGWFRQAPGKEREFVAAITRSGVRS GVSAIYGDSVKDRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAASAIGSGALRRFEYDY SGQGTLVTVSS (SEQ ID NO: 92)

Nanobody B (anti-serum albumin):

EVQLVESGGGLVQPGNSLRLSCAASGTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTL YADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSS (SEQ ID NO: 93)

Nanobody C (directed against therapeutic target):

EVQLVESGGGLVQPGGSLRLSCAASRSIGRLDRMGWYRHRPGEPRELVATITGGSSINY GDSVKGRFTISIDNSKNTVYLQMNSLRPEDTAVYYCNFNYVTSRDTWGQGTLVTVSS (SEQ ID NO: 94)

The resulting designs are listed below in Table K (in each case, the introduced substitutions (if any) for the corresponding nanobodies are given in parentheses). “HIS6” means the N-terminal His tag of 6 histidine residues, and “-Ala” means the C-terminal extension of 1 alanine residue.

Table K: Multivalent Constructs Investigated

HIS6-nanobody A(E1D,L11V, S112K)-35GS-nanobody B-Ala HIS6-nanobody A(E1D,L11V, S112K)-35GS-nanobody B(L11V,S112K)-Ala HIS6-nanobody A(E1D)-35GS-nanobody B HIS6-nanobody A(E1D)-35GS-nanobody B-Ala HIS6-nanobody A(E1D,L11V, S112K)-35GS-nanobody B(L11V, S112K) HIS6-nanobody A(E1D, S112K)-35GS-nanobody B(S112K)-Ala HIS6-nanobody A(E1D, S112Q)-35GS-nanobody B(S112Q)-Ala HIS6-nanobody A(E1D, V89L, S112K)-35GS-nanobody B(V89L, S112K)-Ala HIS6-nanobody A(E1D,L11V, S112Q)-35GS-nanobody B(L11V, S112Q)-Ala HIS6-nanobody B(E1D)-35GS-nanobody A HIS6-nanobody B(E1D)-35GS-nanobody A-Ala HIS6-nanobody A(E1D)-35GS-nanobody B(L11V, S112K)-Ala HIS6-nanobody B(E1D,L11V, S112K)-35GS-nanobody A-Ala HIS6-nanobody B(E1D,)-35GS-nanobody A(L11V, S112K)-Ala HIS6-nanobody A(E1D,V89L, S112Q)-35GS-nanobody B(V89L, S112Q)-Ala HIS6-nanobody B(E1D,L11V, S112K)-35GS-nanobody A(L11V, S112K)-Ala HIS6-nanobody B(S112K)-Ala Nanobody B(L11V, S112K)-Ala Nanobody B(L11V, S112Q)-Ala Nanobody B(S112Q)-Ala HIS6-nanobody A(E1D, S112K)-35GS-nanobody A(S112K)-35GS-nanobody B(S112K)-Ala HIS6-nanobody A(E1D, S112Q)-35GS-nanobody A(S112Q)-35GS-nanobody B(S112Q)-Ala HIS6-nanobody A(E1D,L11V,S112K)-35GS-nanobody A(L11V, S112K)-35GS-nanobody B(L11V, S112K)-Ala HIS6-nanobody A(E1D,V89L, S112K)-35GS-nanobody A(V89L, S112K)-35GS-nanobody B(V89L, S112K)-Ala HIS6-nanobody A(E1D)-35GS-nanobody A-35GS-nanobody B HIS6-nanobody A(E1D)-35GS-nanobody A -35GS-nanobody B-Ala Nanobody C(E1D)-9GS-AlaLB11-9GS-nanobody C HIS6-nanobody A(E1D,L11V, S112K)-35GS-nanobody A(L11V, S112K)-35GS-nanobody B-Ala HIS6-nanobody C(E1D,L11V, S112K)-9GS-nanobody B(L11V, S112K)-9GS-nanobody C(L11V,S112K)-Ala Nanobody C(E1D)-9GS-AlaLB11-9GS-nanobody C-Ala HIS6-nanobody A(E1D,L11V, S112Q)-35GS-nanobody A(L11V, S112Q)-35GS-nanobody B(L11V, S112Q)-Ala HIS6-nanobody A(E1D, V89L, S112Q)-35GS-nanobody A(V89L, S112Q)-35GS-nanobody B(V89L, S112Q)-Ala HIS6-nanobody C(E1D, S112K)-9GS-nanobody B(S112K)-9GS-nanobody C(S112K)-Ala HIS6-nanobody C(E1D, S112Q)-9GS-nanobody B(S112Q)-9GS-nanobody C(S112Q)-Ala HIS6-nanobody C(E1D,L11V, S112Q)-9GS-nanobody B(L11V, S112Q)-9GS-nanobody C(L11V,S112Q)-Ala HIS6-nanobody C(E1D,V89L, S112K)-9GS-nanobody B(V89L, S112K)-9GS-nanobody C(V89L,S112K)-Ala HIS6-nanobody C(E1D, V89L, S112Q)-9GS-nanobody B(V89L, S112Q)-9GS-nanobody C(V89L, S112Q)-Ala HIS6-nanobody A(E1D,L11V,A14P,R39Q,K83R,V89L,T91Y,Q108L)-35GS-nanobody B(L11V,R30S,E44G,P45L,K83R,V89L,Q108L)-Ala HIS6-nanobody A(E1D,L11V,A14P,R39Q,K83R,T87A,V89L,T91Y,Q108L)-35GS-nanobody B(L11V,R30S,E44G,P45L,K83R,T87A,V89L,Q108L)-Ala HIS6-nanobody A(E1D,L11V,A14P,R39Q,K83R,V89L,T91Y,Q108L,T110Q)-35GS-nanobody B(L11V,R30S,E44G,P45L,K83R,V89L,Q108L,T110Q)-Ala HIS6-nanobody A(E1D,L11V,A14P,R39Q,K83R,V89L,T91Y,Q108L,T110K)-35GS-nanobody B(L11V,R30S,E44G,P45L,K83R,V89L,Q108L,T110K)-Ala HIS6-nanobody A(E1D,L11V,A14P,R39Q,K83R,V89L,T91Y,Q108L)-35GS-nanobody A(E1D,L11V,A14P,R39Q,K83R,V89L,T91Y,Q108L)-35GS-nanobody B(L11V ,R30S,E44G,P45L,K83R,V89L,Q108L)-Ala HIS6-nanobody A(E1D,L11V,A14P,R39Q,K83R,T87A,V89L,T91Y,Q108L)-35GS-nanobody A(E1D,L11V,A14P,R39Q,K83R,T87A,V89L,T91Y,Q108L)-35GS- nanobody B(L11V,R30S,E44G,P45L,K83R,T87A,V89L,Q108L)-Ala HIS6-nanobody A(E1D,L11V,A14P,R39Q,K83R,V89L,T91Y,Q108L,T110Q)-35GS-nanobody A(E1D,L11V,A14P,R39Q,K83R,V89L,T91Y,Q108L,T110Q)-35GS- nanobody B(L11V,R30S,E44G,P45L,K83R,V89L,Q108L,T110Q)-Ala HIS6-nanobody A(E1D,L11V,A14P,R39Q,K83R,V89L,T91Y,Q108L,T110K)-35GS-nanobody A(E1D,L11V,A14P,R39Q,K83R,V89L,T91Y,Q108L,T110K)-35GS- nanobody B(L11V,R30S,E44G,P45L,K83R,V89L,Q108L,T110K)-Ala

Representative multivalent constructs were tested for binding to preexisting antibodies present in blood or serum samples obtained from SLE patients and healthy volunteers. Binding was determined using a ProteOn setup essentially as described above.

These representative designs are shown in Table. L (trivalent constructs) and M (bivalent constructs), and the results are presented in Fig. 6-8 and in table. N-Q. The trivalent constructs studied were obtained from the standard nanobody A-35GS-nanobody A-35GS-nanobody B (“standard X”) design, and the bivalent constructs were obtained from the standard nanobody A-35GS-nanobody B (“standard Y”) design. All constructs (except standard constructs) contained, where indicated, a C-terminal alanine residue and, in each of the nanobody A and nanobody B building blocks, the indicated mutations.

Table L. Trivalent constructs studied

Trivalent constructions Mutation Constructs (except the standard one) contain, if indicated, a C-terminal alanine residue, as well as, in each of the blocks, the indicated mutations L11V T87A V89L T110K T110Q 114A Standard X (= nanobody A-35GS-nanobody A-35GS-nanobody B) Standard X+C-terminal Ala x Standard X + L11V + V89L + C-terminal Ala x x x Standard X + L11V + V89L + T110K + C-terminal Ala x x x x Standard X + L11V + T87A + V89L + C-terminal Ala x x x x Standard X + L11V + V89L + T110Q + C-terminal Ala x x x x

Table M. Bivalent constructs studied

Bivalent designs Mutation Constructs (except the standard one) contain, if indicated, a C-terminal alanine residue, as well as, in each of the blocks, the indicated mutations L11V T87A V89L T110K T110Q 114A Standard Y (= Nanobody A-35GS-Nanobody B) Standard Y+C-terminal Ala x Standard Y + L11V + V89L + C-terminal Ala x x x Standard Y + L11V + V89L + T110K + C-terminal Ala x x x x Standard Y + L11V + T87A+ V89L + C-terminal Ala x x x x Standard Y + L11V + V89L + T110Q + C-terminal Ala x x x x

Table N. Results of testing trivalent constructs for binding to preexisting antibodies in 98 serum samples from healthy individuals. The results are also presented in Fig. 6 as a graph in which each dot represents a data point obtained from testing a given construct on one of 98 serum samples.

Nanobody when tested on 98 samples (healthy individuals) The track number on the graph in Fig. 6 Binding level after 125 sec < 10 RU Binding level after 125 sec < 20 RU Binding level after 125 sec > 20 RU Standard X (1) 38 48 50 Standard X+C-terminal Ala (2) 64 75 23 Standard X + L11V + V89L + C-terminal Ala (3) 94 95 3 Standard X + L11V + V89L + T110K + C-terminal Ala (5) 95 96 2 Standard X + L11V + T87A + V89L + C-terminal Ala (6) 95 96 2 Standard X + L11V + V89L + T110Q + C-terminal Ala (4) 92 95 3

Table O. Results of testing trivalent constructs for binding to preexisting antibodies in 30 selected serum samples from healthy individuals. These 30 samples were selected either because they had a high titer of preexisting antibodies or because the preexisting antibodies in the sample exhibited high levels of binding even in the presence of a C-terminal alanine residue. The results are also presented in Fig. 7 in the form of a graph in which each point represents a data point obtained by testing a given construct on one of 30 selected serum samples.

Nanobody when tested on 30 selected samples The track number on the graph in Fig. 7 Binding level after 125 sec < 10 RU Binding level after 125 sec < 20 RU Binding level after 125 sec > 20 RU Standard X+C-terminal Ala (1) 12 13 17 Standard X + L11V + V89L + C-terminal Ala (2) 18 22 8 Standard X + L11V + T87A + V89L + C-terminal Ala (3) 27 27 3 Standard X + L11V + V89L + T110K + C-terminal Ala (4) 26 26 4

Table P. Results of testing bivalent constructs for binding to preexisting antibodies in 98 serum samples from healthy individuals. The results are also presented in Fig. 8 in the form of a graph in which each point represents a data point obtained when testing a given construct on one of 98 serum samples.

Nanobody when tested on 98 samples (healthy individuals) The track number on the graph in Fig. 8 Binding level after 125 sec < 10 RU Binding level after 125 sec < 20 RU Binding level after 125 sec > 20 RU Standard Y (1) 54 67 31 Standard Y+C-terminal Ala (2) 90 92 6 Standard Y + L11V + V89L + C-terminal Ala (3) 97 98 0 Standard Y + L11V + T87A + V89L + C-terminal Ala (4) 98 98 0 Standard Y + L11V + V89L + T110K + C-terminal Ala (5) 96 98 0 Standard Y + L11V + V89L + T110Q + C-terminal Ala (6) 98 98 0

Three representative trivalent constructs were also tested in serum samples obtained from SLE patients. The results are presented in table. Q.

Example 7: Nanobodies and nanobody constructs directed against the Kv1.3 ion channel

In one particular aspect, the V _H domains of the invention (especially the ISVDs of the invention and more preferably the nanobodies of the invention) and compounds of the invention can be directed against the Kv1.3 ion channel.

In the jointly filed US provisional application USSN 62/014,023 (title: “Kv1.3 binding immunoglobulins”; assignee: Ablynx N.V.; filing date: June 18, 2014), as well as in the subsequent US provisional application under the same title, filed on 16 March 2015 (successor: Ablynx N.V.), among other things, described single immunoglobulin variable domains (in particular, nanobodies) that are directed against the potassium-selective voltage-gated ion channel Kv1.3, as well as proteins, polypeptides and other constructs on based on nanobodies that contain at least one such anti-Kv1.3 nanobody.

The mutations described herein (optionally in combination with a C-terminal extension as described herein and/or in WO 12/175741) may also be applicable to nanobodies, proteins, polypeptides and other nanobody-based constructs directed against Kv1. 3, which are described in these two US provisional applications.

Thus, in one aspect, the invention relates to V _H domains directed against Kv1.3, which are as already described here for the ISVD of the invention (ie, contain amino acid residues/mutations as described here).

Again, as with other aspects and embodiments of the invention described herein, when a particular ISVD (such as the anti-Kv1.3 ISVD described in this example) or a compound containing it is said to be “in accordance with the invention” or “as already described herein” , then the preferred aspects/embodiments and preferences generally described herein for the ISVDs or compounds of the invention are also definitely applicable to this particular ISVD or connection accordingly, unless expressly stated otherwise or unless the specific technical context requires otherwise.

Thus, in a preferred aspect, the present invention relates to V _H domains directed against Kv1.3, in which (i) at position 112 there is a K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) at position 89 is L and at position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). In particular, for such V _H domains against Kv1.3:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v).

The anti-Kv1.3 V _H domains illustrated in this example may, in particular, have such CDRs as described on pages 5-10 of USSN 62/014023 (including any preferred aspects/embodiments of such CDRs), or optimized therefor. sequence variants as described in the other US provisional application cited above.

In particular, the anti-Kv1.3 V _H domains shown in this example may, in particular, have such combinations of CDR1, CDR2 and CDR3 that are selected from one of the combinations of CDR1, CDR2 and CDR3 listed as preferred aspects in the list, given on pages 9 and 10 of USSN 62/014,023.

In certain preferred, but not limited to, aspects of the invention:

in the V _H domains of the invention: (i) CDR1 (according to Kabat) has the sequence SED ID NO: 166 or such an amino acid sequence that differs in one or two amino acids from the sequence SEQ ID NO: 166; (ii) CDR2 (according to Kabat) has the sequence SED ID NO: 167 or such an amino acid sequence that differs in one or two amino acids from the sequence SEQ ID NO: 167; and (iii) CDR3 (according to Kabat) has the sequence SED ID NO: 168 or such an amino acid sequence that differs in one or two amino acids from the sequence SEQ ID NO: 168; and even more preferably: (i) CDR1 (according to Kabat) has the sequence SED ID NO: 166; (ii) CDR2 (according to Kabat) has the sequence SED ID NO: 167; and (iii) CDR3 (according to Kabat) has the sequence SED ID NO: 168; and/or

in the V _H domains of the invention: (i) CDR1 (according to AbM) has the sequence SED ID NO: 169 or such an amino acid sequence that differs in one or two amino acids from the sequence SEQ ID NO: 169; (ii) CDR2 (according to AbM) has the sequence SED ID NO: 170 or such an amino acid sequence that differs in one or two amino acids from the sequence SEQ ID NO: 170; and (iii) CDR3 (as defined by AbM) has the sequence SED ID NO: 171 or such an amino acid sequence that differs in one or two amino acids from the sequence SEQ ID NO: 171; and even more preferably: (i) CDR1 (according to AbM) has the sequence SED ID NO: 169; (ii) CDR2 (according to AbM) has the sequence SED ID NO: 170; and (iii) CDR3 (according to AbM) has the sequence SED ID NO: 178.

The anti-Kv1.3 _VH domains of the invention may also be as described herein, in particular again these may be anti-Kv1.3 ISVDs (more preferably nanobodies) or proteins, polypeptides or other compounds or constructs that contain at least at least one such ISVD. Such proteins, polypeptides or other compounds or constructs may also be as already described herein and may have, for example, an increased half-life (i.e., as described herein, for example, half-life - expressed as t _½ -beta - in the human body for at least 1 day, preferably at least 3 days, more preferably at least 7 days, such as at least 10 days), and for this purpose may, for example, contain serum albumin binders nanobodies, which may also be serum albumin-binding nanobodies of the invention (again as described herein).

In addition, such ISVDs may suitably have a C-terminal extension (as already described here and in WO 12/175741), in particular where the ISVD forms the C-terminal end of the protein, polypeptide or other compound or construct containing it (again, as already described here).

For example, and without limitation, the V _H domains of the invention against Kv1.3 may have one of the sequences listed in table. A-1 in USSN 62/014023 (SEQ ID NOs: 1-123 in USSN 62/014023), or one of the sequences listed in table. US Provisional Application A-1 entitled “Kv1.3 binding immunoglobulins” (assignee: Ablynx NV; filing date: March 16, 2015) (SEQ ID NOs: 1-123, 495, 498-513 or 523-540 in this US provisional application; especially the sequence SEQ ID NO: 495), but with suitable mutations/specific amino acid residues described herein for the ISVDs of the invention, optionally with a suitable C-terminal extension.

In one specific aspect, the anti-Kv1.3 nanobodies of the invention are variants of the nanobody SEQ ID NO:137 (which are at least 90% sequence identical to SEQ ID NO:137) in which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v).

Some particularly preferred, but not limited to, examples of the inventive anti-Kv1.3 nanobodies and the inventive compounds containing them are presented in FIG. 9A (monovalent nanobodies: SEQ ID NOs 138-155) and FIG. 9B (trivalent bispecific extended half-life constructs: SEQ ID NOs 156-164). Compounds of the invention that contain or substantially consist of at least one (such as one, two or three) anti-Kv1.3 nanobodies selected from the anti-Kv1.3 nanobodies of SEQ ID NOs: 138-155 form the following aspect inventions. In addition, each of the compounds of SEQ ID NOs: 156-164 forms another aspect of the invention. In one particular aspect, such compounds comprise two such anti-Kv1.3 nanobodies of the invention and one anti-human serum albumin nanobody (which is preferably also a nanobody of the invention). Again, such constructs may contain suitable linkers and C-terminal extensions.

Monovalent anti-Kv1.3 nanobodies of SEQ ID NOs: 138-155 were prepared by introducing the L11V and V89L mutations of the invention into the original sequence SEQ ID NO: 137 (standard). In addition, various combinations of humanizing (or other sequence-optimizing) mutations were introduced, such as E1D, A14P, G19R, M53A or M53Q or M53Y, T62S, A74S, K83R, S94G and/or T97E). The specific mutations introduced into each of SEQ ID NOs: 138-155 are presented in FIG. 9A.

Some of the monovalent anti-Kv1.3 nanobodies in FIG. 9A were also provided in the format of trivalent bispecific constructs containing two inventive anti-Kv1.3 nanobodies and one inventive half-life enhancing nanobody against human serum albumin (SEQ ID NO: 109, also referred to as “ALB-82” in FIG. 9B) . 35GS linkers were used and all constructs contained a C-terminal extension (one C-terminal alanine residue). The sequences of the resulting constructs are given in SEQ ID NOs 156-164. Of these, three constructs (SEQ ID NOs: 156, 157 and 160) were tested for binding to preexisting antibodies in samples obtained from 47 diabetic and 90 healthy individuals using the general procedure described herein. Binding to preexisting antibodies in samples from these two groups was compared to the control construct SEQ ID NO: 165, which is a corresponding trivalent bispecific construct based on the standard anti-Kv1.3 building block of SEQ ID NO: 137 and the serum albumin binding Alb-8 ( SEQ ID NO: 46), again in combination with a C-terminal alanine extension. The results are presented in Fig. 10 (samples from 47 diabetic patients) and FIG. 11 (samples from 90 healthy volunteers). In each case, the V89L and L11V mutation constructs of the invention exhibited reduced binding to preexisting antibodies compared to the control construct.

Example 8 Anti-IL-23 V _H Domains (in particular nanobodies) and compounds of the invention containing them

In one particular aspect, the V _H domains of the invention (especially ISVDs
according to the invention and more preferably nanobodies according to the invention) and compounds according to the invention can be directed against IL-23.

Such anti-IL-23 _VH domains of the invention typically comprise: (i) suitable framework sequences which suitably include the amino acid residues/mutations of the invention as described herein; and (ii) CDR sequences that allow the V _H domains of the invention to specifically bind IL-23. In addition, such anti-IL-23 V _H domains of the invention may also contain a C-terminal extension as described herein, in particular where the V _H domain is monovalent or forms the C-terminal end of the compound of the invention in which it is located. V _H domain (again, as already described here). Such anti-IL-23 _VH domains of the invention may also be those already described herein, in particular they may be ISVDs.

Again, as with other aspects and embodiments of the invention described herein, when a particular ISVD (such as the anti-IL-23 ISVD described in this example) or a compound containing it is said to be “in accordance with the invention” or “as already described herein” , then the preferred aspects/embodiments and preferences generally described herein for the ISVDs or compounds of the invention are also definitely applicable to this particular ISVD or connection accordingly, unless expressly stated otherwise or unless the specific technical context requires otherwise.

Thus, in a preferred aspect, the present invention relates to V _H domains (especially ISVDs) directed against IL-23, which (i) have a K or Q at position 112; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) at position 89 is L and at position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). In particular, such V _H domains against IL-23:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v).

The anti-IL-23 _VH domains of the invention may also be as described herein, in particular, again these may be anti-IL-23 ISVDs (more preferably nanobodies) or proteins, polypeptides or other compounds or constructs that contain at least at least one such ISVD. Such proteins, polypeptides or other compounds or constructs may also be as already described herein and may have, for example, an increased half-life (i.e., as described herein, for example, half-life - expressed as t _½ -beta - in the human body for at least 1 day, preferably at least 3 days, more preferably at least 7 days, such as at least 10 days), and for this purpose may, for example, contain serum albumin binders nanobodies, which may also be serum albumin-binding nanobodies of the invention (again as described herein).

In addition, such ISVDs may suitably have a C-terminal extension (as already described here and in WO 12/175741), in particular where the ISVD forms the C-terminal end of the protein, polypeptide or other compound or construct containing it (again, as already described here).

In one preferred aspect, the anti-IL-23 V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 173 (preferably) or such an amino acid sequence that differs by only one amino acid from the sequence of SEQ ID NO: 173 ; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 174 (which is preferred) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 174; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 175 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 175.

More preferably, the V _H domains of the invention against IL-23 according to this aspect: (i) CDR1 represented by SEQ ID NO: 173; (ii) CDR2 is represented by SEQ ID NO: 174; and (iii) CDR3 is represented by SEQ ID NO: 175.

In one particular aspect, the anti-IL-23 nanobodies of the invention are variants of the nanobody of SEQ ID NO: 172 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 172 ), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). The CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

In another preferred aspect, the anti-IL-23 V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 191 (preferably) or such an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: : 191; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 192 (which is preferred) or such an amino acid sequence that differs in only one amino acid from the sequence of SEQ ID NO: 192; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 193 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 193.

More preferably, the V _H domains of the invention against IL-23 according to this aspect: (i) CDR1 represented by SEQ ID NO: 191; (ii) CDR2 is represented by SEQ ID NO: 192; and (iii) CDR3 is represented by SEQ ID NO: 193.

In one particular aspect, the anti-IL-23 nanobodies of the invention are variants of the nanobody of SEQ ID NO: 190 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 190 ), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). The CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

Some particularly preferred, but not limited to, examples of such anti-IL-23 nanobodies of the invention are presented in FIG. 12A as SEQ ID NOs: 176-189 and FIG. 12B as SEQ ID NOs: 194-207, respectively; and each of these nanobodies forms another aspect of the invention.

The invention also provides anti-IL-23 compounds of the invention that include at least one (such as one, two or three) nanobodies of the invention as defined in SEQ ID NOs: 176-189 and/or 194-207. Such anti-IL-23 compounds of the invention may again be as already described herein and therefore, for example, may contain suitable linkers, may contain a C-terminal extension as described herein, and may have an extended half-life (e.g. because they contain an anti-human serum albumin nanobody, such as (preferably) the anti-human serum albumin nanobody of the invention). We refer you to the table below. R.

As described, for example, in WO 2009/068627, WO 2010/142534 and WO 2011/135026, one particularly preferred class of anti-IL-23 nanobody compounds are biparatope compounds. Thus, in one aspect of the invention, the anti-IL-23 compounds of the invention are biparatope constructs that contain a single ISV that has SEQ ID NO: 172 or (preferably) is an ISV of the invention that is derived from SEQ ID NO: 172 (as described in this Example 8), and one ISV that has SEQ ID NO: 190 or (preferably) is an ISV of the invention that was derived from SEQ ID NO: 190 (as described in this Example 8), provided that at least one (and preferably both) of these ISVs is an ISV according to the invention. Such biparatope constructs may also have an extended half-life (ie, via a serum albumin-binding ISV). Some specific examples of such biparatope designs are provided in SEQ ID NOs: 514-549.

Some particularly preferred examples of the anti-IL-23 compounds of the invention are shown in FIG. 22 as SEQ ID NOs: 514-549; and each of these compounds forms another aspect of the invention. Thus, in another aspect, the invention relates to polypeptides directed against IL-23 and having an amino acid sequence selected from the group consisting of SEQ ID NOs: 514-549. More generally, the anti-IL-23 compounds of the invention may be as described in WO 2009/068627, WO 2010/142534 and WO2011/135026, but contain the ISVs of the invention. They can also be used for the purposes described in WO 2009/068627, WO 2010/142534 and WO 2011/135026.

Table R. Examples of Anti-IL-23 Compounds of the Invention

Polypeptide/construct( ¹ ) General formula ISV units/blocks and linkers Monovalent [IL-23] [IL-23] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with C-terminal extension [IL-23]-X(n) [IL-23] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with extended half-life [IL-23]-L ₁ -[SA]
[SA]-L ₁ -[IL-23] [IL-23] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below) Monovalent with extended half-life and C-terminal extension [IL-23]-L ₁ -[SA]-X(n)
[SA]-L ₁ -[IL-23]-X(n) [IL-23] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent( ² ) [IL-23]-L ₁ -[IL-23] at least one of [IL-23]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below) Bivalent with C-terminal extension ( ² ) [IL-23]-L ₁ -[IL-23]-X(n) at least one of [IL-23]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent with extended half-life ( ² ) [IL-23]-L ₁ -[IL-23]-L ₂ -[SA]
[IL-23]-L ₁ -[SA]-L ₂ -[IL-23]
[SA]-L ₁ -[IL-23]-L ₂ -[IL-23] at least one of [IL-23]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below) Bivalent with extended half-life and C-terminal extension ( ² ) [IL-23]-L ₁ -[IL-23]-L ₂ -[SA]-X(n)
[IL-23]-L ₁ -[SA]-L ₂ -[IL-23]-X(n)
[SA]-L ₁ -[IL-23]-L ₂ -[IL-23]-X(n) at least one of [IL-23]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below) Bispecific ( ³ ) [IL-23]-L ₁ -[Nb]
[Nb]-L ₁ -[IL-23]
[IL-23]-L ₁ -[IL-23]-L ₂ -[Nb]
[IL-23]-L ₁ -[Nb]-L ₂ -[IL-23]
[Nb]-L ₁ -[IL-23]-L ₂ -[IL-23] at least one of [IL-23]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
[Nb] = (see signature below) Bispecific with C-terminal extension ( ³ ) [IL-23]-L ₁ -[Nb]-X(n)
[Nb]-L ₁ -[IL-23]-X(n)
[IL-23]-L ₁ -[IL-23]-L ₂ -[Nb]-X(n)
[IL-23]-L ₁ -[Nb]-L ₂ -[IL-23]-X(n)
[Nb]-L ₁ -[IL-23]-L ₂ -[IL-23]-X(n) at least one of [IL-23]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life ( ³ ) [IL-23]-L ₁ -[Nb]-L ₂ -[SA]
[IL-23]-L ₁ -[SA]-L ₂ -[Nb]
[Nb]-L ₁ -[SA]-L ₂ -[IL-23]
[Nb]-L ₁ -[IL-23]-L ₂ -[SA]
[SA]-L ₁ -[IL-23]-L ₂ -[Nb]
[SA]-L ₁ -[Nb]-L ₂ -[IL-23]
[IL-23]-L ₁ -[IL-23]-L ₂ -[Nb]-L ₃ -[SA]
[Nb]-L ₁ -[IL-23]-L ₂ -[IL-23]-L ₃ -[SA]
[SA]-L ₁ -[IL-23]-L ₂ -[IL-23]-L ₃ -[Nb]
[SA]-L ₁ -[IL-23]-L ₂ -[Nb]-L ₃ -[IL-23]
[IL-23]-L ₁ -[Nb]-L ₂ -[IL-23]-L ₃ -[SA] at least one of [IL-23]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life and C-terminal extension ( ³ ) [IL-23]-L ₁ -[Nb]-L ₂ -[SA]-X(n)
[IL-23]-L ₁ -[SA]-L ₂ -[Nb]-X(n)
[Nb]-L ₁ -[SA]-L ₂ -[IL-23]-X(n)
[Nb]-L ₁ -[IL-23]-L ₂ -[SA]-X(n)
[SA]-L ₁ -[IL-23]-L ₂ -[Nb]-X(n)
[SA]-L ₁ -[Nb]-L ₂ -[IL-23]-X(n)
[IL-23]-L ₁ -[IL-23]-L ₂ -[Nb]-L ₃ -[SA]-X(n)
[Nb]-L ₁ -[IL-23]-L ₂ -[IL-23]-L ₃ -[SA]-X(n)
[SA]-L ₁ -[IL-23]-L ₂ -[IL-23]-L ₃ -[Nb]-X(n)
[SA]-L ₁ -[IL-23]-L ₂ -[Nb]-L ₃ -[IL-23]-X(n)
[IL-23]-L ₁ -[Nb]-L ₂ -[IL-23]-L ₃ -[SA]-X(n) at least one of [IL-23]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below)

Designations

- [SA] means an anti-serum albumin (human) ISV, preferably an anti-serum albumin (human) ISV of the invention, more preferably of SEQ ID NOs: 46 or 61, and even more preferably one of the inventive ISVDs of SEQ ID NOs: 47 , 54, 62, 69, 78, 86, 109, 116, 123, 130 or 496-513.

- Each of L ₁ , L ₂ and L ₃ (independently) means a corresponding linker. Each of L ₁ , L ₂ and L ₃ may (independently) be present or absent. Non-limiting examples of suitable linkers are the Gly-Ser linkers provided herein, such as 9GS, 30GS or 35GS linkers.

- X(n) = C-terminal extension of the type described here and/or in WO 12/175741.

- [Nb] means ISV against another therapeutic target.

Notes

( ¹ ) In this table:

- “Monovalent” generally refers to polypeptides/constructs containing a single anti-IL-23 ISV. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- “Bivalent” generally refers to polypeptides/constructs containing two anti-IL-23 ISVs (which may be the same or different). They may also contain ISVs that prolong half-life (such as ISVs against serum albumin).

- “Bispecific” generally refers to polypeptides/constructs containing at least one (such as 1 or 2) ISV against IL-23 and at least one (such as 1 or 2) other ISV against a therapeutic target. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- In the polypeptides/constructs shown in this table, at least one of the anti-IL-23 ISVs is an ISV of the invention, and preferably all of the anti-IL-23 ISVs in such polypeptides/constructs are ISVs of the invention. And when such polypeptides/constructs contain an ISV that prolongs the half-life and/or an ISV against another therapeutic target, then each of them (and preferably all of them) can also be represented (and preferably all of them are represented) by the ISVs of the invention.

( ² ) All of the “bivalent” constructs in this table can also be biparatopic, that is, they can contain at least two (like two) anti-IL-23 ISVs that are directed against different epitopes on IL-23.

( ³ ) It will be appreciated by those skilled in the art that other/additional bispecific constructs than those shown herein can be made using these units/blocks and linkers.

( ⁴ ) Preferably, each of [IL-23] is selected independently from SEQ ID NOs: 464-477 and/or 482-495. In addition, the data [IL-23] may be the same or different; and in biparatope polypeptides/constructs they must be directed against different epitopes on IL-23.

( ⁵ ) Each of the polypeptides/constructs identified in this column by SEQ ID constitutes separate specific aspects of the invention.

Example 9 Anti-OX40-L _VH domains (in particular nanobodies) and compounds of the invention containing them

In one particular aspect, the V _H domains of the invention (especially the ISVDs of the invention and more preferably the nanobodies of the invention) and compounds of the invention can be directed against OX40-L.

Such anti-OX40-L _VH domains of the invention typically contain: (i) suitable framework sequences which suitably include the amino acid residues/mutations of the invention as described herein; and (ii) CDR sequences that allow the V _H domains of the invention to specifically bind to OX40-L. In addition, such anti-OX40-L _VH domains of the invention may also contain a C-terminal extension as described herein, in particular when the _VH domain is monovalent or forms the C-terminal end of the compound of the invention in which the given VH domain is located. V _H domain (again, as already described here). Such _VH domains according to the invention against OX40-L can also be as already described here, in particular they can be ISVDs.

Again, as with other aspects and embodiments of the invention described herein, when a particular ISVD (such as the anti-OX40-L ISVD described in this example) or a compound containing it is said to be “in accordance with the invention” or “as already described herein” , then the preferred aspects/embodiments and preferences generally described herein for the ISVDs or compounds of the invention are also definitely applicable to this particular ISVD or connection accordingly, unless expressly stated otherwise or unless the specific technical context requires otherwise.

Thus, in a preferred aspect, the present invention relates to V _H domains (especially ISVDs) directed against OX40-L, which (i) have a K or Q at position 112; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) at position 89 is L and at position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). In particular, for such V _H domains against OX40-L:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v).

The anti-OX40-L _VH domains of the invention may also be as described herein, in particular again these may be anti-OX40-L ISVDs (more preferably nanobodies) or proteins, polypeptides or other compounds or constructs that contain at least at least one such ISVD. Such proteins, polypeptides or other compounds or constructs may also be as already described herein and may have, for example, an increased half-life (i.e., as described herein, for example, half-life - expressed as t _½ -beta - in the human body for at least 1 day, preferably at least 3 days, more preferably at least 7 days, such as at least 10 days), and for this purpose may, for example, contain serum albumin binders nanobodies, which may also be serum albumin-binding nanobodies of the invention (again as described herein).

In addition, such ISVDs may suitably have a C-terminal extension (as already described here and in WO 12/175741), in particular where the ISVD forms the C-terminal end of the protein, polypeptide or other compound or construct containing it (again, as already described here).

In one preferred aspect, the anti-OX40-L V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 209 (preferably) or such an amino acid sequence that differs by only one amino acid from the sequence of SEQ ID NO: 209 ; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 210 (which is preferred) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 210; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 211 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 211.

More preferably, in the V _H domains of the invention against OX40-L according to this aspect: (i) CDR1 is represented by SEQ ID NO: 209; (ii) CDR2 is represented by SEQ ID NO: 210; and (iii) CDR3 is represented by SEQ ID NO: 211.

In one particular aspect, the anti-OX40-L nanobodies of the invention are variants of the nanobody of SEQ ID NO: 208 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 208 ), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). The CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

Some particularly preferred, but not limited to, examples of such nanobodies of the invention against OX40-L are presented in FIG. 13 as SEQ ID NOs: 212-225; and each of these nanobodies forms another aspect of the invention.

The invention also provides anti-OX40-L compounds of the invention that include at least one (such as one, two or three) nanobodies of the invention as defined in SEQ ID NOs: 212-225. Such anti-OX40-L compounds of the invention may again be as already described herein and therefore, for example, may contain suitable linkers, may contain a C-terminal extension as described herein, and may have an extended half-life (e.g. because they contain an anti-human serum albumin nanobody, such as (preferably) the anti-human serum albumin nanobody of the invention). We refer you to the table below. S.

Some particularly preferred examples of the anti-OX40-L compounds of the invention are presented in FIG. 23 as SEQ ID NOs: 550-585; and each of these compounds forms another aspect of the invention. Thus, in another aspect, the invention relates to polypeptides directed against OX40-L and having an amino acid sequence selected from the group consisting of SEQ ID NOs: 550-585. More generally, the anti-OX40-L compounds of the invention may be as described in WO 2011/073180, but contain the ISVs of the invention. They can also be used for the purposes described in WO 2011/073180.

Table S. Examples of compounds of the invention against OX40-L

Polypeptide/construct( ¹ ) General formula ISV units/blocks and linkers Monovalent [OX40-L] [OX40-L] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with C-terminal extension [OX40-L]-X(n) [OX40-L] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with extended half-life [OX40-L]-L ₁ -[SA]
[SA]-L ₁ -[OX40-L] [OX40-L] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below) Monovalent with extended half-life and C-terminal extension [OX40-L]-L ₁ -[SA]-X(n)
[SA]-L ₁ -[OX40-L]-X(n) [OX40-L] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent( ² ) [OX40-L]-L ₁ -[OX40-L] at least one of [OX40-L] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below) Bivalent with C-terminal extension ( ² ) [OX40-L]-L ₁ -[OX40-L]-X(n) at least one of [OX40-L] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent with extended half-life ( ² ) [OX40-L]-L ₁ -[OX40-L]-L ₂ -[SA]
[OX40-L]-L ₁ -[SA]-L ₂ -[OX40-L]
[SA]-L ₁ -[OX40-L]-L ₂ -[OX40-L] at least one of [OX40-L] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below) Bivalent with extended half-life and C-terminal extension ( ² ) [OX40-L]-L ₁ -[OX40-L]-L ₂ -[SA]-X(n)
[OX40-L]-L ₁ -[SA]-L ₂ -[OX40-L]-X(n)
[SA]-L ₁ -[OX40-L]-L ₂ -[OX40-L]-X(n) at least one of [OX40-L] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below) Bispecific ( ³ ) [OX40-L]-L ₁ -[Nb]
[Nb]-L ₁ -[OX40-L]
[OX40-L]-L ₁ -[OX40-L]-L ₂ -[Nb]
[OX40-L]-L ₁ -[Nb]-L ₂ -[OX40-L]
[Nb]-L ₁ -[OX40-L]-L ₂ -[OX40-L] at least one of [OX40-L] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
[Nb] = (see signature below) Bispecific with C-terminal extension ( ³ ) [OX40-L]-L ₁ -[Nb]-X(n)
[Nb]-L ₁ -[OX40-L]-X(n)
[OX40-L]-L ₁ -[OX40-L]-L ₂ -[Nb]-X(n)
[OX40-L]-L ₁ -[Nb]-L ₂ -[OX40-L]-X(n)
[Nb]-L ₁ -[OX40-L]-L ₂ -[OX40-L]-X(n) at least one of [OX40-L] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life ( ³ ) [OX40-L]-L ₁ -[Nb]-L ₂ -[SA]
[OX40-L]-L ₁ -[SA]-L ₂ -[Nb]
[Nb]-L ₁ -[SA]-L ₂ -[OX40-L]
[Nb]-L ₁ -[OX40-L]-L ₂ -[SA]
[SA]-L ₁ -[OX40-L]-L ₂ -[Nb]
[SA]-L ₁ -[Nb]-L ₂ -[OX40-L]
[OX40-L]-L ₁ -[OX40-L]-L ₂ -[Nb]-L ₃ -[SA]
[Nb]-L ₁ -[OX40-L]-L ₂ -[OX40-L]-L ₃ -[SA]
[SA]-L ₁ -[OX40-L]-L ₂ -[OX40-L]-L ₃ -[Nb]
[SA]-L ₁ -[OX40-L]-L ₂ -[Nb]-L ₃ -[OX40-L]
[OX40-L]-L ₁ -[Nb]-L ₂ -[OX40-L]-L ₃ -[SA] at least one of [OX40-L] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life and C-terminal extension ( ³ ) [OX40-L]-L ₁ -[Nb]-L ₂ -[SA]-X(n)
[OX40-L]-L ₁ -[SA]-L ₂ -[Nb]-X(n)
[Nb]-L ₁ -[SA]-L ₂ -[OX40-L]-X(n)
[Nb]-L ₁ -[OX40-L]-L ₂ -[SA]-X(n)
[SA]-L ₁ -[OX40-L]-L ₂ -[Nb]-X(n)
[SA]-L ₁ -[Nb]-L ₂ -[OX40-L]-X(n)
[OX40-L]-L ₁ -[OX40-L]-L ₂ -[Nb]-L ₃ -[SA]-X(n)
[Nb]-L ₁ -[OX40-L]-L ₂ -[OX40-L]-L ₃ -[SA]-X(n)
[SA]-L ₁ -[OX40-L]-L ₂ -[OX40-L]-L ₃ -[Nb]-X(n)
[SA]-L ₁ -[OX40-L]-L ₂ -[Nb]-L ₃ -[OX40-L]-X(n)
[OX40-L]-L ₁ -[Nb]-L ₂ -[OX40-L]-L ₃ -[SA]-X(n) at least one of [OX40-L] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below)

Designations

- [SA] means an anti-serum albumin (human) ISV, preferably an anti-serum albumin (human) ISV of the invention, more preferably of SEQ ID NOs: 46 or 61, and even more preferably one of the inventive ISVDs of SEQ ID NOs: 47 , 54, 62, 69, 78, 86, 109, 116, 123, 130 or 496-513.

- Each of L ₁ , L ₂ and L ₃ (independently) means a corresponding linker. Each of L ₁ , L ₂ and L ₃ may (independently) be present or absent. Non-limiting examples of suitable linkers are the Gly-Ser linkers provided herein, such as 9GS, 30GS or 35GS linkers.

- X(n) = C-terminal extension of the type described here and/or in WO 12/175741.

- [Nb] means ISV against another therapeutic target.

Notes

( ¹ ) In this table:

- “Monovalent” generally refers to polypeptides/constructs containing a single ISV against OX40-L. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- “Bivalent” generally refers to polypeptides/constructs containing two anti-OX40-L ISVs (which may be the same or different). They may also contain ISVs that prolong half-life (such as ISVs against serum albumin).

- “Bispecific” generally refers to polypeptides/constructs containing at least one (such as 1 or 2) ISV against OX40-L and at least one (such as 1 or 2) other ISV against a therapeutic target. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- In the polypeptides/constructs shown in this table, at least one of the anti-OX40-L ISVs is an ISV of the invention, and preferably all of the anti-OX40-L ISVs in such polypeptides/constructs are ISVs of the invention. And when such polypeptides/constructs contain an ISV that prolongs the half-life and/or an ISV against another therapeutic target, then each of them (and preferably all of them) can also be represented (and preferably all of them are represented) by the ISVs of the invention.

( ² ) All of the “bivalent” constructs in this table can also be biparatopic, meaning they can contain at least two (like 2) anti-OX40-L ISVs that are directed against different epitopes on OX40-L.

( ³ ) It will be appreciated by those skilled in the art that other/additional bispecific constructs than those given here can be made using the above units/blocks and linkers.

( ⁴ ) Preferably, each of [OX40-L] is independently selected from SEQ ID NOs: 464-477 and/or 482-495. In addition, the data [OX40-L] may be the same or different; and in biparatope polypeptides/constructs they must be directed against different epitopes on OX40-L.

( ⁵ ) Each of the polypeptides/constructs identified in this column by SEQ ID constitutes separate specific aspects of the invention.

Example 10 Anti-IgE _VH domains (in particular nanobodies) and compounds of the invention containing them

In one particular aspect, the V _H domains of the invention (especially ISVDs
according to the invention and more preferably nanobodies according to the invention) and compounds according to the invention can be directed against IgE.

Such anti-IgE _VH domains of the invention typically contain: (i) suitable framework sequences which suitably include the amino acid residues/mutations of the invention as described herein; and (ii) CDR sequences that allow the V _H domains of the invention to specifically bind to IgE. In addition, such anti-IgE V _H domains of the invention may also contain a C-terminal extension as described herein, in particular when the V _H domain is monovalent or forms the C-terminal end of the compound of the invention in which the V domain is located. _H (again, as already described here). Such anti-IgE _VH domains of the invention can also be as already described here, in particular they can be ISVDs.

Again, as with other aspects and embodiments of the invention described herein, when a particular ISVD (such as the anti-IgE ISVD described in this example) or a compound containing it is said to be “in accordance with the invention” or “as already described herein”, then For this particular ISVD or connection, accordingly, the preferred aspects/embodiments and preferences generally described herein for the ISVDs or connections of the invention are also definitely applicable, unless expressly stated otherwise or unless the specific technical context requires otherwise.

Thus, in a preferred aspect, the present invention relates to V _H domains (especially ISVDs) directed against IgE, which (i) have a K or Q at position 112; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) at position 89 is L and at position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). In particular, for such V _H domains against IgE:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v).

The anti-IgE V _H domains of the invention may also be as described herein, in particular again these may be anti-IgE ISVDs (more preferably nanobodies) or proteins, polypeptides or other compounds or constructs that contain at least one such ISVD . Such proteins, polypeptides or other compounds or constructs may also be as already described herein and may have, for example, an increased half-life (i.e., as described herein, for example, half-life - expressed as t _½ -beta - in the human body for at least 1 day, preferably at least 3 days, more preferably at least 7 days, such as at least 10 days), and for this purpose may, for example, contain serum albumin binders nanobodies, which may also be serum albumin-binding nanobodies of the invention (again as described herein).

In addition, such ISVDs may suitably have a C-terminal extension (as already described here and in WO 12/175741), in particular where the ISVD forms the C-terminal end of the protein, polypeptide or other compound or construct containing it (again, as already described here).

In one preferred aspect, the anti-IgE V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 227 (preferably) or such an amino acid sequence that differs by only one amino acid from the sequence of SEQ ID NO: 227; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 228 (which is preferred) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 228; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 229 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 229.

More preferably, the V _H domains of the invention against IgE according to this aspect: (i) CDR1 represented by SEQ ID NO: 227; (ii) CDR2 is represented by SEQ ID NO: 228; and (iii) CDR3 is represented by SEQ ID NO: 229.

In one particular aspect, the anti-IgE nanobodies of the invention are variants of the nanobody of SEQ ID NO: 226 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 226), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). The CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

Some particularly preferred, but not limited to, examples of such anti-IgE nanobodies of the invention are presented in FIG. 14 as SEQ ID NOs: 230-243; and each of these nanobodies forms another aspect of the invention.

The invention also provides anti-IgE compounds of the invention that include at least one (such as one, two or three) nanobodies of the invention as defined in SEQ ID NOs: 230-243. Such anti-IgE compounds of the invention may again be as already described herein and therefore, for example, may contain suitable linkers, may contain a C-terminal extension as described herein, and may have an extended half-life (e.g. because that they contain an anti-human serum albumin nanobody, such as (preferably) the anti-human serum albumin nanobody of the invention). We refer you to the table below. T.

Some particularly preferred examples of the anti-IgE compounds of the invention are shown in FIG. 24 as SEQ ID NOs: 586-594; and each of these compounds forms another aspect of the invention. Thus, in another aspect, the invention relates to polypeptides directed against IgE and having an amino acid sequence selected from the group consisting of SEQ ID NOs: 586-594.

More generally, the anti-IgE compounds of the invention may be as described in WO 2012/175740 and relevant parts of WO 2012/175400, but contain the ISVs of the invention. They can also be used for the purposes described in WO 2012/175740.

Table T. Examples of Anti-IgE Compounds of the Invention

Polypeptide/construct( ¹ ) General formula ISV units/blocks and linkers Monovalent [IgE] [IgE] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with C-terminal extension [IgE]-X(n) [IgE] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with extended half-life [IgE]-L ₁ -[SA]
[SA]-L ₁ -[IgE] [IgE] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below) Monovalent with extended half-life and C-terminal extension [IgE]-L ₁ -[SA]-X(n)
[SA]-L ₁ -[IgE]-X(n) [IgE] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent( ² ) [IgE]-L ₁ -[IgE] at least one of [IgE]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below) Bivalent with C-terminal extension ( ² ) [IgE]-L ₁ -[IgE]-X(n) at least one of [IgE]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent with extended half-life ( ² ) [IgE]-L ₁ -[IgE]-L ₂ -[SA]
[IgE]-L ₁ -[SA]-L ₂ -[IgE]
[SA]-L ₁ -[IgE]-L ₂ -[IgE] at least one of [IgE]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below) Bivalent with extended half-life and C-terminal extension ( ² ) [IgE]-L ₁ -[IgE]-L ₂ -[SA]-X(n)
[IgE]-L ₁ -[SA]-L ₂ -[IgE]-X(n)
[SA]-L ₁ -[IgE]-L ₂ -[IgE]-X(n) at least one of [IgE]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below) Bispecific ( ³ ) [IgE]-L ₁ -[Nb]
[Nb]-L ₁ -[IgE]
[IgE]-L ₁ -[IgE]-L ₂ -[Nb]
[IgE]-L ₁ -[Nb]-L ₂ -[IgE]
[Nb]-L ₁ -[IgE]-L ₂ -[IgE] at least one of [IgE]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
[Nb] = (see signature below) Bispecific with C-terminal extension ( ³ ) [IgE]-L ₁ -[Nb]-X(n)
[Nb]-L ₁ -[IgE]-X(n)
[IgE]-L ₁ -[IgE]-L ₂ -[Nb]-X(n)
[IgE]-L ₁ -[Nb]-L ₂ -[IgE]-X(n)
[Nb]-L ₁ -[IgE]-L ₂ -[IgE]-X(n) at least one of [IgE]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life ( ³ ) [IgE]-L ₁ -[Nb]-L ₂ -[SA]
[IgE]-L ₁ -[SA]-L ₂ -[Nb]
[Nb]-L ₁ -[SA]-L ₂ -[IgE]
[Nb]-L ₁ -[IgE]-L ₂ -[SA]
[SA]-L ₁ -[IgE]-L ₂ -[Nb]
[SA]-L ₁ -[Nb]-L ₂ -[IgE]
[IgE]-L ₁ -[IgE]-L ₂ -[Nb]-L ₃ -[SA]
[Nb]-L ₁ -[IgE]-L ₂ -[IgE]-L ₃ -[SA]
[SA]-L ₁ -[IgE]-L ₂ -[IgE]-L ₃ -[Nb]
[SA]-L ₁ -[IgE]-L ₂ -[Nb]-L ₃ -[IgE]
[IgE]-L ₁ -[Nb]-L ₂ -[IgE]-L ₃ -[SA] at least one of [IgE]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life and C-terminal extension ( ³ ) [IgE]-L ₁ -[Nb]-L ₂ -[SA]-X(n)
[IgE]-L ₁ -[SA]-L ₂ -[Nb]-X(n)
[Nb]-L ₁ -[SA]-L ₂ -[IgE]-X(n)
[Nb]-L ₁ -[IgE]-L ₂ -[SA]-X(n)
[SA]-L ₁ -[IgE]-L ₂ -[Nb]-X(n)
[SA]-L ₁ -[Nb]-L ₂ -[IgE]-X(n)
[IgE]-L ₁ -[IgE]-L ₂ -[Nb]-L ₃ -[SA]-X(n)
[Nb]-L ₁ -[IgE]-L ₂ -[IgE]-L ₃ -[SA]-X(n)
[SA]-L ₁ -[IgE]-L ₂ -[IgE]-L ₃ -[Nb]-X(n)
[SA]-L ₁ -[IgE]-L ₂ -[Nb]-L ₃ -[IgE]-X(n)
[IgE]-L ₁ -[Nb]-L ₂ -[IgE]-L ₃ -[SA]-X(n) at least one of [IgE]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below)

Designations

- [SA] means an anti-serum albumin (human) ISV, preferably an anti-serum albumin (human) ISV of the invention, more preferably of SEQ ID NOs: 46 or 61, and even more preferably one of the inventive ISVDs of SEQ ID NOs: 47 , 54, 62, 69, 78, 86, 109, 116, 123, 130 or 496-513.

- Each of L ₁ , L ₂ and L ₃ (independently) means a corresponding linker. Each of L ₁ , L ₂ and L ₃ may (independently) be present or absent. Non-limiting examples of suitable linkers are the Gly-Ser linkers provided herein, such as 9GS, 30GS or 35GS linkers.

- X(n) = C-terminal extension of the type described here and/or in WO 12/175741.

- [Nb] means ISV against another therapeutic target.

Notes

( ¹ ) In this table:

- “Monovalent” generally refers to polypeptides/constructs containing a single anti-IgE ISV. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- “Bivalent” generally refers to polypeptides/constructs containing two anti-IgE ISVs (which may be the same or different). They may also contain ISVs that prolong half-life (such as ISVs against serum albumin).

- “Bispecific” generally refers to polypeptides/constructs containing at least one (such as 1 or 2) ISV against IgE and at least one (such as 1 or 2) other ISV against a therapeutic target. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- In the polypeptides/constructs shown in this table, at least one of the anti-IgE ISVs is an ISV of the invention, and preferably all of the anti-IgE ISVs in such polypeptides/constructs are ISVs of the invention. And when such polypeptides/constructs contain an ISV that prolongs the half-life and/or an ISV against another therapeutic target, then each of them (and preferably all of them) can also be represented (and preferably all of them are represented) by the ISVs of the invention.

( ² ) All “bivalent” constructs in this table can also be biparatopic, that is, they can contain at least two (like 2) anti-IgE ISVs that are directed against different epitopes on the IgE.

( ³ ) It will be appreciated by those skilled in the art that other/additional bispecific constructs than those given here can be made using the above units/blocks and linkers.

( ⁴ ) Preferably, each of the [IgE] is selected independently from SEQ ID NOs: 464-477 and/or 482-495. In addition, the [IgE] data may be the same or different; and in biparatope polypeptides/constructs they must be directed against different epitopes on IgE.

( ⁵ ) Each of the polypeptides/constructs identified in this column by SEQ ID constitutes separate specific aspects of the invention.

Example 11 Anti-CXCR4 V _H domains (in particular nanobodies) and compounds of the invention containing them

In one particular aspect, the V _H domains of the invention (especially the ISVDs of the invention and more preferably the nanobodies of the invention) and compounds of the invention can be directed against CXCR4.

In one particular aspect, the V _H domains of the invention (especially the ISVDs of the invention and more preferably the nanobodies of the invention) and compounds of the invention can be directed against CXCR4.

Such anti-CXCR4 _VH domains of the invention typically comprise: (i) suitable framework sequences which suitably include the amino acid residues/mutations of the invention as described herein; and (ii) CDR sequences that allow the V _H domains of the invention to specifically bind to CXCR4. In addition, such anti-CXCR4 V _H domains of the invention may also contain a C-terminal extension as described herein, in particular when the V _H domain is monovalent or forms the C-terminal end of the compound of the invention in which the V domain is located _H (again, as already described here). Such anti-CXCR4 _VH domains of the invention may also be as already described herein, in particular they may be ISVDs.

Again, as with other aspects and embodiments of the invention described herein, when a particular ISVD (such as the anti-CXCR4 ISVD described in this example) or a compound containing it is said to be “in accordance with the invention” or “as already described herein”, then For this particular ISVD or connection, accordingly, the preferred aspects/embodiments and preferences generally described herein for the ISVDs or connections of the invention are also definitely applicable, unless expressly stated otherwise or unless the specific technical context requires otherwise.

Thus, in a preferred aspect, the present invention relates to V _H domains (especially ISVDs) directed against CXCR4, which (i) have a K or Q at position 112; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) at position 89 is L and at position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). In particular, such V _H domains against CXCR4:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v).

The anti-CXCR4 _VH domains of the invention may also be as described herein, in particular again these may be anti-CXCR4 ISVDs (more preferably nanobodies) or proteins, polypeptides or other compounds or constructs that contain at least one such ISVD . Such proteins, polypeptides or other compounds or constructs may also be as already described herein and may have, for example, an increased half-life (i.e., as described herein, for example, half-life - expressed as t _½ -beta - in the human body for at least 1 day, preferably at least 3 days, more preferably at least 7 days, such as at least 10 days), and for this purpose may, for example, contain serum albumin binders nanobodies, which may also be serum albumin-binding nanobodies of the invention (again as described herein).

In addition, such ISVDs may suitably have a C-terminal extension (as already described here and in WO 12/175741), in particular where the ISVD forms the C-terminal end of the protein, polypeptide or other compound or construct containing it (again, as already described here).

In one preferred aspect, the anti-CXCR4 V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 245 (preferably) or such an amino acid sequence that differs by only one amino acid from the sequence of SEQ ID NO: 245; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 246 (which is preferred) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 246; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 247 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 247.

More preferably, the V _H domains of the invention against CXCR4 according to this aspect: (i) CDR1 represented by SEQ ID NO: 245; (ii) CDR2 is represented by SEQ ID NO: 246; and (iii) CDR3 is represented by SEQ ID NO: 247.

In one particular aspect, the anti-CXCR4 nanobodies of the invention are variants of the nanobody of SEQ ID NO: 244 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 244), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). The CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

In another preferred aspect, the anti-CXCR4 V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 263 (preferably) or such an amino acid sequence that differs by only one amino acid from the sequence of SEQ ID NO: 263; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 264 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 264; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 265 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 265.

More preferably, in the V _H domains of the invention against CXCR4 according to this aspect: (i) CDR1 is represented by SEQ ID NO: 263; (ii) CDR2 is represented by SEQ ID NO: 264; and (iii) CDR3 is represented by SEQ ID NO: 265.

In one particular aspect, the anti-CXCR4 nanobodies of the invention are variants of the nanobody of SEQ ID NO: 262 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 262), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). Again, the CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

Some particularly preferred, but not limited to, examples of such anti-CXCR4 nanobodies of the invention are presented in FIG. 15A as SEQ ID NOs: 248-261 and FIG. 15B as SEQ ID NOs: 266-279; and each of these nanobodies forms another aspect of the invention.

The invention also provides anti-CXCR4 compounds of the invention that include at least one (such as one, two or three) nanobodies of the invention as defined in SEQ ID NOs: 248-261 and/or 266-279. Such anti-CXCR4 compounds of the invention may again be as already described herein and therefore, for example, may contain suitable linkers, may contain a C-terminal extension as described herein, and may have an extended half-life (e.g. because that they contain an anti-human serum albumin nanobody, such as (preferably) the anti-human serum albumin nanobody of the invention). We refer you to the table below. U.

As described, for example, in WO 2009/138519, WO 2011/042398 and WO 2011/161266, one particularly preferred class of anti-CXCR4 nanobody-based compounds are biparatope compounds. Thus, in one aspect of the invention, the anti-CXCR4 compounds of the invention are biparatope constructs that contain a single ISV that has SEQ ID NO: 244 or (preferably) is an ISV of the invention that was derived from SEQ ID NO: 244 (as described in this example 11), and one ISV that has SEQ ID NO: 262 or (preferably) is such an ISV according to the invention that was derived from SEQ ID NO: 262 (as described in this example 11), provided that at least one (and preferably both) of these ISVs is an ISV according to the invention. Such biparatope constructs may also have an extended half-life (ie, via a serum albumin-binding ISV). Some specific examples of such biparatope designs are given in SEQ ID NOs: 595-603.

Some particularly preferred examples of the anti-CXCR-4 compounds of the invention are presented in FIG. 25 as SEQ ID NOs: 595-603; and each of these compounds forms another aspect of the invention. Thus, in another aspect, the invention relates to polypeptides directed against CXCR-4 and having an amino acid sequence selected from the group consisting of SEQ ID NOs: 595-603. More generally, the anti-CXCR-4 compounds of the invention may be as described in WO 2009/138519, WO 2011/042398 and WO 2011/161266, WO 2011/144749, but contain the ISVs of the invention. They can also be used for the purposes described in WO 2009/138519, WO 2011/042398 and WO 2011/161266.

Table U. Examples of Anti-CXCR-4 Compounds of the Invention

Polypeptide/construct( ¹ ) General formula ISV units/blocks and linkers Monovalent [CXCR-4] [CXCR-4] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with C-terminal extension [CXCR-4]-X(n) [CXCR-4] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with extended half-life [CXCR-4]-L ₁ -[SA]
[SA]-L ₁ -[CXCR-4] [CXCR-4] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below) Monovalent with extended half-life and C-terminal extension [CXCR-4]-L ₁ -[SA]-X(n)
[SA]-L ₁ -[CXCR-4]-X(n) [CXCR-4] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent( ² ) [CXCR-4]-L ₁ -[CXCR-4] at least one of [CXCR-4] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below) Bivalent with C-terminal extension ( ² ) [CXCR-4]-L ₁ -[CXCR-4]-X(n) at least one of [CXCR-4] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent with extended half-life ( ² ) [CXCR-4]-L ₁ -[CXCR-4]-L ₂ -[SA]
[CXCR-4]-L ₁ -[SA]-L ₂ -[CXCR-4]
[SA]-L ₁ -[CXCR-4]-L ₂ -[CXCR-4] at least one of [CXCR-4] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below) Bivalent with extended half-life and C-terminal extension ( ² ) [CXCR-4]-L ₁ -[CXCR-4]-L ₂ -[SA]-X(n)
[CXCR-4]-L ₁ -[SA]-L ₂ -[CXCR-4]-X(n)
[SA]-L ₁ -[CXCR-4]-L ₂ -[CXCR-4]-X(n) at least one of [CXCR-4] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below) Bispecific ( ³ ) [CXCR-4]-L ₁ -[Nb]
[Nb]-L ₁ -[CXCR-4]
[CXCR-4]-L ₁ -[CXCR-4]-L ₂ -[Nb]
[CXCR-4]-L ₁ -[Nb]-L ₂ -[CXCR-4]
[Nb]-L ₁ -[CXCR-4]-L ₂ -[CXCR-4] at least one of [CXCR-4] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
[Nb] = (see signature below) Bispecific with C-terminal extension ( ³ ) [CXCR-4]-L ₁ -[Nb]-X(n)
[Nb]-L ₁ -[CXCR-4]-X(n)
[CXCR-4]-L ₁ -[CXCR-4]-L ₂ -[Nb]-X(n)
[CXCR-4]-L ₁ -[Nb]-L ₂ -[CXCR-4]-X(n)
[Nb]-L ₁ -[CXCR-4]-L ₂ -[CXCR-4]-X(n) at least one of [CXCR-4] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life ( ³ ) [CXCR-4]-L ₁ -[Nb]-L ₂ -[SA]
[CXCR-4]-L ₁ -[SA]-L ₂ -[Nb]
[Nb]-L ₁ -[SA]-L ₂ -[CXCR-4]
[Nb]-L ₁ -[CXCR-4]-L ₂ -[SA]
[SA]-L ₁ -[CXCR-4]-L ₂ -[Nb]
[SA]-L ₁ -[Nb]-L ₂ -[CXCR-4]
[CXCR-4]-L ₁ -[CXCR-4]-L ₂ -[Nb]-L ₃ -[SA]
[Nb]-L ₁ -[CXCR-4]-L ₂ -[CXCR-4]-L ₃ -[SA]
[SA]-L ₁ -[CXCR-4]-L ₂ -[CXCR-4]-L ₃ -[Nb]
[SA]-L ₁ -[CXCR-4]-L ₂ -[Nb]-L ₃ -[CXCR-4]
[CXCR-4]-L ₁ -[Nb]-L ₂ -[CXCR-4]-L ₃ -[SA] at least one of [CXCR-4] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life and C-terminal extension ( ³ ) [CXCR-4]-L ₁ -[Nb]-L ₂ -[SA]-X(n)
[CXCR-4]-L ₁ -[SA]-L ₂ -[Nb]-X(n)
[Nb]-L ₁ -[SA]-L ₂ -[CXCR-4]-X(n)
[Nb]-L ₁ -[CXCR-4]-L ₂ -[SA]-X(n)
[SA]-L ₁ -[CXCR-4]-L ₂ -[Nb]-X(n)
[SA]-L ₁ -[Nb]-L ₂ -[CXCR-4]-X(n)
[CXCR-4]-L ₁ -[CXCR-4]-L ₂ -[Nb]-L ₃ -[SA]-X(n)
[Nb]-L ₁ -[CXCR-4]-L ₂ -[CXCR-4]-L ₃ -[SA]-X(n)
[SA]-L ₁ -[CXCR-4]-L ₂ -[CXCR-4]-L ₃ -[Nb]-X(n)
[SA]-L ₁ -[CXCR-4]-L ₂ -[Nb]-L ₃ -[CXCR-4]-X(n)
[CXCR-4]-L ₁ -[Nb]-L ₂ -[CXCR-4]-L ₃ -[SA]-X(n) at least one of [CXCR-4] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below)

Designations

- [SA] means an anti-serum albumin (human) ISV, preferably an anti-serum albumin (human) ISV of the invention, more preferably of SEQ ID NOs: 46 or 61, and even more preferably one of the inventive ISVDs of SEQ ID NOs: 47 , 54, 62, 69, 78, 86, 109, 116, 123, 130 or 496-513.

- Each of L ₁ , L ₂ and L ₃ (independently) means a corresponding linker. Each of L ₁ , L ₂ and L ₃ may (independently) be present or absent. Non-limiting examples of suitable linkers are the Gly-Ser linkers provided herein, such as 9GS, 30GS or 35GS linkers.

- X(n) = C-terminal extension of the type described here and/or in WO 12/175741.

- [Nb] means ISV against another therapeutic target.

Notes

( ¹ ) In this table:

- “Monovalent” generally refers to polypeptides/constructs containing a single ISV against CXCR-4. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- “Bivalent” generally refers to polypeptides/constructs containing two anti-CXCR-4 ISVs (which may be the same or different). They may also contain ISVs that prolong half-life (such as ISVs against serum albumin).

- “Bispecific” generally refers to polypeptides/constructs containing at least one (such as 1 or 2) ISV against CXCR-4 and at least one (such as 1 or 2) other ISV against a therapeutic target. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- In the polypeptides/constructs shown in this table, at least one of the anti-CXCR-4 ISVs is an ISV of the invention, and preferably all of the anti-CXCR-4 ISVs in such polypeptides/constructs are ISVs of the invention. And when such polypeptides/constructs contain an ISV that prolongs the half-life and/or an ISV against another therapeutic target, then each of them (and preferably all of them) can also be represented (and preferably all of them are represented) by the ISVs of the invention.

( ² ) All “bivalent” constructs in this table can also be biparatopic, that is, they can contain at least two (like 2) anti-CXCR-4 ISVs that are directed against different epitopes on CXCR-4.

( ³ ) It will be appreciated by those skilled in the art that other/additional bispecific constructs than those given here can be made using the above units/blocks and linkers.

( ⁴ ) Preferably, each of [CXCR-4] is selected independently from SEQ ID NOs: 464-477 and/or 482-495. Additionally, the [CXCR-4] data may be the same or different; and in biparatope polypeptides/constructs they must be directed against different epitopes on CXCR-4.

( ⁵ ) Each of the polypeptides/constructs identified in this column by SEQ ID constitutes separate specific aspects of the invention.

Example 12 Anti-HER-3 _VH Domains (In particular Nanobodies) and Compounds of the Invention Containing Them

In one particular aspect, the V _H domains of the invention (especially ISVDs
according to the invention and more preferably nanobodies according to the invention) and compounds according to the invention can be directed against HER-3.

Such anti-HER-3 _VH domains of the invention typically contain: (i) suitable framework sequences which suitably include the amino acid residues/mutations of the invention as described herein; and (ii) CDR sequences that allow the V _H domains of the invention to specifically bind to HER-3. In addition, such anti-HER-3 V _H domains of the invention may also contain a C-terminal extension as described herein, in particular where the V _H domain is monovalent or forms the C-terminal end of the compound of the invention in which it is located. V _H domain (again, as already described here). Such anti-HER-3 _VH domains of the invention may also be those already described herein, in particular they may be ISVDs.

Again, as with other aspects and embodiments of the invention described herein, when a particular ISVD (such as the anti-HER-3 ISVD described in this example) or a compound containing it is said to be “in accordance with the invention” or “as already described herein” , then the preferred aspects/embodiments and preferences generally described herein for the ISVDs or compounds of the invention are also definitely applicable to this particular ISVD or connection accordingly, unless expressly stated otherwise or unless the specific technical context requires otherwise.

Thus, in a preferred aspect, the present invention relates to V _H domains (especially ISVDs) directed against HER-3, which (i) have a K or Q at position 112; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) at position 89 is L and at position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). In particular, such V _H domains against HER-3:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v).

The anti-HER-3 _VH domains of the invention may also be as described herein, in particular again these may be anti-HER-3 ISVDs (more preferably nanobodies) or proteins, polypeptides or other compounds or constructs that contain at least at least one such ISVD. Such proteins, polypeptides or other compounds or constructs may also be as already described herein and may have, for example, an increased half-life (i.e., as described herein, for example, half-life - expressed as t _½ -beta - in the human body for at least 1 day, preferably at least 3 days, more preferably at least 7 days, such as at least 10 days), and for this purpose may, for example, contain serum albumin binders nanobodies, which may also be serum albumin-binding nanobodies of the invention (again as described herein).

In addition, such ISVDs may suitably have a C-terminal extension (as already described here and in WO 12/175741), in particular where the ISVD forms the C-terminal end of the protein, polypeptide or other compound or construct containing it (again, as already described here).

In one preferred aspect, the anti-HER-3 V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 281 (preferably) or such an amino acid sequence that differs by only one amino acid from the sequence of SEQ ID NO: 281 ; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 282 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 282; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 283 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 283.

More preferably, the V _H domains of the invention against HER-3 according to this aspect: (i) CDR1 represented by SEQ ID NO: 281; (ii) CDR2 is represented by SEQ ID NO: 282; and (iii) CDR3 is represented by SEQ ID NO: 283.

In one particular aspect, the anti-HER-3 nanobodies of the invention are variants of the nanobody of SEQ ID NO: 280 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 280 ), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). The CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

In another preferred aspect, the anti-HER-3 V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 299 (preferably) or such an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: : 299; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 300 (which is preferred) or an amino acid sequence that differs by only one amino acid from the sequence of SEQ ID NO: 300; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 301 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 301.

More preferably, the V _H domains of the invention against HER-3 according to this aspect: (i) CDR1 represented by SEQ ID NO: 299; (ii) CDR2 is represented by SEQ ID NO: 300; and (iii) CDR3 is represented by SEQ ID NO: 301.

In one particular aspect, the anti-HER-3 nanobodies of the invention are variants of the nanobody of SEQ ID NO: 298 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 298 ), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). Again, the CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

Some particularly preferred, but not limited to, examples of such anti-HER-3 nanobodies of the invention are presented in FIG. 16A as SEQ ID NOs: 284-297 and FIG. 16B as SEQ ID NOs: 302-315, respectively; and each of these nanobodies forms another aspect of the invention.

The invention also provides anti-HER-3 compounds of the invention that include at least one (such as one, two or three) nanobodies of the invention as defined in SEQ ID NOs: 284-297 and/or 302-315. Such anti-HER-3 compounds of the invention may again be as already described herein and therefore, for example, may contain suitable linkers, may contain a C-terminal extension as described herein, and may have an extended half-life (e.g. because they contain an anti-human serum albumin nanobody, such as (preferably) the anti-human serum albumin nanobody of the invention). We refer you to the table below. V.

As described, for example, in WO 2011/144749, one particularly preferred class of anti-HER-3 nanobody compounds are biparatope compounds. Thus, in one aspect of the invention, the anti-HER-3 compounds of the invention are biparatope constructs that contain a single ISV that has SEQ ID NO: 280 or (preferably) is an ISV of the invention that is derived from SEQ ID NO: 280 (as described in this Example 12), and one ISV that has SEQ ID NO: 298 or (preferably) is an ISV of the invention that was derived from SEQ ID NO: 298 (as described in this Example 12), provided that at least one (and preferably both) of these ISVs is an ISV according to the invention. Such biparatope constructs may also have an extended half-life (ie, via a serum albumin-binding ISV). Some specific examples of such biparatope designs are provided in SEQ ID NOs: 604-639.

Some particularly preferred examples of the anti-HER-3 compounds of the invention are shown in FIG. 26 as SEQ ID NOs: 604-639; and each of these compounds forms another aspect of the invention. Thus, in another aspect, the invention relates to polypeptides directed against HER-3 and having an amino acid sequence selected from the group consisting of SEQ ID NOs: 604-639. More generally, the anti-HER-3 compounds of the invention may be as described in WO 2011/144749, but contain the ISVs of the invention. They can also be used for the purposes described in WO 2011/144749.

Table V. Examples of Anti-HER-3 Compounds of the Invention

Polypeptide/construct( ¹ ) General formula ISV units/blocks and linkers Monovalent [HER-3] [HER-3] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with C-terminal extension [HER-3]-X(n) [HER-3] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with extended half-life [HER-3]-L ₁ -[SA]
[SA]-L ₁ -[HER-3] [HER-3] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below) Monovalent with extended half-life and C-terminal extension [HER-3]-L ₁ -[SA]-X(n)
[SA]-L ₁ -[HER-3]-X(n) [HER-3] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent( ² ) [HER-3]-L ₁ -[HER-3] at least one of [HER-3] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below) Bivalent with C-terminal extension ( ² ) [HER-3]-L ₁ -[HER-3]-X(n) at least one of [HER-3] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent with extended half-life ( ² ) [HER-3]-L ₁ -[HER-3]-L ₂ -[SA]
[HER-3]-L ₁ -[SA]-L ₂ -[HER-3]
[SA]-L ₁ -[HER-3]-L ₂ -[HER-3] at least one of [HER-3] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below) Bivalent with extended half-life and C-terminal extension ( ² ) [HER-3]-L ₁ -[HER-3]-L ₂ -[SA]-X(n)
[HER-3]-L ₁ -[SA]-L ₂ -[HER-3]-X(n)
[SA]-L ₁ -[HER-3]-L ₂ -[HER-3]-X(n) at least one of [HER-3] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below) Bispecific ( ³ ) [HER-3]-L ₁ -[Nb]
[Nb]-L ₁ -[HER-3]
[HER-3]-L ₁ -[HER-3]-L ₂ -[Nb]
[HER-3]-L ₁ -[Nb]-L ₂ -[HER-3]
[Nb]-L ₁ -[HER-3]-L ₂ -[HER-3] at least one of [HER-3] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
[Nb] = (see signature below) Bispecific with C-terminal extension ( ³ ) [HER-3]-L ₁ -[Nb]-X(n)
[Nb]-L ₁ -[HER-3]-X(n)
[HER-3]-L ₁ -[HER-3]-L ₂ -[Nb]-X(n)
[HER-3]-L ₁ -[Nb]-L ₂ -[HER-3]-X(n)
[Nb]-L ₁ -[HER-3]-L ₂ -[HER-3]-X(n) at least one of [HER-3] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life ( ³ ) [HER-3]-L ₁ -[Nb]-L ₂ -[SA]
[HER-3]-L ₁ -[SA]-L ₂ -[Nb]
[Nb]-L ₁ -[SA]-L ₂ -[HER-3]
[Nb]-L ₁ -[HER-3]-L ₂ -[SA]
[SA]-L ₁ -[HER-3]-L ₂ -[Nb]
[SA]-L ₁ -[Nb]-L ₂ -[HER-3]
[HER-3]-L ₁ -[HER-3]-L ₂ -[Nb]-L ₃ -[SA]
[Nb]-L ₁ -[HER-3]-L ₂ -[HER-3]-L ₃ -[SA]
[SA]-L ₁ -[HER-3]-L ₂ -[HER-3]-L ₃ -[Nb]
[SA]-L ₁ -[HER-3]-L ₂ -[Nb]-L ₃ -[HER-3]
[HER-3]-L ₁ -[Nb]-L ₂ -[HER-3]-L ₃ -[SA] at least one of [HER-3] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life and C-terminal extension ( ³ ) [HER-3]-L ₁ -[Nb]-L ₂ -[SA]-X(n)
[HER-3]-L ₁ -[SA]-L ₂ -[Nb]-X(n)
[Nb]-L ₁ -[SA]-L ₂ -[HER-3]-X(n)
[Nb]-L ₁ -[HER-3]-L ₂ -[SA]-X(n)
[SA]-L ₁ -[HER-3]-L ₂ -[Nb]-X(n)
[SA]-L ₁ -[Nb]-L ₂ -[HER-3]-X(n)
[HER-3]-L ₁ -[HER-3]-L ₂ -[Nb]-L ₃ -[SA]-X(n)
[Nb]-L ₁ -[HER-3]-L ₂ -[HER-3]-L ₃ -[SA]-X(n)
[SA]-L ₁ -[HER-3]-L ₂ -[HER-3]-L ₃ -[Nb]-X(n)
[SA]-L ₁ -[HER-3]-L ₂ -[Nb]-L ₃ -[HER-3]-X(n)
[HER-3]-L ₁ -[Nb]-L ₂ -[HER-3]-L ₃ -[SA]-X(n) at least one of [HER-3] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below)

Designations

- [SA] means an anti-serum albumin (human) ISV, preferably an anti-serum albumin (human) ISV of the invention, more preferably of SEQ ID NOs: 46 or 61, and even more preferably one of the inventive ISVDs of SEQ ID NOs: 47 , 54, 62, 69, 78, 86, 109, 116, 123, 130 or 496-513.

- Each of L ₁ , L ₂ and L ₃ (independently) means a corresponding linker. Each of L ₁ , L ₂ and L ₃ may (independently) be present or absent. Non-limiting examples of suitable linkers are the Gly-Ser linkers provided herein, such as 9GS, 30GS or 35GS linkers.

- X(n) = C-terminal extension of the type described here and/or in WO 12/175741.

- [Nb] means ISV against another therapeutic target.

Notes

( ¹ ) In this table:

- “Monovalent” generally refers to polypeptides/constructs containing a single anti-HER-3 ISV. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- “Bivalent” generally refers to polypeptides/constructs containing two anti-HER-3 ISVs (which may be the same or different). They may also contain ISVs that prolong half-life (such as ISVs against serum albumin).

- “Bispecific” generally refers to polypeptides/constructs containing at least one (such as 1 or 2) ISV against HER-3 and at least one (such as 1 or 2) other ISV against a therapeutic target. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- In the polypeptides/constructs shown in this table, at least one of the anti-HER-3 ISVs is an ISV of the invention, and preferably all of the anti-HER-3 ISVs in such polypeptides/constructs are ISVs of the invention. And when such polypeptides/constructs contain an ISV that prolongs the half-life and/or an ISV against another therapeutic target, then each of them (and preferably all of them) can also be represented (and preferably all of them are represented) by the ISVs of the invention.

( ² ) All of the “bivalent” constructs in this table can also be biparatopic, meaning they can contain at least two (like two) anti-HER-3 ISVs that are directed against different epitopes on HER-3.

( ³ ) It will be appreciated by those skilled in the art that other/additional bispecific constructs than those given here can be made using the above units/blocks and linkers.

( ⁴ ) Preferably, each of [HER-3] is selected independently from SEQ ID NOs: 464-477 and/or 482-495. In addition, the [HER-3] data may be the same or different; and in biparatope polypeptides/constructs they must be directed against different epitopes on HER-3.

( ⁵ ) Each of the polypeptides/constructs identified in this column by SEQ ID constitutes separate specific aspects of the invention.

Example 13 Anti-TNF _VH domains (in particular nanobodies) and compounds of the invention containing them

In one particular aspect, the V _H domains of the invention (especially ISVDs
according to the invention and more preferably nanobodies according to the invention) and compounds according to the invention can be directed against TNF.

Such anti-TNF _VH domains of the invention typically contain: (i) suitable framework sequences which suitably include the amino acid residues/mutations of the invention as described herein; and (ii) CDR sequences that allow the V _H domains of the invention to specifically bind to TNF. In addition, such anti-TNF V _H domains of the invention may also contain a C-terminal extension as described herein, particularly when the V _H domain is monovalent or forms the C-terminal end of the compound of the invention in which the V domain is located. _H (again, as already described here). Such anti-TNF _VH domains of the invention may also be those already described herein, in particular they may be ISVDs.

Again, as with other aspects and embodiments of the invention described herein, when a particular ISVD (such as the anti-TNF ISVD described in this example) or a compound containing it is said to be “in accordance with the invention” or “as already described herein”, then For this particular ISVD or connection, accordingly, the preferred aspects/embodiments and preferences generally described herein for the ISVDs or connections of the invention are also definitely applicable, unless expressly stated otherwise or unless the specific technical context requires otherwise.

Thus, in a preferred aspect, the present invention relates to anti-TNF V _H domains (especially ISVDs) having (i) a K or Q at position 112; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) at position 89 is L and at position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). In particular, for such V _H domains against TNF:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v).

The anti-TNF _VH domains of the invention may also be as described herein, in particular again these may be anti-TNF ISVDs (more preferably nanobodies) or proteins, polypeptides or other compounds or constructs that contain at least one such ISVD . Such proteins, polypeptides or other compounds or constructs may also be as already described herein and may have, for example, an increased half-life (i.e., as described herein, for example, half-life - expressed as t _½ -beta - in the human body for at least 1 day, preferably at least 3 days, more preferably at least 7 days, such as at least 10 days), and for this purpose may, for example, contain serum albumin binders nanobodies, which may also be serum albumin-binding nanobodies of the invention (again as described herein).

In addition, such ISVDs may suitably have a C-terminal extension (as already described here and in WO 12/175741), in particular where the ISVD forms the C-terminal end of the protein, polypeptide or other compound or construct containing it (again, as already described here).

In one preferred aspect, the anti-TNF V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 317 (preferably) or an amino acid sequence that differs by only one amino acid from the sequence of SEQ ID NO: 317; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 318 (which is preferred) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 318; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 319 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 319.

More preferably, in the anti-TNF V _H domains of the invention according to this aspect: (i) CDR1 is represented by SEQ ID NO: 317; (ii) CDR2 is represented by SEQ ID NO: 318; and (iii) CDR3 is represented by SEQ ID NO: 319.

In one particular aspect, the anti-TNF nanobodies of the invention are variants of the nanobody of SEQ ID NO: 316 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 316), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). The CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

Some particularly preferred, but not limited to, examples of such anti-TNF nanobodies of the invention are presented in FIG. 17A as SEQ ID NOs: 320-333; and each of these nanobodies forms another aspect of the invention.

The invention also provides anti-TNF compounds of the invention that include at least one (such as one, two or three) nanobodies of the invention as defined in SEQ ID NOs: 320-333. Such anti-TNF compounds of the invention may again be as already described herein and therefore, for example, may contain suitable linkers, may contain a C-terminal extension as described herein, and may have an extended half-life (e.g. because that they contain an anti-human serum albumin nanobody, such as (preferably) the anti-human serum albumin nanobody of the invention). We refer you to the table below. W. In general, since TNF is a multivalent target, compounds of the invention containing two or three anti-TNF ISVs (as well as linkers of appropriate length, see WO 06/122786) are preferred.

Some particularly preferred examples of the anti-TNF compounds of the invention are shown in FIG. 27 as SEQ ID NOs: 640-675; and each of these compounds forms another aspect of the invention. Thus, in another aspect, the invention relates to polypeptides directed against TNF and having an amino acid sequence selected from the group consisting of SEQ ID NOs: 640-675. More generally, the anti-TNF compounds of the invention may be as described in WO 2006/122786, but contain the ISVs of the invention. They can also be used for the purposes described in WO 2006/122786.

Table W. Examples of Anti-TNF Compounds of the Invention

Polypeptide/construct( ¹ ) General formula ISV units/blocks and linkers Monovalent [TNF] [TNF] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with C-terminal extension [TNF]-X(n) [TNF] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with extended half-life [TNF]-L ₁ -[SA]
[SA]-L ₁ -[TNF] [TNF] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below) Monovalent with extended half-life and C-terminal extension [TNF]-L ₁ -[SA]-X(n)
[SA]-L ₁ -[TNF]-X(n) [TNF] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent( ² ) [TNF]-L ₁ -[TNF] at least one of [TNF]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below) Bivalent with C-terminal extension ( ² ) [TNF]-L ₁ -[TNF]-X(n) at least one of [TNF]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent with extended half-life ( ² ) [TNF]-L ₁ -[TNF]-L ₂ -[SA]
[TNF]-L ₁ -[SA]-L ₂ -[TNF]
[SA]-L ₁ -[TNF]-L ₂ -[TNF] at least one of [TNF]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below) Bivalent with extended half-life and C-terminal extension ( ² ) [TNF]-L ₁ -[TNF]-L ₂ -[SA]-X(n)
[TNF]-L ₁ -[SA]-L ₂ -[TNF]-X(n)
[SA]-L ₁ -[TNF]-L ₂ -[TNF]-X(n) at least one of [TNF]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below) Bispecific ( ³ ) [TNF]-L ₁ -[Nb]
[Nb]-L ₁ -[TNF]
[TNF]-L ₁ -[TNF]-L ₂ -[Nb]
[TNF]-L ₁ -[Nb]-L ₂ -[TNF]
[Nb]-L ₁ -[TNF]-L ₂ -[TNF] at least one of [TNF]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
[Nb] = (see signature below) Bispecific with C-terminal extension ( ³ ) [TNF]-L ₁ -[Nb]-X(n)
[Nb]-L ₁ -[TNF]-X(n)
[TNF]-L ₁ -[TNF]-L ₂ -[Nb]-X(n)
[TNF]-L ₁ -[Nb]-L ₂ -[TNF]-X(n)
[Nb]-L ₁ -[TNF]-L ₂ -[TNF]-X(n) at least one of [TNF]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life ( ³ ) [TNF]-L ₁ -[Nb]-L ₂ -[SA]
[TNF]-L ₁ -[SA]-L ₂ -[Nb]
[Nb]-L ₁ -[SA]-L ₂ -[TNF]
[Nb]-L ₁ -[TNF]-L ₂ -[SA]
[SA]-L ₁ -[TNF]-L ₂ -[Nb]
[SA]-L ₁ -[Nb]-L ₂ -[TNF]
[TNF]-L ₁ -[TNF]-L ₂ -[Nb]-L ₃ -[SA]
[Nb]-L ₁ -[TNF]-L ₂ -[TNF]-L ₃ -[SA]
[SA]-L ₁ -[TNF]-L ₂ -[TNF]-L ₃ -[Nb]
[SA]-L ₁ -[TNF]-L ₂ -[Nb]-L ₃ -[TNF]
[TNF]-L ₁ -[Nb]-L ₂ -[TNF]-L ₃ -[SA] at least one of [TNF]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life and C-terminal extension ( ³ ) [TNF]-L ₁ -[Nb]-L ₂ -[SA]-X(n)
[TNF]-L ₁ -[SA]-L ₂ -[Nb]-X(n)
[Nb]-L ₁ -[SA]-L ₂ -[TNF]-X(n)
[Nb]-L ₁ -[TNF]-L ₂ -[SA]-X(n)
[SA]-L ₁ -[TNF]-L ₂ -[Nb]-X(n)
[SA]-L ₁ -[Nb]-L ₂ -[TNF]-X(n)
[TNF]-L ₁ -[TNF]-L ₂ -[Nb]-L ₃ -[SA]-X(n)
[Nb]-L ₁ -[TNF]-L ₂ -[TNF]-L ₃ -[SA]-X(n)
[SA]-L ₁ -[TNF]-L ₂ -[TNF]-L ₃ -[Nb]-X(n)
[SA]-L ₁ -[TNF]-L ₂ -[Nb]-L ₃ -[TNF]-X(n)
[TNF]-L ₁ -[Nb]-L ₂ -[TNF]-L ₃ -[SA]-X(n) at least one of [TNF]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below)

Designations

- [SA] means an anti-serum albumin (human) ISV, preferably an anti-serum albumin (human) ISV of the invention, more preferably of SEQ ID NOs: 46 or 61, and even more preferably one of the inventive ISVDs of SEQ ID NOs: 47 , 54, 62, 69, 78, 86, 109, 116, 123, 130 or 496-513.

- Each of L ₁ , L ₂ and L ₃ (independently) means a corresponding linker. Each of L ₁ , L ₂ and L ₃ may (independently) be present or absent. Non-limiting examples of suitable linkers are the Gly-Ser linkers provided herein, such as 9GS, 30GS or 35GS linkers.

- X(n) = C-terminal extension of the type described here and/or in WO 12/175741.

- [Nb] means ISV against another therapeutic target.

Notes

( ¹ ) In this table:

- “Monovalent” generally refers to polypeptides/constructs containing a single anti-TNF ISV. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- “Bivalent” generally refers to polypeptides/constructs containing two anti-TNF ISVs (which may be the same or different). They may also contain ISVs that prolong half-life (such as ISVs against serum albumin).

- “Bispecific” generally refers to polypeptides/constructs containing at least one (such as 1 or 2) ISV against TNF and at least one (such as 1 or 2) other ISV against a therapeutic target. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- In the polypeptides/constructs shown in this table, at least one of the anti-TNF ISVs is an ISV of the invention, and preferably all of the anti-TNF ISVs in such polypeptides/constructs are ISVs of the invention. And when such polypeptides/constructs contain an ISV that prolongs the half-life and/or an ISV against another therapeutic target, then each of them (and preferably all of them) can also be represented (and preferably all of them are represented) by the ISVs of the invention.

( ² ) All of the “bivalent” constructs in this table can also be biparatopic, meaning they can contain at least two (like 2) anti-TNF ISVs that are directed against different epitopes on TNF.

( ³ ) It will be appreciated by those skilled in the art that other/additional bispecific constructs than those given here can be made using the above units/blocks and linkers.

( ⁴ ) Preferably, each of [TNF] is selected independently from SEQ ID NOs: 464-477 and/or 482-495. In addition, the [TNF] data may be the same or different; and in biparatope polypeptides/constructs they must be directed against different epitopes on TNF.

( ⁵ ) Each of the polypeptides/constructs identified in this column by SEQ ID constitutes separate specific aspects of the invention.

Example 14 Other anti-TNF _VH domains (in particular nanobodies) and compounds of the invention containing them

In one particular aspect, the V _H domains of the invention (especially ISVDs
according to the invention and more preferably nanobodies according to the invention) and compounds according to the invention can be directed against TNF.

Such anti-TNF _VH domains of the invention typically contain: (i) suitable framework sequences which suitably include the amino acid residues/mutations of the invention as described herein; and (ii) CDR sequences that allow the V _H domains of the invention to specifically bind to TNF. In addition, such anti-TNF V _H domains of the invention may also contain a C-terminal extension as described herein, particularly when the V _H domain is monovalent or forms the C-terminal end of the compound of the invention in which the V domain is located. _H (again, as already described here). Such anti-TNF _VH domains of the invention may also be those already described herein, in particular they may be ISVDs.

Again, as with other aspects and embodiments of the invention described herein, when a particular ISVD (such as the anti-TNF ISVD described in this example) or a compound containing it is said to be “in accordance with the invention” or “as already described herein”, then For this particular ISVD or connection, accordingly, the preferred aspects/embodiments and preferences generally described herein for the ISVDs or connections of the invention are also definitely applicable, unless expressly stated otherwise or unless the specific technical context requires otherwise.

Thus, in a preferred aspect, the present invention relates to anti-TNF V _H domains (especially ISVDs) having (i) a K or Q at position 112; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) at position 89 is L and at position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). In particular, for such V _H domains against TNF:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v).

The anti-TNF _VH domains of the invention may also be as described herein, in particular again these may be anti-TNF ISVDs (more preferably nanobodies) or proteins, polypeptides or other compounds or constructs that contain at least one such ISVD . Such proteins, polypeptides or other compounds or constructs may also be as already described herein and may have, for example, an increased half-life (i.e., as described herein, for example, half-life - expressed as t _½ -beta - in the human body for at least 1 day, preferably at least 3 days, more preferably at least 7 days, such as at least 10 days), and for this purpose may, for example, contain serum albumin binders nanobodies, which may also be serum albumin-binding nanobodies of the invention (again as described herein).

In addition, such ISVDs may suitably have a C-terminal extension (as already described here and in WO 12/175741), in particular where the ISVD forms the C-terminal end of the protein, polypeptide or other compound or construct containing it (again, as already described here).

In one preferred aspect, the anti-TNF V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 335 (preferably) or such an amino acid sequence that differs by only one amino acid from the sequence of SEQ ID NO: 335; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 336 (which is preferred) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 336; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 337 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 337.

More preferably, in the anti-TNF V _H domains of the invention according to this aspect: (i) CDR1 is represented by SEQ ID NO: 335; (ii) CDR2 is represented by SEQ ID NO: 336; and (iii) CDR3 is represented by SEQ ID NO: 337.

In one particular aspect, the anti-TNF nanobodies of the invention are variants of the nanobody of SEQ ID NO: 334 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 334), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). The CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

Some particularly preferred, but not limited to, examples of such anti-TNF nanobodies of the invention are presented in FIG. 17B as SEQ ID NOs: 338-351; and each of these nanobodies forms another aspect of the invention.

The invention also provides anti-TNF compounds of the invention that include at least one (such as one, two or three) nanobodies of the invention as defined in SEQ ID NOs: 338-351. Such anti-TNF compounds of the invention may again be as already described herein and therefore, for example, may contain suitable linkers, may contain a C-terminal extension as described herein, and may have an extended half-life (e.g. because that they contain an anti-human serum albumin nanobody, such as (preferably) the anti-human serum albumin nanobody of the invention). We refer you to the table below. X. In general, since TNF is a multivalent target, compounds of the invention containing two or three anti-TNF ISVs are preferred.

Table X. Examples of Anti-TNF Compounds of the Invention

Polypeptide/construct( ¹ ) General formula ISV units/blocks and linkers Monovalent [TNF] [TNF] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with C-terminal extension [TNF]-X(n) [TNF] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with extended half-life [TNF]-L ₁ -[SA]
[SA]-L ₁ -[TNF] [TNF] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below) Monovalent with extended half-life and C-terminal extension [TNF]-L ₁ -[SA]-X(n)
[SA]-L ₁ -[TNF]-X(n) [TNF] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent( ² ) [TNF]-L ₁ -[TNF] at least one of [TNF]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below) Bivalent with C-terminal extension ( ² ) [TNF]-L ₁ -[TNF]-X(n) at least one of [TNF]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent with extended half-life ( ² ) [TNF]-L ₁ -[TNF]-L ₂ -[SA]
[TNF]-L ₁ -[SA]-L ₂ -[TNF]
[SA]-L ₁ -[TNF]-L ₂ -[TNF] at least one of [TNF]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below) Bivalent with extended half-life and C-terminal extension ( ² ) [TNF]-L ₁ -[TNF]-L ₂ -[SA]-X(n)
[TNF]-L ₁ -[SA]-L ₂ -[TNF]-X(n)
[SA]-L ₁ -[TNF]-L ₂ -[TNF]-X(n) at least one of [TNF]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below) Bispecific ( ³ ) [TNF]-L ₁ -[Nb]
[Nb]-L ₁ -[TNF]
[TNF]-L ₁ -[TNF]-L ₂ -[Nb]
[TNF]-L ₁ -[Nb]-L ₂ -[TNF]
[Nb]-L ₁ -[TNF]-L ₂ -[TNF] at least one of [TNF]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
[Nb] = (see signature below) Bispecific with C-terminal extension ( ³ ) [TNF]-L ₁ -[Nb]-X(n)
[Nb]-L ₁ -[TNF]-X(n)
[TNF]-L ₁ -[TNF]-L ₂ -[Nb]-X(n)
[TNF]-L ₁ -[Nb]-L ₂ -[TNF]-X(n)
[Nb]-L ₁ -[TNF]-L ₂ -[TNF]-X(n) at least one of [TNF]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life ( ³ ) [TNF]-L ₁ -[Nb]-L ₂ -[SA]
[TNF]-L ₁ -[SA]-L ₂ -[Nb]
[Nb]-L ₁ -[SA]-L ₂ -[TNF]
[Nb]-L ₁ -[TNF]-L ₂ -[SA]
[SA]-L ₁ -[TNF]-L ₂ -[Nb]
[SA]-L ₁ -[Nb]-L ₂ -[TNF]
[TNF]-L ₁ -[TNF]-L ₂ -[Nb]-L ₃ -[SA]
[Nb]-L ₁ -[TNF]-L ₂ -[TNF]-L ₃ -[SA]
[SA]-L ₁ -[TNF]-L ₂ -[TNF]-L ₃ -[Nb]
[SA]-L ₁ -[TNF]-L ₂ -[Nb]-L ₃ -[TNF]
[TNF]-L ₁ -[Nb]-L ₂ -[TNF]-L ₃ -[SA] at least one of [TNF]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life and C-terminal extension ( ³ ) [TNF]-L ₁ -[Nb]-L ₂ -[SA]-X(n)
[TNF]-L ₁ -[SA]-L ₂ -[Nb]-X(n)
[Nb]-L ₁ -[SA]-L ₂ -[TNF]-X(n)
[Nb]-L ₁ -[TNF]-L ₂ -[SA]-X(n)
[SA]-L ₁ -[TNF]-L ₂ -[Nb]-X(n)
[SA]-L ₁ -[Nb]-L ₂ -[TNF]-X(n)
[TNF]-L ₁ -[TNF]-L ₂ -[Nb]-L ₃ -[SA]-X(n)
[Nb]-L ₁ -[TNF]-L ₂ -[TNF]-L ₃ -[SA]-X(n)
[SA]-L ₁ -[TNF]-L ₂ -[TNF]-L ₃ -[Nb]-X(n)
[SA]-L ₁ -[TNF]-L ₂ -[Nb]-L ₃ -[TNF]-X(n)
[TNF]-L ₁ -[Nb]-L ₂ -[TNF]-L ₃ -[SA]-X(n) at least one of [TNF]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below)

Designations

- [SA] means an anti-serum albumin (human) ISV, preferably an anti-serum albumin (human) ISV of the invention, more preferably of SEQ ID NOs: 46 or 61, and even more preferably one of the inventive ISVDs of SEQ ID NOs: 47 , 54, 62, 69, 78, 86, 109, 116, 123, 130 or 496-513.

- Each of L ₁ , L ₂ and L ₃ (independently) means a corresponding linker. Each of L ₁ , L ₂ and L ₃ may (independently) be present or absent. Non-limiting examples of suitable linkers are the Gly-Ser linkers provided herein, such as 9GS, 30GS or 35GS linkers.

- X(n) = C-terminal extension of the type described here and/or in WO 12/175741.

- [Nb] means ISV against another therapeutic target.

Notes

( ¹ ) In this table:

- “Monovalent” generally refers to polypeptides/constructs containing a single anti-TNF ISV. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- “Bivalent” generally refers to polypeptides/constructs containing two anti-TNF ISVs (which may be the same or different). They may also contain ISVs that prolong half-life (such as ISVs against serum albumin).

- “Bispecific” generally refers to polypeptides/constructs containing at least one (such as 1 or 2) ISV against TNF and at least one (such as 1 or 2) other ISV against a therapeutic target. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- In the polypeptides/constructs shown in this table, at least one of the anti-TNF ISVs is an ISV of the invention, and preferably all of the anti-TNF ISVs in such polypeptides/constructs are ISVs of the invention. And when such polypeptides/constructs contain an ISV that prolongs the half-life and/or an ISV against another therapeutic target, then each of them (and preferably all of them) can also be represented (and preferably all of them are represented) by the ISVs of the invention.

( ² ) All of the “bivalent” constructs in this table can also be biparatopic, meaning they can contain at least two (like 2) anti-TNF ISVs that are directed against different epitopes on TNF.

( ³ ) It will be appreciated by those skilled in the art that other/additional bispecific constructs than those given here can be made using the above units/blocks and linkers.

( ⁴ ) Preferably, each of [TNF] is selected independently from SEQ ID NOs: 464-477 and/or 482-495. In addition, the [TNF] data may be the same or different; and in biparatope polypeptides/constructs they must be directed against different epitopes on TNF.

( ⁵ ) Each of the polypeptides/constructs identified in this column by SEQ ID constitutes separate specific aspects of the invention.

Example 15 Anti-c- _Met VH domains (in particular nanobodies) and compounds of the invention containing them

In one particular aspect, the V _H domains of the invention (especially ISVDs
according to the invention and more preferably nanobodies according to the invention) and compounds according to the invention can be directed against c-Met.

Such anti-c-Met _VH domains of the invention typically contain: (i) suitable framework sequences which suitably include the amino acid residues/mutations of the invention as described herein; and (ii) CDR sequences that allow the V _H domains of the invention to specifically bind c-Met. In addition, such anti-c- _Met VH domains of the invention may also contain a C-terminal extension as described herein, in particular when the _VH domain is monovalent or forms the C-terminal end of the compound of the invention in which this V _H domain (again, as already described here). Such anti-c-Met _VH domains of the invention may also be as already described herein, in particular they may be ISVDs.

Again, as with other aspects and embodiments of the invention described herein, when a particular ISVD (such as the anti-c-Met ISVD described in this example) or a compound containing it is said to be “in accordance with the invention” or “as already described herein” , then the preferred aspects/embodiments and preferences generally described herein for the ISVDs or compounds of the invention are also definitely applicable to this particular ISVD or connection accordingly, unless expressly stated otherwise or unless the specific technical context requires otherwise.

Thus, in a preferred aspect, the present invention relates to V _H domains (especially ISVDs) directed against c-Met, which (i) have a K or Q at position 112; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) at position 89 is L and at position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). In particular, for such V _H domains against c-Met:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v).

The anti-c-Met _VH domains of the invention may also be as described herein, in particular again these may be anti-c-Met ISVDs (more preferably nanobodies) or proteins, polypeptides or other compounds or constructs that contain at least at least one such ISVD. Such proteins, polypeptides or other compounds or constructs may also be as already described herein and may have, for example, an increased half-life (i.e., as described herein, for example, half-life - expressed as t _½ -beta - in the human body for at least 1 day, preferably at least 3 days, more preferably at least 7 days, such as at least 10 days), and for this purpose may, for example, contain serum albumin binders nanobodies, which may also be serum albumin-binding nanobodies of the invention (again as described herein).

In addition, such ISVDs may suitably have a C-terminal extension (as already described here and in WO 12/175741), in particular where the ISVD forms the C-terminal end of the protein, polypeptide or other compound or construct containing it (again, as already described here).

In one preferred aspect, the anti-c-Met V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 353 (which is preferred) or such an amino acid sequence that differs by only one amino acid from the sequence of SEQ ID NO: 353 ; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 354 (which is preferred) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 354; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 355 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 355.

More preferably, the V _H domains of the invention against IL-23 according to this aspect: (i) CDR1 represented by SEQ ID NO: 353; (ii) CDR2 is represented by SEQ ID NO: 354; and (iii) CDR3 is represented by SEQ ID NO: 355.

In one particular aspect, the anti-c-Met nanobodies of the invention are variants of the nanobody of SEQ ID NO: 352 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 352 ), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). The CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

In another preferred aspect, the anti-c-Met V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 371 (preferably) or such an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: : 371; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 372 (which is preferred) or an amino acid sequence that differs by only one amino acid from the sequence of SEQ ID NO: 372; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 373 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 373.

More preferably, such _VH domains of the invention against c-Met in this aspect: (i) CDR1 is represented by SEQ ID NO: 371; (ii) CDR2 is represented by SEQ ID NO: 372; and (iii) CDR3 is represented by SEQ ID NO: 373.

In one particular aspect, the anti-c-Met nanobodies of the invention are variants of the nanobody of SEQ ID NO: 370 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 370 ), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). Again, the CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

Some particularly preferred, but not limited to, examples of such anti-IL-23 nanobodies of the invention are presented in FIG. 18A as SEQ ID NOs: 356-369 and FIG. 18B as SEQ ID NOs: 374-387, respectively; and each of these nanobodies forms another aspect of the invention.

The invention also provides anti-c-Met compounds of the invention that include at least one (such as one, two or three) nanobodies of the invention as defined in SEQ ID NOs: 356-369 and/or 374-387. Such anti-c-Met compounds of the invention may again be as already described herein and therefore, for example, may contain suitable linkers, may contain a C-terminal extension as described herein, and may have an extended half-life (e.g. because they contain an anti-human serum albumin nanobody, such as (preferably) the anti-human serum albumin nanobody of the invention). We refer you to the table below. Y.

As described, for example, in WO 2013/045707, one particularly preferred class of anti-c-Met nanobody compounds are biparatope compounds. Thus, in one aspect of the invention, the anti-c-Met compounds of the invention are biparatope constructs that contain a single ISV that has SEQ ID NO: 352 or (preferably) is an ISV of the invention that is derived from SEQ ID NO: 352 (as described in this Example 15), and one ISV that has SEQ ID NO: 370 or (preferably) is an ISV of the invention that was derived from SEQ ID NO: 370 (as described in this Example 15), provided that at least one (and preferably both) of these ISVs is an ISV according to the invention. Such biparatope constructs may also have an extended half-life (ie, via a serum albumin-binding ISV). Some specific examples of such biparatope designs are given in SEQ ID NOs: 676-693. In addition, anti-c-Met bispecific constructs may also include anti-VEGF or EGFR ISVs. Again, we refer to WO 2014/341309.

Some particularly preferred examples of the anti-c-Met compounds of the invention are presented in FIG. 28A and 28B as SEQ ID NOs: 676-694; and each of these compounds forms another aspect of the invention. Thus, in another aspect, the invention relates to polypeptides directed against c-Met and having an amino acid sequence selected from the group consisting of SEQ ID NOs: 676-694. More generally, the anti-c-Met compounds of the invention may be as described in WO 2013/045707, but contain the ISVs of the invention. They can also be used for the purposes described in WO 2013/045707.

Table Y. Examples of Anti-c-Met Compounds of the Invention

Polypeptide/construct( ¹ ) General formula ISV units/blocks and linkers Monovalent [c-Met] [c-Met] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with C-terminal extension [c-Met]-X(n) [c-Met] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with extended half-life [c-Met]-L ₁ -[SA]
[SA]-L ₁ -[c-Met] [c-Met] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below) Monovalent with extended half-life and C-terminal extension [c-Met]-L ₁ -[SA]-X(n)
[SA]-L ₁ -[c-Met]-X(n) [c-Met] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent( ² ) [c-Met]-L ₁ -[c-Met] at least one of [c-Met]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below) Bivalent with C-terminal extension ( ² ) [c-Met]-L ₁ -[c-Met]-X(n) at least one of [c-Met]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent with extended half-life ( ² ) [c-Met]-L ₁ -[c-Met]-L ₂ -[SA]
[c-Met]-L ₁ -[SA]-L ₂ -[c-Met]
[SA]-L ₁ -[c-Met]-L ₂ -[c-Met] at least one of [c-Met]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below) Bivalent with extended half-life and C-terminal extension ( ² ) [c-Met]-L ₁ -[c-Met]-L ₂ -[SA]-X(n)
[c-Met]-L ₁ -[SA]-L ₂ -[c-Met]-X(n)
[SA]-L ₁ -[c-Met]-L ₂ -[c-Met]-X(n) at least one of [c-Met]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below) Bispecific ( ³ ) [c-Met]-L ₁ -[Nb]
[Nb]-L ₁ -[c-Met]
[c-Met]-L ₁ -[c-Met]-L ₂ -[Nb]
[c-Met]-L ₁ -[Nb]-L ₂ -[c-Met]
[Nb]-L ₁ -[c-Met]-L ₂ -[c-Met] at least one of [c-Met]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
[Nb] = (see signature below) Bispecific with C-terminal extension ( ³ ) [c-Met]-L ₁ -[Nb]-X(n)
[Nb]-L ₁ -[c-Met]-X(n)
[c-Met]-L ₁ -[c-Met]-L ₂ -[Nb]-X(n)
[c-Met]-L ₁ -[Nb]-L ₂ -[c-Met]-X(n)
[Nb]-L ₁ -[c-Met]-L ₂ -[c-Met]-X(n) at least one of [c-Met]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life ( ³ ) [c-Met]-L ₁ -[Nb]-L ₂ -[SA]
[c-Met]-L ₁ -[SA]-L ₂ -[Nb]
[Nb]-L ₁ -[SA]-L ₂ -[c-Met]
[Nb]-L ₁ -[c-Met]-L ₂ -[SA]
[SA]-L ₁ -[c-Met]-L ₂ -[Nb]
[SA]-L ₁ -[Nb]-L ₂ -[c-Met]
[c-Met]-L ₁ -[c-Met]-L ₂ -[Nb]-L ₃ -[SA]
[Nb]-L ₁ -[c-Met]-L ₂ -[c-Met]-L ₃ -[SA]
[SA]-L ₁ -[c-Met]-L ₂ -[c-Met]-L ₃ -[Nb]
[SA]-L ₁ -[c-Met]-L ₂ -[Nb]-L ₃ -[c-Met]
[c-Met]-L ₁ -[Nb]-L ₂ -[c-Met]-L ₃ -[SA] at least one of [c-Met]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life and C-terminal extension ( ³ ) [c-Met]-L ₁ -[Nb]-L ₂ -[SA]-X(n)
[c-Met]-L ₁ -[SA]-L ₂ -[Nb]-X(n)
[Nb]-L ₁ -[SA]-L ₂ -[c-Met]-X(n)
[Nb]-L ₁ -[c-Met]-L ₂ -[SA]-X(n)
[SA]-L ₁ -[c-Met]-L ₂ -[Nb]-X(n)
[SA]-L ₁ -[Nb]-L ₂ -[c-Met]-X(n)
[c-Met]-L ₁ -[c-Met]-L ₂ -[Nb]-L ₃ -[SA]-X(n)
[Nb]-L ₁ -[c-Met]-L ₂ -[c-Met]-L ₃ -[SA]-X(n)
[SA]-L ₁ -[c-Met]-L ₂ -[c-Met]-L ₃ -[Nb]-X(n)
[SA]-L ₁ -[c-Met]-L ₂ -[Nb]-L ₃ -[c-Met]-X(n)
[c-Met]-L ₁ -[Nb]-L ₂ -[c-Met]-L ₃ -[SA]-X(n) at least one of [c-Met]
= one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below)

Designations

- [SA] means an anti-serum albumin (human) ISV, preferably an anti-serum albumin (human) ISV of the invention, more preferably of SEQ ID NOs: 46 or 61, and even more preferably one of the inventive ISVDs of SEQ ID NOs: 47 , 54, 62, 69, 78, 86, 109, 116, 123, 130 or 496-513.

- Each of L ₁ , L ₂ and L ₃ (independently) means a corresponding linker. Each of L ₁ , L ₂ and L ₃ may (independently) be present or absent. Non-limiting examples of suitable linkers are the Gly-Ser linkers provided herein, such as 9GS, 30GS or 35GS linkers.

- X(n) = C-terminal extension of the type described here and/or in WO 12/175741.

- [Nb] means ISV against another therapeutic target.

Notes

( ¹ ) In this table:

- “Monovalent” generally refers to polypeptides/constructs containing a single anti-c-Met ISV. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- “Bivalent” generally refers to polypeptides/constructs containing two anti-c-Met ISVs (which may be the same or different). They may also contain ISVs that prolong half-life (such as ISVs against serum albumin).

- “Bispecific” generally refers to polypeptides/constructs containing at least one (such as 1 or 2) ISV against c-Met and at least one (such as 1 or 2) other ISV against a therapeutic target. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- In the polypeptides/constructs shown in this table, at least one of the anti-c-Met ISVs is an ISV of the invention, and preferably all of the anti-c-Met ISVs in such polypeptides/constructs are ISVs of the invention. And when such polypeptides/constructs contain an ISV that prolongs the half-life and/or an ISV against another therapeutic target, then each of them (and preferably all of them) can also be represented (and preferably all of them are represented) by the ISVs of the invention.

( ² ) All of the “bivalent” constructs in this table can also be biparatopic, that is, they can contain at least two (like two) anti-c-Met ISVs that are directed against different epitopes on c-Met.

( ³ ) It will be appreciated by those skilled in the art that other/additional bispecific constructs than those given here can be made using the above units/blocks and linkers.

( ⁴ ) Preferably, each of [c-Met] is selected independently from SEQ ID NOs: 464-477 and/or 482-495. In addition, the [c-Met] data may be the same or different; and in biparatope polypeptides/constructs they must be directed against different epitopes on c-Met.

( ⁵ ) Each of the polypeptides/constructs identified in this column by SEQ ID constitutes separate specific aspects of the invention.

Example 16 Anti-RANK-L _VH domains (in particular nanobodies) and compounds of the invention containing them

In one particular aspect, the V _H domains of the invention (especially ISVDs
according to the invention and more preferably nanobodies according to the invention) and compounds according to the invention can be directed against RANK-L.

Such anti-RANK-L _VH domains of the invention typically contain: (i) suitable framework sequences which suitably include the amino acid residues/mutations of the invention as described herein; and (ii) CDR sequences that allow the V _H domains of the invention to specifically bind to RANK-L. In addition, such anti-RANK- _{L VH} domains of the invention may also contain a C-terminal extension as described herein, in particular when the _VH domain is monovalent or forms the C-terminal end of the compound of the invention in which this V _H domain (again, as already described here). Such anti-RANK-L _VH domains of the invention may also be as already described herein, in particular they may be ISVDs.

Again, as with other aspects and embodiments of the invention described herein, when a particular ISVD (such as the ISVD versus RANK-L described in this example) or a compound containing it is said to be “in accordance with the invention” or “as already described herein” , then the preferred aspects/embodiments and preferences generally described herein for the ISVDs or compounds of the invention are also definitely applicable to this particular ISVD or connection accordingly, unless expressly stated otherwise or unless the specific technical context requires otherwise.

Thus, in a preferred aspect, the present invention relates to V _H domains (especially ISVDs) directed against RANK-L, which (i) have a K or Q at position 112; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) at position 89 is L and at position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). In particular, for such V _H domains against RANK-L:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v).

The anti-RANK-L _VH domains of the invention may also be as described herein, in particular again these may be anti-RANK-L ISVDs (more preferably nanobodies) or proteins, polypeptides or other compounds or constructs that contain at least at least one such ISVD. Such proteins, polypeptides or other compounds or constructs may also be as already described herein and may have, for example, an increased half-life (i.e., as described herein, for example, half-life - expressed as t _½ -beta - in the human body for at least 1 day, preferably at least 3 days, more preferably at least 7 days, such as at least 10 days), and for this purpose may, for example, contain serum albumin binders nanobodies, which may also be serum albumin-binding nanobodies of the invention (again as described herein).

In addition, such ISVDs may suitably have a C-terminal extension (as already described here and in WO 12/175741), in particular where the ISVD forms the C-terminal end of the protein, polypeptide or other compound or construct containing it (again, as already described here).

In one preferred aspect, the anti-RANK-L V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 389 (preferably) or such an amino acid sequence that differs by only one amino acid from the sequence of SEQ ID NO: 389 ; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 390 (which is preferred) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 390; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 391 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 391.

More preferably, in the V _H domains of the invention against RANK-L according to this aspect: (i) CDR1 is represented by SEQ ID NO: 389; (ii) CDR2 is represented by SEQ ID NO: 390; and (iii) CDR3 is represented by SEQ ID NO: 391.

In one particular aspect, the anti-RANK-L nanobodies of the invention are variants of the nanobody of SEQ ID NO: 388 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 388 ), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). The CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

Some particularly preferred, but not limited to, examples of such anti-RANK-L nanobodies of the invention are presented in FIG. 19 as SEQ ID NOs: 392-405; and each of these nanobodies forms another aspect of the invention.

The invention also provides anti-RANK-L compounds of the invention that include at least one (such as one, two or three) nanobodies of the invention as defined in SEQ ID NOs: 392-405. Such anti-RANK-L compounds of the invention may again be as already described herein and therefore, for example, may contain suitable linkers, may contain a C-terminal extension as described herein, and may have an extended half-life (e.g. because they contain an anti-human serum albumin nanobody, such as (preferably) the anti-human serum albumin nanobody of the invention). We refer you to the table below. Z.

Some particularly preferred examples of the anti-RANK-L compounds of the invention are presented in FIG. 29 as SEQ ID NOs: 694-729; and each of these compounds forms another aspect of the invention. Thus, in another aspect, the invention relates to polypeptides directed against RANK-L and having an amino acid sequence selected from the group consisting of SEQ ID NOs: 694-729.

More generally, the anti-RANK-L compounds of the invention may be as described in WO 2008/142164, but contain the ISVs of the invention. They can also be used for the purposes described in WO 2008/142164.

Table Z. Examples of compounds of the invention against RANK-L

Polypeptide/construct( ¹ ) General formula ISV units/blocks and linkers Monovalent [RANK-L] [RANK-L] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with C-terminal extension [RANK-L]-X(n) [RANK-L] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with extended half-life [RANK-L]-L ₁ -[SA]
[SA]-L ₁ -[RANK-L] [RANK-L] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below) Monovalent with extended half-life and C-terminal extension [RANK-L]-L ₁ -[SA]-X(n)
[SA]-L ₁ -[RANK-L]-X(n) [RANK-L] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent( ² ) [RANK-L]-L ₁ -[RANK-L] at least one of [RANK-L] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below) Bivalent with C-terminal extension ( ² ) [RANK-L]-L ₁ -[RANK-L]-X(n) at least one of [RANK-L] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent with extended half-life ( ² ) [RANK-L]-L ₁ -[RANK-L]-L ₂ -[SA]
[RANK-L]-L ₁ -[SA]-L ₂ -[RANK-L]
[SA]-L ₁ -[RANK-L]-L ₂ -[RANK-L] at least one of [RANK-L] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below) Bivalent with extended half-life and C-terminal extension ( ² ) [RANK-L]-L ₁ -[RANK-L]-L ₂ -[SA]-X(n)
[RANK-L]-L ₁ -[SA]-L ₂ -[RANK-L]-X(n)
[SA]-L ₁ -[RANK-L]-L ₂ -[RANK-L]-X(n) at least one of [RANK-L] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below) Bispecific ( ³ ) [RANK-L]-L ₁ -[Nb]
[Nb]-L ₁ -[RANK-L]
[RANK-L]-L ₁ -[RANK-L]-L ₂ -[Nb]
[RANK-L]-L ₁ -[Nb]-L ₂ -[RANK-L]
[Nb]-L ₁ -[RANK-L]-L ₂ -[RANK-L] at least one of [RANK-L] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
[Nb] = (see signature below) Bispecific with C-terminal extension ( ³ ) [RANK-L]-L ₁ -[Nb]-X(n)
[Nb]-L ₁ -[RANK-L]-X(n)
[RANK-L]-L ₁ -[RANK-L]-L ₂ -[Nb]-X(n)
[RANK-L]-L ₁ -[Nb]-L ₂ -[RANK-L]-X(n)
[Nb]-L ₁ -[RANK-L]-L ₂ -[RANK-L]-X(n) at least one of [RANK-L] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life ( ³ ) [RANK-L]-L ₁ -[Nb]-L ₂ -[SA]
[RANK-L]-L ₁ -[SA]-L ₂ -[Nb]
[Nb]-L ₁ -[SA]-L ₂ -[RANK-L]
[Nb]-L ₁ -[RANK-L]-L ₂ -[SA]
[SA]-L ₁ -[RANK-L]-L ₂ -[Nb]
[SA]-L ₁ -[Nb]-L ₂ -[RANK-L]
[RANK-L]-L ₁ -[RANK-L]-L ₂ -[Nb]-L ₃ -[SA]
[Nb]-L ₁ -[RANK-L]-L ₂ -[RANK-L]-L ₃ -[SA]
[SA]-L ₁ -[RANK-L]-L ₂ -[RANK-L]-L ₃ -[Nb]
[SA]-L ₁ -[RANK-L]-L ₂ -[Nb]-L ₃ -[RANK-L]
[RANK-L]-L ₁ -[Nb]-L ₂ -[RANK-L]-L ₃ -[SA] at least one of [RANK-L] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life and C-terminal extension ( ³ ) [RANK-L]-L ₁ -[Nb]-L ₂ -[SA]-X(n)
[RANK-L]-L ₁ -[SA]-L ₂ -[Nb]-X(n)
[Nb]-L ₁ -[SA]-L ₂ -[RANK-L]-X(n)
[Nb]-L ₁ -[RANK-L]-L ₂ -[SA]-X(n)
[SA]-L ₁ -[RANK-L]-L ₂ -[Nb]-X(n)
[SA]-L ₁ -[Nb]-L ₂ -[RANK-L]-X(n)
[RANK-L]-L ₁ -[RANK-L]-L ₂ -[Nb]-L ₃ -[SA]-X(n)
[Nb]-L ₁ -[RANK-L]-L ₂ -[RANK-L]-L ₃ -[SA]-X(n)
[SA]-L ₁ -[RANK-L]-L ₂ -[RANK-L]-L ₃ -[Nb]-X(n)
[SA]-L ₁ -[RANK-L]-L ₂ -[Nb]-L ₃ -[RANK-L]-X(n)
[RANK-L]-L ₁ -[Nb]-L ₂ -[RANK-L]-L ₃ -[SA]-X(n) at least one of [RANK-L] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below)

Designations

- [SA] means an anti-serum albumin (human) ISV, preferably an anti-serum albumin (human) ISV of the invention, more preferably of SEQ ID NOs: 46 or 61, and even more preferably one of the inventive ISVDs of SEQ ID NOs: 47 , 54, 62, 69, 78, 86, 109, 116, 123, 130 or 496-513.

- Each of L ₁ , L ₂ and L ₃ (independently) means a corresponding linker. Each of L ₁ , L ₂ and L ₃ may (independently) be present or absent. Non-limiting examples of suitable linkers are the Gly-Ser linkers provided herein, such as 9GS, 30GS or 35GS linkers.

- X(n) = C-terminal extension of the type described here and/or in WO 12/175741.

- [Nb] means ISV against another therapeutic target.

Notes

( ¹ ) In this table:

- “Monovalent” generally refers to polypeptides/constructs containing a single ISV against RANK-L. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- “Bivalent” generally refers to polypeptides/constructs containing two anti-RANK-L ISVs (which may be the same or different). They may also contain ISVs that prolong half-life (such as ISVs against serum albumin).

- “Bispecific” generally refers to polypeptides/constructs containing at least one (such as 1 or 2) ISV against RANK-L and at least one (such as 1 or 2) other ISV against a therapeutic target. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- In the polypeptides/constructs shown in this table, at least one of the anti-RANK-L ISVs is an ISV of the invention, and preferably all of the anti-RANK-L ISVs in such polypeptides/constructs are ISVs of the invention. And when such polypeptides/constructs contain an ISV that prolongs the half-life and/or an ISV against another therapeutic target, then each of them (and preferably all of them) can also be represented (and preferably all of them are represented) by the ISVs of the invention.

( ² ) All “bivalent” constructs in this table can also be biparatopic, meaning they can contain at least two (like 2) anti-RANK-L ISVs that are directed against different epitopes on RANK-L.

( ³ ) It will be appreciated by those skilled in the art that other/additional bispecific constructs than those given here can be made using the above units/blocks and linkers.

( ⁴ ) Preferably, each of [RANK-L] is selected independently from SEQ ID NOs: 464-477 and/or 482-495. In addition, the [RANK-L] data may be the same or different; and in biparatope polypeptides/constructs they must be directed against different epitopes on RANK-L.

( ⁵ ) Each of the polypeptides/constructs identified in this column by SEQ ID constitutes separate specific aspects of the invention.

Example 17 Anti-CXCR-7 V _H domains (in particular nanobodies) and compounds of the invention containing them

In one particular aspect, the V _H domains of the invention (especially ISVDs
according to the invention and more preferably nanobodies according to the invention) and compounds according to the invention can be directed against CXCR-7.

Such anti-CXCR-7 V _H domains of the invention typically contain: (i) suitable framework sequences which suitably include the amino acid residues/mutations of the invention as described herein; and (ii) CDR sequences that allow the V _H domains of the invention to specifically bind to CXCR-7. In addition, such anti-CXCR-7 V _H domains of the invention may also contain a C-terminal extension as described herein, in particular when the V _H domain is monovalent or forms the C-terminal end of the compound of the invention in which the given V H domain is located. V _H domain (again, as already described here). Such anti-CXCR-7 _VH domains of the invention may also be as already described herein, in particular they may be ISVDs.

Again, as with other aspects and embodiments of the invention described herein, when a particular ISVD (such as the anti-CXCR-7 ISVD described in this example) or a compound containing it is said to be “in accordance with the invention” or “as already described herein” , then the preferred aspects/embodiments and preferences generally described herein for the ISVDs or compounds of the invention are also definitely applicable to this particular ISVD or connection accordingly, unless expressly stated otherwise or unless the specific technical context requires otherwise.

Thus, in a preferred aspect, the present invention relates to V _H domains (especially ISVDs) directed against CXCR-7, which (i) have a K or Q at position 112; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) at position 89 is L and at position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). In particular, such V _H domains against CXCR-7:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v).

The anti-CXCR-7 V _H domains of the invention may also be as described herein, in particular again these may be anti-CXCR-7 ISVDs (more preferably nanobodies) or proteins, polypeptides or other compounds or constructs that contain at least at least one such ISVD. Such proteins, polypeptides or other compounds or constructs may also be as already described herein and may have, for example, an increased half-life (i.e., as described herein, for example, half-life - expressed as t _½ -beta - in the human body for at least 1 day, preferably at least 3 days, more preferably at least 7 days, such as at least 10 days), and for this purpose may, for example, contain serum albumin binders nanobodies, which may also be serum albumin-binding nanobodies of the invention (again as described herein).

In addition, such ISVDs may suitably have a C-terminal extension (as already described here and in WO 12/175741), in particular where the ISVD forms the C-terminal end of the protein, polypeptide or other compound or construct containing it (again, as already described here).

In one preferred aspect, the anti-CXCR-7 V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 407 (preferably) or such an amino acid sequence that differs by only one amino acid from the sequence of SEQ ID NO: 407 ; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 408 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 408; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 409 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 409.

More preferably, the V _H domains of the invention against CXCR-7 according to this aspect: (i) CDR1 represented by SEQ ID NO: 407; (ii) CDR2 is represented by SEQ ID NO: 408; and (iii) CDR3 is represented by SEQ ID NO: 409.

In one particular aspect, the anti-CXCR-7 nanobodies of the invention are variants of the nanobody of SEQ ID NO: 406 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 406 ), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). The CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

In another preferred aspect, the anti-CXCR-7 V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 425 (which is preferred) or such an amino acid sequence that differs by only one amino acid from the sequence of SEQ ID NO: 425 ; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 426 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 426; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 427 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 427.

More preferably, in the V _H domains of the invention against CXCR-7 according to this aspect: (i) CDR1 is represented by SEQ ID NO: 425; (ii) CDR2 is represented by SEQ ID NO: 426; and (iii) CDR3 is represented by SEQ ID NO: 427.

In one particular aspect, the anti-CXCR-7 nanobodies of the invention are variants of the nanobody of SEQ ID NO: 424 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 424 ), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). Again, the CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

Some particularly preferred, but not limited to, examples of such anti-CXCR-7 nanobodies of the invention are presented in FIG. 20A as SEQ ID NOs: 410-423 and FIG. 20B as SEQ ID NOs: 428-441; and each of these nanobodies forms another aspect of the invention.

The invention also provides anti-CXCR-7 compounds of the invention that include at least one (such as one, two or three) nanobodies of the invention as defined in SEQ ID NOs: 410-423 and/or 428-441. Such anti-CXCR-7 compounds of the invention may again be as already described herein and therefore, for example, may contain suitable linkers, may contain a C-terminal extension as described herein, and may have an extended half-life (e.g. because they contain an anti-human serum albumin nanobody, such as (preferably) the anti-human serum albumin nanobody of the invention). We refer you to the table below. AA.

As described, for example, in WO 2012/130874, one particularly preferred class of anti-CXCR-7 nanobody compounds are biparatope compounds. Thus, in one aspect of the invention, the anti-CXCR-7 compounds of the invention are biparatope constructs that contain a single ISV that has SEQ ID NO: 406 or (preferably) is an ISV of the invention that is derived from SEQ ID NO: 406 (as described in this Example 17), and one ISV that has SEQ ID NO: 424 or (preferably) is an ISV of the invention that was derived from SEQ ID NO: 424 (as described in this Example 17), provided that at least one (and preferably both) of these ISVs is an ISV according to the invention. Such biparatope constructs may also have an extended half-life (ie, via a serum albumin-binding ISV).

More generally, the anti-CXCR-7 compounds of the invention may be as described in WO 2012/130874, but contain the ISVs of the invention. They can also be used for the purposes described in WO 2012/130874.

Table AA. Examples of Anti-CXCR-7 Compounds of the Invention

Polypeptide/construct( ¹ ) General formula ISV units/blocks and linkers Monovalent [CXCR-7] [CXCR-7] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with C-terminal extension [CXCR-7]-X(n) [CXCR-7] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with extended half-life [CXCR-7]-L ₁ -[SA]
[SA]-L ₁ -[CXCR-7] [CXCR-7] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below) Monovalent with extended half-life and C-terminal extension [CXCR-7]-L ₁ -[SA]-X(n)
[SA]-L ₁ -[CXCR-7]-X(n) [CXCR-7] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent( ² ) [CXCR-7]-L ₁ -[CXCR-7] at least one of [CXCR-7] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below) Bivalent with C-terminal extension ( ² ) [CXCR-7]-L ₁ -[CXCR-7]-X(n) at least one of [CXCR-7] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent with extended half-life ( ² ) [CXCR-7]-L ₁ -[CXCR-7]-L ₂ -[SA]
[CXCR-7]-L ₁ -[SA]-L ₂ -[CXCR-7]
[SA]-L ₁ -[CXCR-7]-L ₂ -[CXCR-7] at least one of [CXCR-7] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below) Bivalent with extended half-life and C-terminal extension ( ² ) [CXCR-7]-L ₁ -[CXCR-7]-L ₂ -[SA]-X(n)
[CXCR-7]-L ₁ -[SA]-L ₂ -[CXCR-7]-X(n)
[SA]-L ₁ -[CXCR-7]-L ₂ -[CXCR-7]-X(n) at least one of [CXCR-7] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below) Bispecific ( ³ ) [CXCR-7]-L ₁ -[Nb]
[Nb]-L ₁ -[CXCR-7]
[CXCR-7]-L ₁ -[CXCR-7]-L ₂ -[Nb]
[CXCR-7]-L ₁ -[Nb]-L ₂ -[CXCR-7]
[Nb]-L ₁ -[CXCR-7]-L ₂ -[CXCR-7] at least one of [CXCR-7] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
[Nb] = (see signature below) Bispecific with C-terminal extension ( ³ ) [CXCR-7]-L ₁ -[Nb]-X(n)
[Nb]-L ₁ -[CXCR-7]-X(n)
[CXCR-7]-L ₁ -[CXCR-7]-L ₂ -[Nb]-X(n)
[CXCR-7]-L ₁ -[Nb]-L ₂ -[CXCR-7]-X(n)
[Nb]-L ₁ -[CXCR-7]-L ₂ -[CXCR-7]-X(n) at least one of [CXCR-7] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life ( ³ ) [CXCR-7]-L ₁ -[Nb]-L ₂ -[SA]
[CXCR-7]-L ₁ -[SA]-L ₂ -[Nb]
[Nb]-L ₁ -[SA]-L ₂ -[CXCR-7]
[Nb]-L ₁ -[CXCR-7]-L ₂ -[SA]
[SA]-L ₁ -[CXCR-7]-L ₂ -[Nb]
[SA]-L ₁ -[Nb]-L ₂ -[CXCR-7]
[CXCR-7]-L ₁ -[CXCR-7]-L ₂ -[Nb]-L ₃ -[SA]
[Nb]-L ₁ -[CXCR-7]-L ₂ -[CXCR-7]-L ₃ -[SA]
[SA]-L ₁ -[CXCR-7]-L ₂ -[CXCR-7]-L ₃ -[Nb]
[SA]-L ₁ -[CXCR-7]-L ₂ -[Nb]-L ₃ -[CXCR-7]
[CXCR-7]-L ₁ -[Nb]-L ₂ -[CXCR-7]-L ₃ -[SA] at least one of [CXCR-7] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life and C-terminal extension ( ³ ) [CXCR-7]-L ₁ -[Nb]-L ₂ -[SA]-X(n)
[CXCR-7]-L ₁ -[SA]-L ₂ -[Nb]-X(n)
[Nb]-L ₁ -[SA]-L ₂ -[CXCR-7]-X(n)
[Nb]-L ₁ -[CXCR-7]-L ₂ -[SA]-X(n)
[SA]-L ₁ -[CXCR-7]-L ₂ -[Nb]-X(n)
[SA]-L ₁ -[Nb]-L ₂ -[CXCR-7]-X(n)
[CXCR-7]-L ₁ -[CXCR-7]-L ₂ -[Nb]-L ₃ -[SA]-X(n)
[Nb]-L ₁ -[CXCR-7]-L ₂ -[CXCR-7]-L ₃ -[SA]-X(n)
[SA]-L ₁ -[CXCR-7]-L ₂ -[CXCR-7]-L ₃ -[Nb]-X(n)
[SA]-L ₁ -[CXCR-7]-L ₂ -[Nb]-L ₃ -[CXCR-7]-X(n)
[CXCR-7]-L ₁ -[Nb]-L ₂ -[CXCR-7]-L ₃ -[SA]-X(n) at least one of [CXCR-7] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below)

Designations

- [SA] means an anti-serum albumin (human) ISV, preferably an anti-serum albumin (human) ISV of the invention, more preferably of SEQ ID NOs: 46 or 61, and even more preferably one of the inventive ISVDs of SEQ ID NOs: 47 , 54, 62, 69, 78, 86, 109, 116, 123, 130 or 496-513.

- Each of L ₁ , L ₂ and L ₃ (independently) means a corresponding linker. Each of L ₁ , L ₂ and L ₃ may (independently) be present or absent. Non-limiting examples of suitable linkers are the Gly-Ser linkers provided herein, such as 9GS, 30GS or 35GS linkers.

- X(n) = C-terminal extension of the type described here and/or in WO 12/175741.

- [Nb] means ISV against another therapeutic target.

Notes

( ¹ ) In this table:

- “Monovalent” generally refers to polypeptides/constructs containing a single ISV against CXCR-7. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- “Bivalent” generally refers to polypeptides/constructs containing two anti-CXCR-7 ISVs (which may be the same or different). They may also contain ISVs that prolong half-life (such as ISVs against serum albumin).

- “Bispecific” generally refers to polypeptides/constructs containing at least one (such as 1 or 2) ISV against CXCR-7 and at least one (such as 1 or 2) other ISV against a therapeutic target. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- In the polypeptides/constructs shown in this table, at least one of the anti-CXCR-7 ISVs is an ISV of the invention, and preferably all of the anti-CXCR-7 ISVs in such polypeptides/constructs are ISVs of the invention. And when such polypeptides/constructs contain an ISV that prolongs the half-life and/or an ISV against another therapeutic target, then each of them (and preferably all of them) can also be represented (and preferably all of them are represented) by the ISVs of the invention.

( ² ) All of the “bivalent” constructs in this table can also be biparatopic, meaning they can contain at least two (like 2) anti-CXCR-7 ISVs that are directed against different epitopes on CXCR-7.

( ³ ) It will be appreciated by those skilled in the art that other/additional bispecific constructs than those given here can be made using the above units/blocks and linkers.

( ⁴ ) Preferably, each of [CXCR-7] is independently selected from SEQ ID NOs: 464-477 and/or 482-495. In addition, the [CXCR-7] data may be the same or different; and in biparatope polypeptides/constructs they must be directed against different epitopes on CXCR-7.

( ⁵ ) Each of the polypeptides/constructs identified in this column by SEQ ID constitutes separate specific aspects of the invention.

Example 18 Anti-A-beta _VH domains (in particular nanobodies) and compounds of the invention containing them

In one particular aspect, the V _H domains of the invention (especially the ISVDs of the invention and more preferably the nanobodies of the invention) and compounds of the invention can be directed against A-beta.

Such anti-Abeta _VH domains of the invention typically contain: (i) suitable framework sequences which suitably include the amino acid residues/mutations of the invention as described herein; and (ii) CDR sequences that allow the V _H domains of the invention to specifically bind to A-beta. In addition, such anti-Abeta V _H domains of the invention may also contain a C-terminal extension as described herein, in particular when the V _H domain is monovalent or forms the C-terminal end of the compound of the invention in which the given V H domain is located. V _H domain (again, as already described here). Such anti-Abeta _VH domains of the invention may also be those already described herein, in particular they may be ISVDs.

Again, as with other aspects and embodiments of the invention described herein, when a particular ISVD (such as the anti-A-beta ISVD described in this example) or a compound containing it is said to be “in accordance with the invention” or “as already described herein” , then the preferred aspects/embodiments and preferences generally described herein for the ISVDs or compounds of the invention are also definitely applicable to this particular ISVD or connection accordingly, unless expressly stated otherwise or unless the specific technical context requires otherwise.

Thus, in a preferred aspect, the present invention relates to V _H domains (especially ISVDs) directed against A-beta, which (i) have a K or Q at position 112; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) at position 89 is L and at position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). In particular, in such V _H domains against A-beta:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v).

The anti-A-beta _VH domains of the invention may also be as described herein, in particular again these may be anti-A-beta ISVDs (more preferably nanobodies) or proteins, polypeptides or other compounds or constructs that contain at least at least one such ISVD. Such proteins, polypeptides or other compounds or constructs may also be as already described herein and may have, for example, an increased half-life (i.e., as described herein, for example, half-life - expressed as t _½ -beta - in the human body for at least 1 day, preferably at least 3 days, more preferably at least 7 days, such as at least 10 days), and for this purpose may, for example, contain serum albumin binders nanobodies, which may also be serum albumin-binding nanobodies of the invention (again as described herein).

In addition, such ISVDs may suitably have a C-terminal extension (as already described here and in WO 12/175741), in particular where the ISVD forms the C-terminal end of the protein, polypeptide or other compound or construct containing it (again, as already described here).

In one preferred aspect, the anti-Abeta V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 461 (preferably) or such an amino acid sequence that differs by only one amino acid from the sequence of SEQ ID NO: 461 ; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 462 (which is preferred) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 462; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 463 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 463.

More preferably, in the anti-A-beta V _H domains of the invention according to this aspect: (i) CDR1 is represented by SEQ ID NO: 461; (ii) CDR2 is represented by SEQ ID NO: 462; and (iii) CDR3 is represented by SEQ ID NO: 463.

In one particular aspect, the anti-A-beta nanobodies of the invention are variants of the nanobody of SEQ ID NO: 460 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 460 ), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). The CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

In another preferred aspect, the anti-Abeta V _H domains of the invention include (i) a CDR1 sequence that has the sequence of SEQ ID NO: 479 (preferably) or such an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 479 : 479; (ii) a CDR2 sequence that has the sequence of SEQ ID NO: 480 (which is preferred) or such an amino acid sequence that differs in only one amino acid from the sequence of SEQ ID NO: 480; and (iii) a CDR3 sequence that has the sequence of SEQ ID NO: 481 (preferably) or an amino acid sequence that differs in only one or two amino acids from the sequence of SEQ ID NO: 481.

More preferably, in the anti-A-beta V _H domains of the invention according to this aspect: (i) CDR1 is represented by SEQ ID NO: 479; (ii) CDR2 is represented by SEQ ID NO: 480; and (iii) CDR3 is represented by SEQ ID NO: 481.

In one particular aspect, the anti-Abeta nanobodies of the invention are variants of the nanobody of SEQ ID NO: 478 (and are at least 90% sequence identical, such as at least 95% sequence identical to SEQ ID NO: 478 ), which:

- the amino acid residue at position 11 is preferably selected from L, V and K (most preferably V);

- the amino acid residue at position 14 is preferably selected from A and P;

- the amino acid residue at position 41 is preferably selected from A and P;

- the amino acid residue at position 89 is preferably selected from T, V and L;

- the amino acid residue at position 108 is preferably selected from Q and L;

- the amino acid residue at position 110 is preferably selected from T, K and Q;

- the amino acid residue at position 112 is preferably selected from S, K and Q;

so that either (i) position 112 is K or Q; or (ii) at position 110 is K or Q and at position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). Again, the CDR regions of such ISVs are preferably as defined in the previous two paragraphs.

Some particularly preferred, but not limited to, examples of such anti-A-beta nanobodies of the invention are presented in FIG. 21A as SEQ ID NOs: 464-477 and FIG. 21B as SEQ ID NOs: 482-495, respectively; and each of these nanobodies forms another aspect of the invention.

The invention also provides anti-A-beta compounds of the invention that include at least one (such as one, two or three) nanobodies of the invention as defined in SEQ ID NOs: 464-477 and/or 482-495. Such anti-A-beta compounds of the invention may again be as already described herein and therefore, for example, may contain suitable linkers, may contain a C-terminal extension as described herein, and may have an extended half-life (e.g. because they contain an anti-human serum albumin nanobody, such as (preferably) the anti-human serum albumin nanobody of the invention). We refer you to the table below. V.

As described, for example, in WO 2006/040153, and in particular as described in EP 2542579, one particularly preferred class of nanobody-based anti-A-beta compounds are biparatope compounds. Thus, in one aspect of the invention, the anti-A-beta compounds of the invention are biparatope constructs that contain a single ISV that has SEQ ID NO: 460 or (preferably) is an ISV of the invention that is derived from SEQ ID NO: 460 (as described in this Example 18), and one ISV that has SEQ ID NO: 478 or (preferably) is an ISV of the invention that was derived from SEQ ID NO: 478 (as described in this Example 18), provided that at least one (and preferably both) of these ISVs is an ISV according to the invention. Such biparatope constructs may also have an extended half-life (ie, via a serum albumin-binding ISV). Some specific examples of such biparatope designs are provided in SEQ ID NOs: 730-766.

Some particularly preferred examples of anti-A-beta compounds of the invention are presented in FIG. 30 as SEQ ID NOs: 730-766; and each of these compounds forms another aspect of the invention. Thus, in another aspect, the invention relates to polypeptides directed against A-beta and having an amino acid sequence selected from the group consisting of SEQ ID NOs: 730-766. More generally, the anti-A-beta compounds of the invention may be as described in WO 2006/040153, and in particular as described in EP 2542579, but contain the ISVs of the invention. They can also be used for the purposes described in WO 2006/040153 and in particular in EP 2542579.

Table BB. Examples of Anti-A-beta Compounds of the Invention

Polypeptide/construct( ¹ ) General formula ISV units/blocks and linkers Monovalent [A-beta] [A-beta] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with C-terminal extension [A-beta]-X(n) [A-beta] = one of SEQ ID NOs: 464-477 and/or 482-495 Monovalent with extended half-life [A-beta]-L ₁ -[SA]
[SA]-L ₁ -[A-beta] [A-beta] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below) Monovalent with extended half-life and C-terminal extension [A-beta]-L ₁ -[SA]-X(n)
[SA]-L ₁ -[A-beta]-X(n) [A-beta] = one of SEQ ID NOs: 464-477 and/or 482-495
[SA] = (see signature below)
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent( ² ) [A-beta]-L ₁ -[A-beta] at least one of [A-beta] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below) Bivalent with C-terminal extension ( ² ) [A-beta]-L ₁ -[A-beta]-X(n) at least one of [A-beta] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
X(n) = (see signature below) Bivalent with extended half-life ( ² ) [A-beta]-L ₁ -[A-beta]-L ₂ -[SA]
[A-beta]-L ₁ -[SA]-L ₂ -[A-beta]
[SA]-L ₁ -[A-beta]-L ₂ -[A-beta] at least one of [A-beta] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below) Bivalent with extended half-life and C-terminal extension ( ² ) [A-beta]-L ₁ -[A-beta]-L ₂ -[SA]-X(n)
[A-beta]-L ₁ -[SA]-L ₂ -[A-beta]-X(n)
[SA]-L ₁ -[A-beta]-L ₂ -[A-beta]-X(n) at least one of [A-beta] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below) Bispecific ( ³ ) [A-beta]-L ₁ -[Nb]
[Nb]-L ₁ -[A-beta]
[A-beta]-L ₁ -[A-beta]-L ₂ -[Nb]
[A-beta]-L ₁ -[Nb]-L ₂ -[A-beta]
[Nb]-L ₁ -[A-beta]-L ₂ -[A-beta] at least one of [A-beta] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
[Nb] = (see signature below) Bispecific with C-terminal extension ( ³ ) [A-beta]-L ₁ -[Nb]-X(n)
[Nb]-L ₁ -[A-beta]-X(n)
[A-beta]-L ₁ -[A-beta]-L ₂ -[Nb]-X(n)
[A-beta]-L ₁ -[Nb]-L ₂ -[A-beta]-X(n)
[Nb]-L ₁ -[A-beta]-L ₂ -[A-beta]-X(n) at least one of [A-beta] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
L ₁ = (see signature below)
L ₂ = (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life ( ³ ) [A-beta]-L ₁ -[Nb]-L ₂ -[SA]
[A-beta]-L ₁ -[SA]-L ₂ -[Nb]
[Nb]-L ₁ -[SA]-L ₂ -[A-beta]
[Nb]-L ₁ -[A-beta]-L ₂ -[SA]
[SA]-L ₁ -[A-beta]-L ₂ -[Nb]
[SA]-L ₁ -[Nb]-L ₂ -[A-beta]
[A-beta]-L ₁ -[A-beta]-L ₂ -[Nb]-L ₃ -[SA]
[Nb]-L ₁ -[A-beta]-L ₂ -[A-beta]-L ₃ -[SA]
[SA]-L ₁ -[A-beta]-L ₂ -[A-beta]-L ₃ -[Nb]
[SA]-L ₁ -[A-beta]-L ₂ -[Nb]-L ₃ -[A-beta]
[A-beta]-L ₁ -[Nb]-L ₂ -[A-beta]-L ₃ -[SA] at least one of [A-beta] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
[Nb] = (see signature below) Bispecific with extended half-life and C-terminal extension ( ³ ) [A-beta]-L ₁ -[Nb]-L ₂ -[SA]-X(n)
[A-beta]-L ₁ -[SA]-L ₂ -[Nb]-X(n)
[Nb]-L ₁ -[SA]-L ₂ -[A-beta]-X(n)
[Nb]-L ₁ -[A-beta]-L ₂ -[SA]-X(n)
[SA]-L ₁ -[A-beta]-L ₂ -[Nb]-X(n)
[SA]-L ₁ -[Nb]-L ₂ -[A-beta]-X(n)
[A-beta]-L ₁ -[A-beta]-L ₂ -[Nb]-L ₃ -[SA]-X(n)
[Nb]-L ₁ -[A-beta]-L ₂ -[A-beta]-L ₃ -[SA]-X(n)
[SA]-L ₁ -[A-beta]-L ₂ -[A-beta]-L ₃ -[Nb]-X(n)
[SA]-L ₁ -[A-beta]-L ₂ -[Nb]-L ₃ -[A-beta]-X(n)
[A-beta]-L ₁ -[Nb]-L ₂ -[A-beta]-L ₃ -[SA]-X(n) at least one of [A-beta] = one of SEQ ID NOs: 464-477 and/or 482-495 ( ⁴ )
[SA] = (see signature below)
L ₁ , L ₂ , L ₃ (see signature below)
X(n) = (see signature below)
[Nb] = (see signature below)

Designations

- [SA] means an anti-serum albumin (human) ISV, preferably an anti-serum albumin (human) ISV of the invention, more preferably of SEQ ID NOs: 46 or 61, and even more preferably one of the inventive ISVDs of SEQ ID NOs: 47 , 54, 62, 69, 78, 86, 109, 116, 123, 130 or 496-513.

- Each of L ₁ , L ₂ and L ₃ (independently) means a corresponding linker. Each of L ₁ , L ₂ and L ₃ may (independently) be present or absent. Non-limiting examples of suitable linkers are the Gly-Ser linkers provided herein, such as 9GS, 30GS or 35GS linkers.

- X(n) = C-terminal extension of the type described here and/or in WO 12/175741.

- [Nb] means ISV against another therapeutic target.

Notes

( ¹ ) In this table:

- “Monovalent” generally refers to polypeptides/constructs containing a single ISV against A-beta. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- “Bivalent” generally refers to polypeptides/constructs containing two anti-A-beta ISVs (which may be the same or different). They may also contain ISVs that prolong half-life (such as ISVs against serum albumin).

- “Bispecific” generally refers to polypeptides/constructs containing at least one (such as 1 or 2) ISV against A-beta and at least one (such as 1 or 2) other ISV against a therapeutic target. They may also contain ISVs that prolong half-life (such as anti-serum albumin ISVs).

- In the polypeptides/constructs shown in this table, at least one of the anti-A-beta ISVs is an ISV of the invention, and preferably all of the anti-A-beta ISVs in such polypeptides/constructs are ISVs of the invention. And when such polypeptides/constructs contain an ISV that prolongs the half-life and/or an ISV against another therapeutic target, then each of them (and preferably all of them) can also be represented (and preferably all of them are represented) by the ISVs of the invention.

( ² ) All “bivalent” constructs in this table can also be biparatopic, that is, they can contain at least two (like 2) anti-A-beta ISVs that are directed against different epitopes on A-beta.

( ³ ) It will be appreciated by those skilled in the art that other/additional bispecific constructs than those given here can be made using the above units/blocks and linkers.

( ⁴ ) Preferably, each of [A-beta] is selected independently from SEQ ID NOs: 464-477 and/or 482-495. In addition, the [A-beta] data may be the same or different; and in biparatopic polypeptides/constructs they must be directed against different epitopes on A-beta.

( ⁵ ) Each of the polypeptides/constructs identified in this column by SEQ ID constitutes separate specific aspects of the invention.

Example 19: Testing Anti-Abeta Constructs for Binding to Preexisting Antibodies

Three extended half-life anti-A-beta constructs (using the general formula [A-beta-1]-9GS-ALB8-9GS-[A-beta-2]-A) were tested and compared for binding to preexisting antibodies using the general formula described herein. methodology. Two of the inventive constructs had the inventive mutations specified in all three units/blocks (ie, the two anti-A-beta nanobodies and the serum albumin-binding nanobody). The control construct (SEQ ID NO: 766) did not have mutations of the invention in any of the units/blocks. All tested constructs contained a C-terminal alanine. The results are presented in table. CC-1 and Fig. 31A.

Table CC-1. Testing anti-A-beta constructs for binding to pre-existing antibodies

Nanobody under testing
on 92 samples (healthy individuals) Fig. number 31A Binding level after 125 sec < 10 RU Binding level after 125 sec < 20 RU Binding level after 125 sec > 20 RU SEQ ID NO: 766 (control) (1) 0 1 91 SEQ ID NO: 733 (invention: L11V + V89L) (2) eleven 41 51 SEQ ID NO: 749 (Invention: L11V + V89L + T110K) (3) 16 56 36

Anti-A-beta nanobodies that were present at the C-terminal end of the constructs were also tested separately as monovalent constructs (with a C-terminal alanine). The results are presented in table. CC-2 and Fig. 31A.

Table CC-2. Testing monovalent anti-A-beta nanobodies for binding to pre-existing antibodies

Nanobody under testing
on 145 samples (healthy individuals) Fig. number 31A Binding level after 125 sec < 10 RU Binding level after 125 sec < 20 RU Binding level after 125 sec > 20 RU SEQ ID NO: 478 (control) (*) (1) 67 87 58 SEQ ID NO: 489 (invention: L11V + V89L) (*) (2) 74 103 42 SEQ ID NO: 490 (by invention: L11V + V89L + T110K) (*) (3) 116 138 7

(*) All 3 monovalent nanobodies contained the addition of a C-terminal alanine

Example 20: Overview of Serum Albumin Binding Nanobodies of the Invention

The following Tables DD and EE present some preferred, but not limited to, examples of serum albumin binding nanobodies of the invention based on Alb-8 (Table DD) and Alb-23 (Table EE), respectively.

As already noted, the invention also relates to polypeptides, proteins, compounds or constructs (in particular, compounds of the invention) containing one of the serum albumin binding nanobodies listed below in table. DD or EE. Such polypeptides, proteins, compounds or constructs (especially the compounds of the invention) may further comprise at least one (such as one, two or three) binding domain or binding block (such as an ISVD, especially the ISV of the invention) directed against at least one therapeutic target. Again, such polypeptides, proteins, compounds or constructs may respectively be monospecific, bispecific or trispecific with respect to therapeutic targets and may be bivalent, trivalent, tetravalent or higher valency. Typically they also contain suitable linkers and may contain a C-terminal extension as described here.

In particular, such polypeptides, proteins, compounds or constructs may be compounds of the invention (as described herein) and/or may be as already described herein for compounds of the invention (including preferred embodiments for compounds of the invention, with particularly preferred compounds containing ISVDs and especially nanobodies). Accordingly, compounds of the invention containing one of the serum albumin binding nanobodies listed in Table DD or EE constitute additional aspects of the invention.

--->

LIST OF SEQUENCES

<110> Ablynx NV

<120> Improved Immunoglobulin Variable Domains

<130> 180970

<140> PCT/EP2015/060643

<141> 2015-05-13

<150> US 61/994552

<151> 2014-05-16

<150> US 61/014015

<151> 2014-06-18

<150> US 62/040167

<151> 2014-08-21

<150> US 62/047560

<151> 2014-09-08

<150> US 62/133600

<151> 2015-03-16

<160> 766

<170> Patent In version 3.5

<210> 1

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> C-terminal amino acid sequence

<400> 1

Val Thr Val Lys Ser

15

<210> 2

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> C-terminal amino acid sequence

<400> 2

Val Thr Val Gln Ser

15

<210> 3

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 3

Trp Gly Gln Gly Thr Gln Val Thr Val Lys Ser

1 5 10

<210> 4

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 4

Trp Gly Lys Gly Thr Leu Val Thr Val Lys Ser

1 5 10

<210> 5

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 5

Arg Gly Gln Gly Thr Arg Val Thr Val Lys Ser

1 5 10

<210> 6

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 6

Trp Gly Leu Gly Thr Gln Val Thr Ile Ser Ser

1 5 10

<210> 7

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 7

Gly Ser Gln Gly Thr Gln Val Thr Val Lys Ser

1 5 10

<210> 8

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 8

Leu Arg Gly Gly Thr Gln Val Thr Val Lys Ser

1 5 10

<210> 9

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 9

Arg Gly Gln Gly Thr Leu Val Thr Val Lys Ser

1 5 10

<210> 10

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 10

Arg Ser Arg Gly Ile Gln Val Thr Val Lys Ser

1 5 10

<210> 11

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 11

Trp Gly Lys Gly Thr Gln Val Thr Val Lys Ser

1 5 10

<210> 12

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 12

Trp Gly Gln Gly Thr Gln Val Thr Val Gln Ser

1 5 10

<210> 13

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 13

Trp Gly Lys Gly Thr Leu Val Thr Val Gln Ser

1 5 10

<210> 14

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 14

Arg Gly Gln Gly Thr Arg Val Thr Val Gln Ser

1 5 10

<210> 15

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 15

Trp Gly Leu Gly Thr Gln Val Thr Ile Ser Ser

1 5 10

<210> 16

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 16

Gly Ser Gln Gly Thr Gln Val Thr Val Gln Ser

1 5 10

<210> 17

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 17

Leu Arg Gly Gly Thr Gln Val Thr Val Gln Ser

1 5 10

<210> 18

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 18

Arg Gly Gln Gly Thr Leu Val Thr Val Gln Ser

1 5 10

<210> 19

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 19

Arg Ser Arg Gly Ile Gln Val Thr Val Gln Ser

1 5 10

<210> 20

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 20

Trp Gly Lys Gly Thr Gln Val Thr Val Gln Ser

1 5 10

<210> 21

<211> 6

<212>PRT

<213> Artificial Sequence

<220>

<223> C-terminal amino acid sequence

<220>

<221> SITE

<222> (6)..(6)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 21

Val Thr Val Lys Ser Xaa

15

<210> 22

<211> 6

<212>PRT

<213> Artificial Sequence

<220>

<223> C-terminal amino acid sequence

<220>

<221> SITE

<222> (6)..(6)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 22

Val Thr Val Gln Ser Xaa

15

<210> 23

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 23

Trp Gly Gln Gly Thr Gln Val Thr Val Lys Ser Xaa

1 5 10

<210> 24

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 24

Trp Gly Lys Gly Thr Leu Val Thr Val Lys Ser Xaa

1 5 10

<210> 25

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 25

Arg Gly Gln Gly Thr Arg Val Thr Val Lys Ser Xaa

1 5 10

<210> 26

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 26

Trp Gly Leu Gly Thr Gln Val Thr Ile Ser Ser Xaa

1 5 10

<210> 27

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 27

Gly Ser Gln Gly Thr Gln Val Thr Val Lys Ser Xaa

1 5 10

<210> 28

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 28

Leu Arg Gly Gly Thr Gln Val Thr Val Lys Ser Xaa

1 5 10

<210> 29

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 29

Arg Gly Gln Gly Thr Leu Val Thr Val Lys Ser Xaa

1 5 10

<210> 30

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 30

Arg Ser Arg Gly Ile Gln Val Thr Val Lys Ser Xaa

1 5 10

<210> 31

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 31

Trp Gly Lys Gly Thr Gln Val Thr Val Lys Ser Xaa

1 5 10

<210> 32

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 32

Trp Gly Gln Gly Thr Gln Val Thr Val Gln Ser Xaa

1 5 10

<210> 33

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 33

Trp Gly Lys Gly Thr Leu Val Thr Val Gln Ser Xaa

1 5 10

<210> 34

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 34

Arg Gly Gln Gly Thr Arg Val Thr Val Gln Ser Xaa

1 5 10

<210> 35

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 35

Trp Gly Leu Gly Thr Gln Val Thr Ile Ser Ser Xaa

1 5 10

<210> 36

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 36

Gly Ser Gln Gly Thr Gln Val Thr Val Gln Ser Xaa

1 5 10

<210> 37

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 37

Leu Arg Gly Gly Thr Gln Val Thr Val Gln Ser Xaa

1 5 10

<210> 38

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 38

Arg Gly Gln Gly Thr Leu Val Thr Val Gln Ser Xaa

1 5 10

<210> 39

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 39

Arg Ser Arg Gly Ile Gln Val Thr Val Gln Ser Xaa

1 5 10

<210> 40

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 40

Trp Gly Lys Gly Thr Gln Val Thr Val Gln Ser Xaa

1 5 10

<210> 41

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 41

Ser Phe Gly Met Ser

15

<210> 42

<211> 17

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 42

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 43

<211> 6

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 43

Gly Gly Ser Leu Ser Arg

15

<210> 44

<211> 121

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 44

His His His His His Glu Val Gln Leu Val Glu Ser Gly Gly Gly

1 5 10 15

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

20 25 30

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

35 40 45

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

50 55 60

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

65 70 75 80

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

85 90 95

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 45

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 45

His His His His His Glu Val Gln Leu Val Glu Ser Gly Gly Gly

1 5 10 15

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

20 25 30

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

35 40 45

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

50 55 60

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

65 70 75 80

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

85 90 95

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Ala

115 120

<210> 46

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 46

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 47

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 47

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser

115

<210> 48

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 48

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser Ala

115

<210> 49

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 49

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser Ala Ala

115

<210> 50

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 50

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser Ala Ala Ala

115

<210> 51

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 51

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser Gly

115

<210> 52

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 52

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser Gly Gly

115

<210> 53

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 53

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser Gly Gly Gly

115

<210> 54

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 54

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser

115

<210> 55

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 55

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser Ala

115

<210> 56

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 56

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser Ala Ala

115

<210> 57

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 57

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser Ala Ala Ala

115

<210> 58

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 58

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser Gly

115

<210> 59

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 59

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser Gly Gly

115

<210> 60

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 60

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser Gly Gly Gly

115

<210> 61

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 61

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 62

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 62

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser

115

<210> 63

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 63

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser Ala

115

<210> 64

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 64

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser Ala Ala

115

<210> 65

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 65

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser Ala Ala Ala

115

<210> 66

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 66

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser Gly

115

<210> 67

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 67

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser Gly Gly

115

<210> 68

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 68

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser Gly Gly Gly

115

<210> 69

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 69

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser

115

<210> 70

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 70

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser Ala

115

<210> 71

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 71

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser Ala Ala

115

<210> 72

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 72

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser Ala Ala Ala

115

<210> 73

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 73

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser Gly

115

<210> 74

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 74

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser Gly Gly

115

<210> 75

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 75

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser Gly Gly Gly

115

<210> 76

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> C-terminal sequence

<400> 76

Val Thr Val Ser Ser

15

<210> 77

<211> 6

<212>PRT

<213> Artificial Sequence

<220>

<223> C-terminal sequence

<220>

<221> SITE

<222> (6)..(6)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 77

Val Thr Val Ser Ser Xaa

15

<210> 78

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 78

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 79

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 79

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Ala

115

<210> 80

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 80

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Ala Ala

115

<210> 81

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 81

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Ala Ala Ala

115

<210> 82

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 82

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly

115

<210> 83

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 83

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly

115

<210> 84

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 84

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly

115

<210> 85

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 85

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 86

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 86

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Ala

115

<210> 87

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 87

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Ala Ala

115

<210> 88

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 88

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Ala Ala Ala

115

<210> 89

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 89

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly

115

<210> 90

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 90

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly

115

<210> 91

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 91

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly

115

<210> 92

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 92

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr

50 55 60

Gly Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

85 90 95

Val Tyr Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg

100 105 110

Phe Glu Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 93

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 93

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 94

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 94

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 95

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> C-terminal amino acid sequence

<400> 95

Val Lys Val Ser Ser

15

<210> 96

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> C-terminal amino acid sequence

<400> 96

Val Gln Val Ser Ser

15

<210> 97

<211> 6

<212>PRT

<213> Artificial Sequence

<220>

<223> C-terminal amino acid sequence

<220>

<221> SITE

<222> (6)..(6)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 97

Val Lys Val Ser Ser Xaa

15

<210> 98

<211> 6

<212>PRT

<213> Artificial Sequence

<220>

<223> C-terminal amino acid sequence

<220>

<221> SITE

<222> (6)..(6)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 98

Val Gln Val Ser Ser Xaa

15

<210> 99

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 99

Ser Ser Gln Gly Thr Leu Val Thr Val Lys Ser

1 5 10

<210> 100

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 100

Ser Ser Gln Gly Thr Leu Val Thr Val Gln Ser

1 5 10

<210> 101

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 101

Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser

1 5 10

<210> 102

<211> 11

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<400> 102

Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser

1 5 10

<210> 103

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 103

Ser Ser Gln Gly Thr Leu Val Thr Val Lys Ser Xaa

1 5 10

<210> 104

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 104

Ser Ser Gln Gly Thr Leu Val Thr Val Gln Ser Xaa

1 5 10

<210> 105

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 105

Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser Xaa

1 5 10

<210> 106

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223>FR4 sequence

<220>

<221> SITE

<222> (12)..(12)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 106

Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser Xaa

1 5 10

<210> 107

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> C-terminal amino acid sequence

<220>

<221> SITE

<222> (2)..(2)

<223> X is independently K or Q

<220>

<221> SITE

<222> (4)..(4)

<223> X is independently K or Q

<400> 107

Val Xaa Val Xaa Ser

15

<210> 108

<211> 6

<212>PRT

<213> Artificial Sequence

<220>

<223> C-terminal amino acid sequence

<220>

<221> SITE

<222> (2)..(2)

<223> X is independently K or Q

<220>

<221> SITE

<222> (4)..(4)

<223> X is independently K or Q

<220>

<221> SITE

<222> (6)..(6)

<223> Xaa stands for (X)n which means C-terminal extension with n amino acids, wherein each position is chosen independently from any amino acids

<400> 108

Val Xaa Val Xaa Ser Xaa

15

<210> 109

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 109

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 110

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 110

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Ala

115

<210> 111

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 111

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Ala Ala

115

<210> 112

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 112

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Ala Ala Ala

115

<210> 113

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 113

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly

115

<210> 114

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 114

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly

115

<210> 115

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 115

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly

115

<210> 116

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 116

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 117

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 117

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Ala

115

<210> 118

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 118

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Ala Ala

115

<210> 119

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 119

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Ala Ala Ala

115

<210> 120

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 120

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly

115

<210> 121

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 121

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly

115

<210> 122

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 122

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly

115

<210> 123

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 123

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser

115

<210> 124

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 124

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Ala

115

<210> 125

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 125

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Ala Ala

115

<210> 126

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 126

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Ala Ala Ala

115

<210> 127

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 127

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly

115

<210> 128

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 128

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly

115

<210> 129

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 129

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly

115

<210> 130

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 130

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser

115

<210> 131

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 131

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Ala

115

<210> 132

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 132

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Ala Ala

115

<210> 133

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 133

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Ala Ala Ala

115

<210> 134

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 134

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly

115

<210> 135

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 135

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly

115

<210> 136

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 136

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly

115

<210> 137

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 137

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Gly Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Met Gly Gly Ser Ile Asn Tyr Ala Asp Thr Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ser

85 90 95

Ser Trp Arg Thr Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 138

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 138

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Ala Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Thr Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 139

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 139

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Ala Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Ser Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 140

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 140

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Ala Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 141

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 141

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Gln Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Thr Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 142

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 142

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Gln Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Ser Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 143

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 143

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Gln Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 144

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 144

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Tyr Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Thr Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 145

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 145

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Tyr Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Ser Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 146

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 146

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Tyr Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 147

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 147

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Ala Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Thr Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 148

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 148

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Ala Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Ser Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 149

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 149

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Ala Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 150

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 150

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Gln Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Thr Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 151

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 151

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Gln Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Ser Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 152

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 152

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Gln Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 153

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 153

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Tyr Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Thr Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 154

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 154

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Tyr Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Ser Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 155

<211> 116

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 155

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Tyr Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 156

<211> 418

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 156

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Gln Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Thr Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

145 150 155 160

Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ser Ala Ser

165 170 175

Gly Leu Leu Phe Ser Arg Asn Ser Ala Gly Trp Tyr Arg Gln Ala Pro

180 185 190

Gly Lys Gln Arg Glu Phe Val Ala Arg Ile Arg Gln Gly Gly Ser Ile

195 200 205

Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

210 215 220

Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

225 230 235 240

Thr Ala Leu Tyr Tyr Cys Ser Gly Trp Arg Thr Gly Phe Tyr Glu Tyr

245 250 255

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

260 265 270

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

275 280 285

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

290 295 300

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

305 310 315 320

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

325 330 335

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

340 345 350

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

355 360 365

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

370 375 380

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

385 390 395 400

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

405 410 415

Ser Ala

<210> 157

<211> 418

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 157

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Gln Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Ser Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

145 150 155 160

Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ser Ala Ser

165 170 175

Gly Leu Leu Phe Ser Arg Asn Ser Ala Gly Trp Tyr Arg Gln Ala Pro

180 185 190

Gly Lys Gln Arg Glu Phe Val Ala Arg Ile Arg Gln Gly Gly Ser Ile

195 200 205

Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

210 215 220

Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

225 230 235 240

Thr Ala Leu Tyr Tyr Cys Ser Ser Trp Arg Glu Gly Phe Tyr Glu Tyr

245 250 255

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

260 265 270

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

275 280 285

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

290 295 300

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

305 310 315 320

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

325 330 335

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

340 345 350

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

355 360 365

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

370 375 380

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

385 390 395 400

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

405 410 415

Ser Ala

<210> 158

<211> 418

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 158

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Ala Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Thr Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

145 150 155 160

Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ser Ala Ser

165 170 175

Gly Leu Leu Phe Ser Arg Asn Ser Ala Gly Trp Tyr Arg Gln Ala Pro

180 185 190

Gly Lys Gln Arg Glu Phe Val Ala Arg Ile Arg Ala Gly Gly Ser Ile

195 200 205

Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

210 215 220

Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

225 230 235 240

Thr Ala Leu Tyr Tyr Cys Ser Gly Trp Arg Thr Gly Phe Tyr Glu Tyr

245 250 255

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

260 265 270

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

275 280 285

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

290 295 300

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

305 310 315 320

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

325 330 335

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

340 345 350

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

355 360 365

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

370 375 380

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

385 390 395 400

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

405 410 415

Ser Ala

<210> 159

<211> 418

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 159

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Ala Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Ser Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

145 150 155 160

Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ser Ala Ser

165 170 175

Gly Leu Leu Phe Ser Arg Asn Ser Ala Gly Trp Tyr Arg Gln Ala Pro

180 185 190

Gly Lys Gln Arg Glu Phe Val Ala Arg Ile Arg Ala Gly Gly Ser Ile

195 200 205

Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

210 215 220

Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

225 230 235 240

Thr Ala Leu Tyr Tyr Cys Ser Ser Trp Arg Glu Gly Phe Tyr Glu Tyr

245 250 255

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

260 265 270

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

275 280 285

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

290 295 300

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

305 310 315 320

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

325 330 335

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

340 345 350

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

355 360 365

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

370 375 380

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

385 390 395 400

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

405 410 415

Ser Ala

<210> 160

<211> 418

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 160

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Ala Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

145 150 155 160

Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ser Ala Ser

165 170 175

Gly Leu Leu Phe Ser Arg Asn Ser Ala Gly Trp Tyr Arg Gln Ala Pro

180 185 190

Gly Lys Gln Arg Glu Phe Val Ala Arg Ile Arg Ala Gly Gly Ser Ile

195 200 205

Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

210 215 220

Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

225 230 235 240

Thr Ala Leu Tyr Tyr Cys Ser Gly Trp Arg Glu Gly Phe Tyr Glu Tyr

245 250 255

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

260 265 270

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

275 280 285

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

290 295 300

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

305 310 315 320

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

325 330 335

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

340 345 350

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

355 360 365

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

370 375 380

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

385 390 395 400

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

405 410 415

Ser Ala

<210> 161

<211> 418

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 161

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Tyr Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Thr Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

145 150 155 160

Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ser Ala Ser

165 170 175

Gly Leu Leu Phe Ser Arg Asn Ser Ala Gly Trp Tyr Arg Gln Ala Pro

180 185 190

Gly Lys Gln Arg Glu Phe Val Ala Arg Ile Arg Tyr Gly Gly Ser Ile

195 200 205

Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

210 215 220

Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

225 230 235 240

Thr Ala Leu Tyr Tyr Cys Ser Gly Trp Arg Thr Gly Phe Tyr Glu Tyr

245 250 255

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

260 265 270

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

275 280 285

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

290 295 300

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

305 310 315 320

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

325 330 335

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

340 345 350

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

355 360 365

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

370 375 380

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

385 390 395 400

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

405 410 415

Ser Ala

<210> 162

<211> 418

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 162

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Tyr Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Ser Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

145 150 155 160

Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ser Ala Ser

165 170 175

Gly Leu Leu Phe Ser Arg Asn Ser Ala Gly Trp Tyr Arg Gln Ala Pro

180 185 190

Gly Lys Gln Arg Glu Phe Val Ala Arg Ile Arg Tyr Gly Gly Ser Ile

195 200 205

Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

210 215 220

Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

225 230 235 240

Thr Ala Leu Tyr Tyr Cys Ser Ser Trp Arg Glu Gly Phe Tyr Glu Tyr

245 250 255

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

260 265 270

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

275 280 285

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

290 295 300

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

305 310 315 320

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

325 330 335

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

340 345 350

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

355 360 365

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

370 375 380

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

385 390 395 400

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

405 410 415

Ser Ala

<210> 163

<211> 418

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 163

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Tyr Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

145 150 155 160

Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ser Ala Ser

165 170 175

Gly Leu Leu Phe Ser Arg Asn Ser Ala Gly Trp Tyr Arg Gln Ala Pro

180 185 190

Gly Lys Gln Arg Glu Phe Val Ala Arg Ile Arg Tyr Gly Gly Ser Ile

195 200 205

Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

210 215 220

Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

225 230 235 240

Thr Ala Leu Tyr Tyr Cys Ser Gly Trp Arg Glu Gly Phe Tyr Glu Tyr

245 250 255

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

260 265 270

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

275 280 285

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

290 295 300

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

305 310 315 320

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

325 330 335

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

340 345 350

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

355 360 365

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

370 375 380

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

385 390 395 400

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

405 410 415

Ser Ala

<210> 164

<211> 418

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 164

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Gln Gly Gly Ser Ile Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ser

85 90 95

Gly Trp Arg Glu Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

145 150 155 160

Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ser Ala Ser

165 170 175

Gly Leu Leu Phe Ser Arg Asn Ser Ala Gly Trp Tyr Arg Gln Ala Pro

180 185 190

Gly Lys Gln Arg Glu Phe Val Ala Arg Ile Arg Gln Gly Gly Ser Ile

195 200 205

Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

210 215 220

Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

225 230 235 240

Thr Ala Leu Tyr Tyr Cys Ser Gly Trp Arg Glu Gly Phe Tyr Glu Tyr

245 250 255

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

260 265 270

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

275 280 285

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

290 295 300

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

305 310 315 320

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

325 330 335

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

340 345 350

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

355 360 365

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

370 375 380

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

385 390 395 400

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

405 410 415

Ser Ala

<210> 165

<211> 418

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 165

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Gly Leu Ser Cys Ser Ala Ser Gly Leu Leu Phe Ser Arg Asn

20 25 30

Ser Ala Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Arg Ile Arg Met Gly Gly Ser Ile Asn Tyr Ala Asp Thr Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ser

85 90 95

Ser Trp Arg Thr Gly Phe Tyr Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

145 150 155 160

Gly Leu Val Gln Ala Gly Gly Ser Leu Gly Leu Ser Cys Ser Ala Ser

165 170 175

Gly Leu Leu Phe Ser Arg Asn Ser Ala Gly Trp Tyr Arg Gln Ala Pro

180 185 190

Gly Lys Gln Arg Glu Phe Val Ala Arg Ile Arg Met Gly Gly Ser Ile

195 200 205

Asn Tyr Ala Asp Thr Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

210 215 220

Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp

225 230 235 240

Thr Ala Val Tyr Tyr Cys Ser Ser Trp Arg Thr Gly Phe Tyr Glu Tyr

245 250 255

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

260 265 270

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

275 280 285

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

290 295 300

Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu

305 310 315 320

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

325 330 335

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

340 345 350

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

355 360 365

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

370 375 380

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile

385 390 395 400

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

405 410 415

Ser Ala

<210> 166

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 166

Arg Asn Ser Ala Gly

15

<210> 167

<211> 16

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 167

Arg Ile Arg Met Gly Gly Ser Ile Asn Tyr Ala Asp Thr Val Lys Gly

1 5 10 15

<210> 168

<211> 8

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 168

Trp Arg Thr Gly Phe Tyr Glu Tyr

15

<210> 169

<211> 10

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 169

Gly Leu Leu Phe Ser Arg Asn Ser Ala Gly

1 5 10

<210> 170

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 170

Arg Ile Arg Met Gly Gly Ser Ile Asn

15

<210> 171

<211> 8

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 171

Trp Arg Thr Gly Phe Tyr Glu Tyr

15

<210> 172

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 172

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Val Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 173

<211> 14

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 173

Leu Pro Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala

1 5 10

<210> 174

<211> 26

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 174

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

1 5 10 15

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly

20 25

<210> 175

<211> 8

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 175

Ser Gly Ser Gly Ser Pro Asn Phe

15

<210> 176

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 176

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 177

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 177

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 178

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 178

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Val Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 179

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 179

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Val Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 180

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 180

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Val Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120 125

<210> 181

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 181

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Val Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120 125

<210> 182

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 182

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Thr Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 183

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 183

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 184

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 184

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 185

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 185

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 186

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 186

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Val Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 187

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 187

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Val Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 188

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 188

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Val Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120 125

<210> 189

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 189

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Val Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120 125

<210> 190

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 190

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ser Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu Leu Ser

100 105 110

Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 191

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 191

Ser Tyr Ala Met Gly

15

<210> 192

<211> 17

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 192

Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 193

<211> 19

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 193

Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu Leu Ser Gly Ser

1 5 10 15

Tyr Asp Ser

<210> 194

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 194

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ser Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu Leu Ser

100 105 110

Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 195

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 195

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ser Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu Leu Ser

100 105 110

Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 196

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 196

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ser Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu Leu Ser

100 105 110

Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 197

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 197

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ser Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu Leu Ser

100 105 110

Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 198

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 198

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ser Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu Leu Ser

100 105 110

Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120 125

<210> 199

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 199

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ser Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu Leu Ser

100 105 110

Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120 125

<210> 200

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 200

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ser Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu Leu Ser

100 105 110

Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 201

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 201

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ser Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu Leu Ser

100 105 110

Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 202

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 202

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ser Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu Leu Ser

100 105 110

Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 203

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 203

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ser Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu Leu Ser

100 105 110

Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 204

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 204

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ser Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu Leu Ser

100 105 110

Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 205

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 205

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ser Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu Leu Ser

100 105 110

Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 206

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 206

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ser Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu Leu Ser

100 105 110

Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120 125

<210> 207

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 207

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ser Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu Leu Ser

100 105 110

Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120 125

<210> 208

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 208

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 209

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 209

Leu Asp Arg Met Gly

15

<210> 210

<211> 16

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 210

Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly

1 5 10 15

<210> 211

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 211

Asn Lys Tyr Val Thr Ser Arg Asp Thr

15

<210> 212

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 212

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser

115

<210> 213

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 213

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser

115

<210> 214

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 214

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser

115

<210> 215

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 215

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser

115

<210> 216

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 216

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Lys Ser

115

<210> 217

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 217

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Gln Ser

115

<210> 218

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 218

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 219

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 219

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 220

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 220

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser

115

<210> 221

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 221

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser

115

<210> 222

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 222

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser

115

<210> 223

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 223

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser

115

<210> 224

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 224

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Lys Ser

115

<210> 225

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 225

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Gln Ser

115

<210> 226

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 226

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 227

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 227

Asn Tyr Asp Met Ala

15

<210> 228

<211> 17

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 228

Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 229

<211> 13

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 229

Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr

1 5 10

<210> 230

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 230

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 231

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 231

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 232

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 232

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 233

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 233

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 234

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 234

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120

<210> 235

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 235

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120

<210> 236

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 236

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 237

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 237

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 238

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 238

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 239

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 239

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 240

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 240

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 241

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 241

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 242

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 242

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120

<210> 243

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 243

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120

<210> 244

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 244

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 245

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 245

Ser Tyr Ala Met Ser

15

<210> 246

<211> 17

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 246

Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val Lys

1 5 10 15

Gly

<210> 247

<211> 13

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 247

Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn

1 5 10

<210> 248

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 248

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 249

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 249

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 250

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 250

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 251

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 251

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 252

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 252

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120

<210> 253

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 253

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120

<210> 254

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 254

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 255

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 255

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 256

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 256

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 257

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 257

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 258

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 258

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 259

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 259

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 260

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 260

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120

<210> 261

<211> 122

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 261

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120

<210> 262

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 262

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr

50 55 60

Gly Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

85 90 95

Val Tyr Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg

100 105 110

Phe Glu Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 263

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 263

Asn Tyr Ala Met Gly

15

<210> 264

<211> 21

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 264

Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr Gly

1 5 10 15

Asp Ser Val Lys Asp

20

<210> 265

<211> 15

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 265

Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg Phe Glu Tyr Asp Tyr

1 5 10 15

<210> 266

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 266

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr

50 55 60

Gly Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

85 90 95

Leu Tyr Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg

100 105 110

Phe Glu Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 267

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 267

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr

50 55 60

Gly Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

85 90 95

Leu Tyr Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg

100 105 110

Phe Glu Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 268

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 268

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr

50 55 60

Gly Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

85 90 95

Val Tyr Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg

100 105 110

Phe Glu Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 269

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 269

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr

50 55 60

Gly Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

85 90 95

Val Tyr Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg

100 105 110

Phe Glu Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 270

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 270

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr

50 55 60

Gly Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

85 90 95

Val Tyr Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg

100 105 110

Phe Glu Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120 125

<210> 271

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 271

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr

50 55 60

Gly Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

85 90 95

Val Tyr Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg

100 105 110

Phe Glu Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120 125

<210> 272

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 272

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr

50 55 60

Gly Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

85 90 95

Thr Tyr Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg

100 105 110

Phe Glu Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 273

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 273

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr

50 55 60

Gly Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

85 90 95

Leu Tyr Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg

100 105 110

Phe Glu Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 274

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 274

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr

50 55 60

Gly Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

85 90 95

Leu Tyr Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg

100 105 110

Phe Glu Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 275

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 275

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr

50 55 60

Gly Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

85 90 95

Leu Tyr Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg

100 105 110

Phe Glu Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 276

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 276

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr

50 55 60

Gly Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

85 90 95

Val Tyr Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg

100 105 110

Phe Glu Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 277

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 277

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr

50 55 60

Gly Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

85 90 95

Val Tyr Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg

100 105 110

Phe Glu Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 278

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 278

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr

50 55 60

Gly Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

85 90 95

Val Tyr Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg

100 105 110

Phe Glu Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120 125

<210> 279

<211> 128

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 279

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr

50 55 60

Gly Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

65 70 75 80

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

85 90 95

Val Tyr Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg

100 105 110

Phe Glu Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120 125

<210> 280

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 280

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 281

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 281

Leu Asn Ala Met Ala

15

<210> 282

<211> 16

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 282

Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys Gly

1 5 10 15

<210> 283

<211> 10

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 283

Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr

1 5 10

<210> 284

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 284

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Lys Val Ser Ser

115

<210> 285

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 285

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Gln Val Ser Ser

115

<210> 286

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 286

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Lys Val Ser Ser

115

<210> 287

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 287

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Gln Val Ser Ser

115

<210> 288

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 288

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Lys Ser

115

<210> 289

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 289

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Gln Ser

115

<210> 290

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 290

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 291

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 291

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 292

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 292

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Lys Val Ser Ser

115

<210> 293

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 293

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Gln Val Ser Ser

115

<210> 294

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 294

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Lys Val Ser Ser

115

<210> 295

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 295

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Gln Val Ser Ser

115

<210> 296

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 296

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Lys Ser

115

<210> 297

<211> 118

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 297

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Gln Ser

115

<210> 298

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 298

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Asp Trp Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Asp Thr Pro Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr

100 105 110

Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 299

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 299

Leu Asn Ala Met Gly

15

<210> 300

<211> 17

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 300

Ala Ile Asp Trp Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 301

<211> 16

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 301

Asp Thr Pro Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser

1 5 10 15

<210> 302

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 302

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Asp Trp Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Asp Thr Pro Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr

100 105 110

Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 303

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 303

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Asp Trp Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Asp Thr Pro Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr

100 105 110

Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 304

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 304

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Asp Trp Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Asp Thr Pro Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr

100 105 110

Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 305

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 305

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Asp Trp Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Asp Thr Pro Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr

100 105 110

Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 306

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 306

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Asp Trp Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Asp Thr Pro Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr

100 105 110

Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120 125

<210> 307

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 307

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Asp Trp Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Asp Thr Pro Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr

100 105 110

Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120 125

<210> 308

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 308

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Asp Trp Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Ala Ala Asp Thr Pro Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr

100 105 110

Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 309

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 309

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Asp Trp Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Asp Thr Pro Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr

100 105 110

Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 310

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 310

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Asp Trp Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Asp Thr Pro Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr

100 105 110

Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 311

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 311

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Asp Trp Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Asp Thr Pro Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr

100 105 110

Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 312

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 312

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Asp Trp Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Asp Thr Pro Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr

100 105 110

Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 313

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 313

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Asp Trp Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Asp Thr Pro Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr

100 105 110

Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 314

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 314

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Asp Trp Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Asp Thr Pro Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr

100 105 110

Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120 125

<210> 315

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 315

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Ala Ile Asp Trp Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Asp Thr Pro Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr

100 105 110

Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120 125

<210> 316

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 316

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 317

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 317

Asp Tyr Trp Met Tyr

15

<210> 318

<211> 17

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 318

Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 319

<211> 6

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 319

Ser Pro Ser Gly Phe Asn

15

<210> 320

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 320

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser

115

<210> 321

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 321

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser

115

<210> 322

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 322

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser

115

<210> 323

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 323

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser

115

<210> 324

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 324

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser

115

<210> 325

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 325

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser

115

<210> 326

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 326

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 327

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 327

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 328

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 328

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser

115

<210> 329

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 329

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser

115

<210> 330

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 330

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser

115

<210> 331

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 331

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser

115

<210> 332

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 332

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser

115

<210> 333

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 333

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser

115

<210> 334

<211> 121

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 334

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Thr Ala

20 25 30

Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Arg Ile Ser Gly Ile Asp Gly Thr Thr Tyr Tyr Asp Glu Pro Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Arg Ser Pro Arg Tyr Ala Asp Gln Trp Ser Ala Tyr Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 335

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 335

Thr Ala Asp Met Gly

15

<210> 336

<211> 17

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 336

Arg Ile Ser Gly Ile Asp Gly Thr Thr Tyr Tyr Asp Glu Pro Val Lys

1 5 10 15

Gly

<210> 337

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 337

Pro Arg Tyr Ala Asp Gln Trp Ser Ala Tyr Asp Tyr

1 5 10

<210> 338

<211> 121

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 338

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Thr Ala

20 25 30

Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Arg Ile Ser Gly Ile Asp Gly Thr Thr Tyr Tyr Asp Glu Pro Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Arg Ser Pro Arg Tyr Ala Asp Gln Trp Ser Ala Tyr Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 339

<211> 121

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 339

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Thr Ala

20 25 30

Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Arg Ile Ser Gly Ile Asp Gly Thr Thr Tyr Tyr Asp Glu Pro Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Arg Ser Pro Arg Tyr Ala Asp Gln Trp Ser Ala Tyr Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 340

<211> 121

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 340

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Thr Ala

20 25 30

Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Arg Ile Ser Gly Ile Asp Gly Thr Thr Tyr Tyr Asp Glu Pro Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Arg Ser Pro Arg Tyr Ala Asp Gln Trp Ser Ala Tyr Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 341

<211> 121

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 341

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Thr Ala

20 25 30

Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Arg Ile Ser Gly Ile Asp Gly Thr Thr Tyr Tyr Asp Glu Pro Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Arg Ser Pro Arg Tyr Ala Asp Gln Trp Ser Ala Tyr Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 342

<211> 121

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 342

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Thr Ala

20 25 30

Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Arg Ile Ser Gly Ile Asp Gly Thr Thr Tyr Tyr Asp Glu Pro Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Arg Ser Pro Arg Tyr Ala Asp Gln Trp Ser Ala Tyr Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Ser

115 120

<210> 343

<211> 121

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 343

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Thr Ala

20 25 30

Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Arg Ile Ser Gly Ile Asp Gly Thr Thr Tyr Tyr Asp Glu Pro Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Arg Ser Pro Arg Tyr Ala Asp Gln Trp Ser Ala Tyr Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Gln Ser

115 120

<210> 344

<211> 121

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 344

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Thr Ala

20 25 30

Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Arg Ile Ser Gly Ile Asp Gly Thr Thr Tyr Tyr Asp Glu Pro Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Arg Ser Pro Arg Tyr Ala Asp Gln Trp Ser Ala Tyr Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 345

<211> 121

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 345

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Thr Ala

20 25 30

Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Arg Ile Ser Gly Ile Asp Gly Thr Thr Tyr Tyr Asp Glu Pro Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Arg Ser Pro Arg Tyr Ala Asp Gln Trp Ser Ala Tyr Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 346

<211> 121

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 346

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Thr Ala

20 25 30

Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Arg Ile Ser Gly Ile Asp Gly Thr Thr Tyr Tyr Asp Glu Pro Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Arg Ser Pro Arg Tyr Ala Asp Gln Trp Ser Ala Tyr Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 347

<211> 121

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 347

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Thr Ala

20 25 30

Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Arg Ile Ser Gly Ile Asp Gly Thr Thr Tyr Tyr Asp Glu Pro Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Arg Ser Pro Arg Tyr Ala Asp Gln Trp Ser Ala Tyr Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 348

<211> 121

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 348

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Thr Ala

20 25 30

Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Arg Ile Ser Gly Ile Asp Gly Thr Thr Tyr Tyr Asp Glu Pro Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Arg Ser Pro Arg Tyr Ala Asp Gln Trp Ser Ala Tyr Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 349

<211> 121

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 349

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Thr Ala

20 25 30

Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Arg Ile Ser Gly Ile Asp Gly Thr Thr Tyr Tyr Asp Glu Pro Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Arg Ser Pro Arg Tyr Ala Asp Gln Trp Ser Ala Tyr Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 350

<211> 121

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 350

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Thr Ala

20 25 30

Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Arg Ile Ser Gly Ile Asp Gly Thr Thr Tyr Tyr Asp Glu Pro Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Arg Ser Pro Arg Tyr Ala Asp Gln Trp Ser Ala Tyr Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Lys Ser

115 120

<210> 351

<211> 121

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 351

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Thr Ala

20 25 30

Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Arg Ile Ser Gly Ile Asp Gly Thr Thr Tyr Tyr Asp Glu Pro Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Arg Ser Pro Arg Tyr Ala Asp Gln Trp Ser Ala Tyr Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Gln Ser

115 120

<210> 352

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 352

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 353

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 353

Tyr Tyr Ala Ile Gly

15

<210> 354

<211> 17

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 354

Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 355

<211> 16

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 355

Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr Asp Tyr

1 5 10 15

<210> 356

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 356

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 357

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 357

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 358

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 358

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 359

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 359

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 360

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 360

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120 125

<210> 361

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 361

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120 125

<210> 362

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 362

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 363

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 363

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 364

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 364

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 365

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 365

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 366

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 366

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 367

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 367

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 368

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 368

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120 125

<210> 369

<211> 125

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 369

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120 125

<210> 370

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 370

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 371

<211> 6

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 371

Asp Asp Tyr Ala Ile Gly

15

<210> 372

<211> 17

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 372

Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 373

<211> 15

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 373

Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp Tyr

1 5 10 15

<210> 374

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 374

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 375

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 375

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 376

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 376

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 377

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 377

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 378

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 378

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120

<210> 379

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 379

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120

<210> 380

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 380

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 381

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 381

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 382

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 382

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 383

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 383

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 384

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 384

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 385

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 385

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 386

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 386

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120

<210> 387

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 387

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120

<210> 388

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 388

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 389

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 389

Ser Tyr Pro Met Gly

15

<210> 390

<211> 17

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 390

Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 391

<211> 17

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 391

Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp

1 5 10 15

Tyr

<210> 392

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 392

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 393

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 393

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 394

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 394

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 395

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 395

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 396

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 396

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120 125

<210> 397

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 397

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120 125

<210> 398

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 398

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 399

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 399

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 400

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 400

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 401

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 401

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 402

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 402

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 403

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 403

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 404

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 404

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120 125

<210> 405

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 405

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120 125

<210> 406

<211> 120

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 406

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Ile Ser Cys Ala Ala Ser Gly Ser Ile Tyr Leu Ile Asn

20 25 30

Tyr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Thr Leu Thr Ser Gly Gly Ser Thr Asn Tyr Ala Gly Ser Val Lys

50 55 60

Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Ile Gly Gly Thr Leu Tyr Asp Arg Arg Arg Phe Glu Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 407

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 407

Ile Asn Tyr Met Gly

15

<210> 408

<211> 16

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 408

Thr Leu Thr Ser Gly Gly Ser Thr Asn Tyr Ala Gly Ser Val Lys Gly

1 5 10 15

<210> 409

<211> 12

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 409

Gly Gly Thr Leu Tyr Asp Arg Arg Arg Phe Glu Ser

1 5 10

<210> 410

<211> 120

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 410

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Ile Ser Cys Ala Ala Ser Gly Ser Ile Tyr Leu Ile Asn

20 25 30

Tyr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Thr Leu Thr Ser Gly Gly Ser Thr Asn Tyr Ala Gly Ser Val Lys

50 55 60

Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Ile Gly Gly Thr Leu Tyr Asp Arg Arg Arg Phe Glu Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 411

<211> 120

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 411

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Ile Ser Cys Ala Ala Ser Gly Ser Ile Tyr Leu Ile Asn

20 25 30

Tyr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Thr Leu Thr Ser Gly Gly Ser Thr Asn Tyr Ala Gly Ser Val Lys

50 55 60

Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Ile Gly Gly Thr Leu Tyr Asp Arg Arg Arg Phe Glu Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 412

<211> 120

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 412

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Ile Ser Cys Ala Ala Ser Gly Ser Ile Tyr Leu Ile Asn

20 25 30

Tyr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Thr Leu Thr Ser Gly Gly Ser Thr Asn Tyr Ala Gly Ser Val Lys

50 55 60

Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Ile Gly Gly Thr Leu Tyr Asp Arg Arg Arg Phe Glu Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 413

<211> 120

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 413

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Ile Ser Cys Ala Ala Ser Gly Ser Ile Tyr Leu Ile Asn

20 25 30

Tyr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Thr Leu Thr Ser Gly Gly Ser Thr Asn Tyr Ala Gly Ser Val Lys

50 55 60

Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Ile Gly Gly Thr Leu Tyr Asp Arg Arg Arg Phe Glu Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 414

<211> 120

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 414

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Ile Ser Cys Ala Ala Ser Gly Ser Ile Tyr Leu Ile Asn

20 25 30

Tyr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Thr Leu Thr Ser Gly Gly Ser Thr Asn Tyr Ala Gly Ser Val Lys

50 55 60

Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Ile Gly Gly Thr Leu Tyr Asp Arg Arg Arg Phe Glu Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Lys Ser

115 120

<210> 415

<211> 120

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 415

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Ile Ser Cys Ala Ala Ser Gly Ser Ile Tyr Leu Ile Asn

20 25 30

Tyr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Thr Leu Thr Ser Gly Gly Ser Thr Asn Tyr Ala Gly Ser Val Lys

50 55 60

Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Ile Gly Gly Thr Leu Tyr Asp Arg Arg Arg Phe Glu Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Gln Ser

115 120

<210> 416

<211> 120

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 416

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Ile Ser Cys Ala Ala Ser Gly Ser Ile Tyr Leu Ile Asn

20 25 30

Tyr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Thr Leu Thr Ser Gly Gly Ser Thr Asn Tyr Ala Gly Ser Val Lys

50 55 60

Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Thr Tyr Tyr Cys Asn

85 90 95

Ile Gly Gly Thr Leu Tyr Asp Arg Arg Arg Phe Glu Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 417

<211> 120

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 417

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Ile Ser Cys Ala Ala Ser Gly Ser Ile Tyr Leu Ile Asn

20 25 30

Tyr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Thr Leu Thr Ser Gly Gly Ser Thr Asn Tyr Ala Gly Ser Val Lys

50 55 60

Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Ile Gly Gly Thr Leu Tyr Asp Arg Arg Arg Phe Glu Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 418

<211> 120

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 418

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Ile Ser Cys Ala Ala Ser Gly Ser Ile Tyr Leu Ile Asn

20 25 30

Tyr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Thr Leu Thr Ser Gly Gly Ser Thr Asn Tyr Ala Gly Ser Val Lys

50 55 60

Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Ile Gly Gly Thr Leu Tyr Asp Arg Arg Arg Phe Glu Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 419

<211> 120

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 419

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Ile Ser Cys Ala Ala Ser Gly Ser Ile Tyr Leu Ile Asn

20 25 30

Tyr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Thr Leu Thr Ser Gly Gly Ser Thr Asn Tyr Ala Gly Ser Val Lys

50 55 60

Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Ile Gly Gly Thr Leu Tyr Asp Arg Arg Arg Phe Glu Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 420

<211> 120

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 420

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Ile Ser Cys Ala Ala Ser Gly Ser Ile Tyr Leu Ile Asn

20 25 30

Tyr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Thr Leu Thr Ser Gly Gly Ser Thr Asn Tyr Ala Gly Ser Val Lys

50 55 60

Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Ile Gly Gly Thr Leu Tyr Asp Arg Arg Arg Phe Glu Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 421

<211> 120

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 421

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Ile Ser Cys Ala Ala Ser Gly Ser Ile Tyr Leu Ile Asn

20 25 30

Tyr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Thr Leu Thr Ser Gly Gly Ser Thr Asn Tyr Ala Gly Ser Val Lys

50 55 60

Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Ile Gly Gly Thr Leu Tyr Asp Arg Arg Arg Phe Glu Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 422

<211> 120

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 422

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Ile Ser Cys Ala Ala Ser Gly Ser Ile Tyr Leu Ile Asn

20 25 30

Tyr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Thr Leu Thr Ser Gly Gly Ser Thr Asn Tyr Ala Gly Ser Val Lys

50 55 60

Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Ile Gly Gly Thr Leu Tyr Asp Arg Arg Arg Phe Glu Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Lys Ser

115 120

<210> 423

<211> 120

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 423

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Ile Ser Cys Ala Ala Ser Gly Ser Ile Tyr Leu Ile Asn

20 25 30

Tyr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Thr Leu Thr Ser Gly Gly Ser Thr Asn Tyr Ala Gly Ser Val Lys

50 55 60

Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn

85 90 95

Ile Gly Gly Thr Leu Tyr Asp Arg Arg Arg Phe Glu Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 424

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 424

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Ala

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Ala Ile Thr Pro Arg Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Val Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Gln Leu Val Gly Ser Gly Ser Asn Leu Gly Arg Gln Glu Ser

100 105 110

Tyr Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 425

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 425

Asn Tyr Ala Met Gly

15

<210> 426

<211> 17

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 426

Ala Ile Thr Pro Arg Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 427

<211> 17

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 427

Gln Leu Val Gly Ser Gly Ser Asn Leu Gly Arg Gln Glu Ser Tyr Ala

1 5 10 15

Tyr

<210> 428

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 428

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Ala

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Ala Ile Thr Pro Arg Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Val Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Gln Leu Val Gly Ser Gly Ser Asn Leu Gly Arg Gln Glu Ser

100 105 110

Tyr Ala Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 429

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 429

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Ala

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Ala Ile Thr Pro Arg Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Val Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Gln Leu Val Gly Ser Gly Ser Asn Leu Gly Arg Gln Glu Ser

100 105 110

Tyr Ala Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 430

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 430

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Ala

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Ala Ile Thr Pro Arg Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Val Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Gln Leu Val Gly Ser Gly Ser Asn Leu Gly Arg Gln Glu Ser

100 105 110

Tyr Ala Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 431

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 431

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Ala

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Ala Ile Thr Pro Arg Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Val Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Gln Leu Val Gly Ser Gly Ser Asn Leu Gly Arg Gln Glu Ser

100 105 110

Tyr Ala Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 432

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 432

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Ala

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Ala Ile Thr Pro Arg Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Val Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Gln Leu Val Gly Ser Gly Ser Asn Leu Gly Arg Gln Glu Ser

100 105 110

Tyr Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120 125

<210> 433

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 433

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Ala

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Ala Ile Thr Pro Arg Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Val Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Gln Leu Val Gly Ser Gly Ser Asn Leu Gly Arg Gln Glu Ser

100 105 110

Tyr Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120 125

<210> 434

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 434

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Ala

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Ala Ile Thr Pro Arg Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Val Ser Leu Lys Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Ala Ala Gln Leu Val Gly Ser Gly Ser Asn Leu Gly Arg Gln Glu Ser

100 105 110

Tyr Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 435

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 435

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Thr Gly Ala

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Ala Ile Thr Pro Arg Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Val Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Gln Leu Val Gly Ser Gly Ser Asn Leu Gly Arg Gln Glu Ser

100 105 110

Tyr Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 436

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 436

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Thr Gly Ala

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Ala Ile Thr Pro Arg Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Val Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Gln Leu Val Gly Ser Gly Ser Asn Leu Gly Arg Gln Glu Ser

100 105 110

Tyr Ala Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 437

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 437

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Thr Gly Ala

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Ala Ile Thr Pro Arg Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Val Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Gln Leu Val Gly Ser Gly Ser Asn Leu Gly Arg Gln Glu Ser

100 105 110

Tyr Ala Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 438

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 438

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Thr Gly Ala

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Ala Ile Thr Pro Arg Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Val Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Gln Leu Val Gly Ser Gly Ser Asn Leu Gly Arg Gln Glu Ser

100 105 110

Tyr Ala Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120 125

<210> 439

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 439

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Thr Gly Ala

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Ala Ile Thr Pro Arg Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Val Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Gln Leu Val Gly Ser Gly Ser Asn Leu Gly Arg Gln Glu Ser

100 105 110

Tyr Ala Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120 125

<210> 440

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 440

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Thr Gly Ala

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Ala Ile Thr Pro Arg Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Val Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Gln Leu Val Gly Ser Gly Ser Asn Leu Gly Arg Gln Glu Ser

100 105 110

Tyr Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120 125

<210> 441

<211> 126

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 441

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Thr Gly Ala

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr

20 25 30

Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Ala Ile Thr Pro Arg Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Val Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Gln Leu Val Gly Ser Gly Ser Asn Leu Gly Arg Gln Glu Ser

100 105 110

Tyr Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120 125

<210> 442

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 442

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ala Tyr

20 25 30

Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys

50 55 60

Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Ala Gly Leu Arg Gly Arg Gln Tyr Ser Asn Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 443

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 443

Ala Tyr Ile Met Gly

15

<210> 444

<211> 16

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 444

Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys Gly

1 5 10 15

<210> 445

<211> 16

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 445

Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys Gly

1 5 10 15

<210> 446

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 446

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ala Tyr

20 25 30

Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys

50 55 60

Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala

85 90 95

Ala Gly Leu Arg Gly Arg Gln Tyr Ser Asn Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser

115

<210> 447

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 447

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ala Tyr

20 25 30

Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys

50 55 60

Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala

85 90 95

Ala Gly Leu Arg Gly Arg Gln Tyr Ser Asn Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser

115

<210> 448

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 448

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ala Tyr

20 25 30

Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys

50 55 60

Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Ala Gly Leu Arg Gly Arg Gln Tyr Ser Asn Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser

115

<210> 449

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 449

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ala Tyr

20 25 30

Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys

50 55 60

Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Ala Gly Leu Arg Gly Arg Gln Tyr Ser Asn Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser

115

<210> 450

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 450

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ala Tyr

20 25 30

Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys

50 55 60

Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Ala Gly Leu Arg Gly Arg Gln Tyr Ser Asn Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Lys Ser

115

<210> 451

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 451

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ala Tyr

20 25 30

Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys

50 55 60

Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Ala Gly Leu Arg Gly Arg Gln Tyr Ser Asn Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Lys Ser

115

<210> 452

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 452

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ala Tyr

20 25 30

Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys

50 55 60

Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Thr Tyr Tyr Cys Ala

85 90 95

Ala Gly Leu Arg Gly Arg Gln Tyr Ser Asn Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 453

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 453

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ala Gly Glu

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ala Tyr

20 25 30

Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys

50 55 60

Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala

85 90 95

Ala Gly Leu Arg Gly Arg Gln Tyr Ser Asn Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 454

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 454

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ala Gly Glu

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ala Tyr

20 25 30

Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys

50 55 60

Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala

85 90 95

Ala Gly Leu Arg Gly Arg Gln Tyr Ser Asn Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser

115

<210> 455

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 455

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ala Gly Glu

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ala Tyr

20 25 30

Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys

50 55 60

Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala

85 90 95

Ala Gly Leu Arg Gly Arg Gln Tyr Ser Asn Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser

115

<210> 456

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 456

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ala Gly Glu

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ala Tyr

20 25 30

Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys

50 55 60

Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Ala Gly Leu Arg Gly Arg Gln Tyr Ser Asn Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser

115

<210> 457

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 457

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ala Gly Glu

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ala Tyr

20 25 30

Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys

50 55 60

Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Ala Gly Leu Arg Gly Arg Gln Tyr Ser Asn Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser

115

<210> 458

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 458

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ala Gly Glu

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ala Tyr

20 25 30

Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys

50 55 60

Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Ala Gly Leu Arg Gly Arg Gln Tyr Ser Asn Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Lys Ser

115

<210> 459

<211> 117

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 459

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ala Gly Glu

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ala Tyr

20 25 30

Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ala Gly Ile Trp Ser Gly Gly Tyr Thr His Leu Ala Asp Ser Ala Lys

50 55 60

Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Ala Gly Leu Arg Gly Arg Gln Tyr Ser Asn Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Gln Ser

115

<210> 460

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 460

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 461

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 461

Thr Asp Thr Met Gly

15

<210> 462

<211> 17

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 462

Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 463

<211> 15

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 463

His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg Tyr

1 5 10 15

<210> 464

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 464

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 465

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 465

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 466

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 466

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 467

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 467

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 468

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 468

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120

<210> 469

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 469

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120

<210> 470

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 470

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Thr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 471

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 471

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 472

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 472

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 473

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 473

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 474

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 474

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 475

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 475

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 476

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 476

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120

<210> 477

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 477

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120

<210> 478

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 478

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr Ser

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 479

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 479

Asn Tyr Asn Met Gly

15

<210> 480

<211> 17

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 480

Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 481

<211> 15

<212>PRT

<213> Artificial Sequence

<220>

<223> CDR sequence

<400> 481

Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr Ser Ser

1 5 10 15

<210> 482

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 482

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr Ser

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 483

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 483

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr Ser

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 484

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 484

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr Ser

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 485

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 485

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr Ser

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 486

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 486

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr Ser

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120

<210> 487

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 487

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr Ser

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120

<210> 488

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 488

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr Ser

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 489

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 489

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr Ser

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 490

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 490

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr Ser

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 491

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 491

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr Ser

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 492

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 492

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr Ser

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser

115 120

<210> 493

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 493

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr Ser

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser

115 120

<210> 494

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 494

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr Ser

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Lys Ser

115 120

<210> 495

<211> 124

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 495

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr

20 25 30

Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr Ser

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Gln Ser

115 120

<210> 496

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 496

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser

115

<210> 497

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 497

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser

115

<210> 498

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 498

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser

115

<210> 499

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 499

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser

115

<210> 500

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 500

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser

115

<210> 501

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 501

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser

115

<210> 502

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 502

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser

115

<210> 503

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 503

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser

115

<210> 504

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 504

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser

115

<210> 505

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 505

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser

115

<210> 506

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 506

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser

115

<210> 507

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 507

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser

115

<210> 508

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 508

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser

115

<210> 509

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 509

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser

115

<210> 510

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 510

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser

115

<210> 511

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 511

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser

115

<210> 512

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 512

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Lys Ser

115

<210> 513

<211> 115

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody sequence

<400> 513

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Gln Ser

115

<210> 514

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 514

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val

370 375 380

Ser Ser Ala

385

<210> 515

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 515

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val

370 375 380

Ser Ser Ala

385

<210> 516

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 516

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val

370 375 380

Ser Ser Ala

385

<210> 517

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 517

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val

370 375 380

Ser Ser Ala

385

<210> 518

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 518

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val

370 375 380

Ser Ser Ala

385

<210> 519

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 519

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val

370 375 380

Ser Ser Ala

385

<210> 520

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 520

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val

370 375 380

Ser Ser Ala

385

<210> 521

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 521

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val

370 375 380

Ser Ser Ala

385

<210> 522

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 522

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val

370 375 380

Ser Ser Ala

385

<210> 523

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 523

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val

370 375 380

Ser Ser Ala

385

<210> 524

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 524

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val

370 375 380

Ser Ser Ala

385

<210> 525

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 525

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val

370 375 380

Ser Ser Ala

385

<210> 526

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 526

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val

370 375 380

Ser Ser Ala

385

<210> 527

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 527

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val

370 375 380

Ser Ser Ala

385

<210> 528

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 528

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val

370 375 380

Ser Ser Ala

385

<210> 529

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 529

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val

370 375 380

Ser Ser Ala

385

<210> 530

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 530

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val

370 375 380

Ser Ser Ala

385

<210> 531

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 531

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val

370 375 380

Ser Ser Ala

385

<210> 532

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 532

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val

370 375 380

Ser Ser Ala

385

<210> 533

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 533

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val

370 375 380

Ser Ser Ala

385

<210> 534

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 534

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val

370 375 380

Ser Ser Ala

385

<210> 535

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 535

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val

370 375 380

Ser Ser Ala

385

<210> 536

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 536

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val

370 375 380

Ser Ser Ala

385

<210> 537

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 537

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val

370 375 380

Ser Ser Ala

385

<210> 538

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 538

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val

370 375 380

Ser Ser Ala

385

<210> 539

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 539

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val

370 375 380

Ser Ser Ala

385

<210> 540

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 540

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val

370 375 380

Ser Ser Ala

385

<210> 541

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 541

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val

370 375 380

Ser Ser Ala

385

<210> 542

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 542

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val

370 375 380

Ser Ser Ala

385

<210> 543

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 543

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val

370 375 380

Ser Ser Ala

385

<210> 544

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 544

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val

370 375 380

Ser Ser Ala

385

<210> 545

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 545

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val

370 375 380

Ser Ser Ala

385

<210> 546

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 546

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val

370 375 380

Ser Ser Ala

385

<210> 547

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 547

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val

370 375 380

Ser Ser Ala

385

<210> 548

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 548

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Lys Val

370 375 380

Ser Ser Ala

385

<210> 549

<211> 387

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 549

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Leu Pro

20 25 30

Ala Ser Gly Asn Ile Phe Asn Leu Leu Thr Ile Ala Trp Tyr Arg Gln

35 40 45

Ala Pro Gly Lys Gly Arg Glu Leu Val Ala Thr Ile Asn Ser Gly Ser

50 55 60

Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

65 70 75 80

Asp Asn Ser Lys Lys Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro

85 90 95

Glu Asp Thr Ala Leu Tyr Tyr Cys Gln Thr Ser Gly Ser Gly Ser Pro

100 105 110

Asn Phe Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro

260 265 270

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser

275 280 285

Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu

290 295 300

Phe Val Ala Arg Ile Ser Gln Gly Gly Thr Ala Ile Tyr Tyr Ala Asp

305 310 315 320

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

325 330 335

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

340 345 350

Tyr Cys Ala Lys Asp Pro Ser Pro Tyr Tyr Arg Gly Ser Ala Tyr Leu

355 360 365

Leu Ser Gly Ser Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Gln Val

370 375 380

Ser Ser Ala

385

<210> 550

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 550

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360 365

<210> 551

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 551

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360 365

<210> 552

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 552

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360 365

<210> 553

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 553

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360 365

<210> 554

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 554

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360 365

<210> 555

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 555

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360 365

<210> 556

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 556

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360 365

<210> 557

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 557

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360 365

<210> 558

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 558

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360 365

<210> 559

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 559

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360 365

<210> 560

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 560

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360 365

<210> 561

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 561

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360 365

<210> 562

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 562

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360 365

<210> 563

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 563

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360 365

<210> 564

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 564

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360 365

<210> 565

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 565

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360 365

<210> 566

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 566

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360 365

<210> 567

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 567

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360 365

<210> 568

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 568

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360 365

<210> 569

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 569

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360 365

<210> 570

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 570

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360 365

<210> 571

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 571

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360 365

<210> 572

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 572

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360 365

<210> 573

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 573

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360 365

<210> 574

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 574

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360 365

<210> 575

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 575

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360 365

<210> 576

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 576

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360 365

<210> 577

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 577

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360 365

<210> 578

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 578

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360 365

<210> 579

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 579

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360 365

<210> 580

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 580

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360 365

<210> 581

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 581

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360 365

<210> 582

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 582

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360 365

<210> 583

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 583

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360 365

<210> 584

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 584

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360 365

<210> 585

<211> 368

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 585

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp

20 25 30

Arg Met Gly Trp Tyr Arg His Arg Pro Gly Glu Pro Arg Glu Leu Val

35 40 45

Ala Thr Ile Thr Gly Gly Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn

85 90 95

Phe Asn Lys Tyr Val Thr Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu

100 105 110

Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val

115 120 125

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu

130 135 140

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met

145 150 155 160

Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser

165 170 175

Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly

180 185 190

Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln

195 200 205

Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile

210 215 220

Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser

225 230 235 240

Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu

245 250 255

Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

260 265 270

Ala Ala Ser Arg Ser Ile Gly Arg Leu Asp Arg Met Gly Trp Tyr Arg

275 280 285

His Arg Pro Gly Glu Pro Arg Glu Leu Val Ala Thr Ile Thr Gly Gly

290 295 300

Ser Ser Ile Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

305 310 315 320

Ile Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

325 330 335

Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Asn Phe Asn Lys Tyr Val Thr

340 345 350

Ser Arg Asp Thr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360 365

<210> 586

<211> 247

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 586

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln

130 135 140

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

145 150 155 160

Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro

165 170 175

Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala

180 185 190

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

195 200 205

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

210 215 220

Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr

225 230 235 240

Leu Val Thr Val Ser Ser Ala

245

<210> 587

<211> 247

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 587

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln

130 135 140

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

145 150 155 160

Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro

165 170 175

Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala

180 185 190

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

195 200 205

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

210 215 220

Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr

225 230 235 240

Leu Val Lys Val Ser Ser Ala

245

<210> 588

<211> 247

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 588

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln

130 135 140

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

145 150 155 160

Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro

165 170 175

Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala

180 185 190

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

195 200 205

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

210 215 220

Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr

225 230 235 240

Leu Val Gln Val Ser Ser Ala

245

<210> 589

<211> 247

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 589

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln

130 135 140

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

145 150 155 160

Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro

165 170 175

Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala

180 185 190

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

195 200 205

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

210 215 220

Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr

225 230 235 240

Leu Val Thr Val Ser Ser Ala

245

<210> 590

<211> 247

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 590

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln

130 135 140

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

145 150 155 160

Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro

165 170 175

Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala

180 185 190

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

195 200 205

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

210 215 220

Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr

225 230 235 240

Leu Val Lys Val Ser Ser Ala

245

<210> 591

<211> 247

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 591

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln

130 135 140

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

145 150 155 160

Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro

165 170 175

Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala

180 185 190

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

195 200 205

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

210 215 220

Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr

225 230 235 240

Leu Val Gln Val Ser Ser Ala

245

<210> 592

<211> 247

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 592

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln

130 135 140

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

145 150 155 160

Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro

165 170 175

Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala

180 185 190

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

195 200 205

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

210 215 220

Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr

225 230 235 240

Leu Val Thr Val Ser Ser Ala

245

<210> 593

<211> 247

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 593

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln

130 135 140

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

145 150 155 160

Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro

165 170 175

Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala

180 185 190

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

195 200 205

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

210 215 220

Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr

225 230 235 240

Leu Val Lys Val Ser Ser Ala

245

<210> 594

<211> 247

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 594

Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Arg Pro Glu Trp Val

35 40 45

Ser Ser Ile Asp Thr Gly Gly Asp Ile Thr His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Trp Cys

85 90 95

Ala Thr Asp Glu Glu Tyr Ala Leu Gly Pro Asn Glu Phe Asp Tyr Tyr

100 105 110

Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln

130 135 140

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

145 150 155 160

Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro

165 170 175

Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala

180 185 190

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

195 200 205

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

210 215 220

Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr

225 230 235 240

Leu Val Gln Val Ser Ser Ala

245

<210> 595

<211> 271

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 595

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

130 135 140

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu

145 150 155 160

Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr Ala Met

165 170 175

Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala

180 185 190

Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr Gly Asp

195 200 205

Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr

210 215 220

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

225 230 235 240

Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg Phe Glu

245 250 255

Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

260 265 270

<210> 596

<211> 271

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 596

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

130 135 140

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu

145 150 155 160

Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr Ala Met

165 170 175

Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala

180 185 190

Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr Gly Asp

195 200 205

Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr

210 215 220

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

225 230 235 240

Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg Phe Glu

245 250 255

Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

260 265 270

<210> 597

<211> 271

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 597

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

130 135 140

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu

145 150 155 160

Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr Ala Met

165 170 175

Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala

180 185 190

Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr Gly Asp

195 200 205

Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr

210 215 220

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

225 230 235 240

Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg Phe Glu

245 250 255

Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

260 265 270

<210> 598

<211> 271

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 598

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

130 135 140

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu

145 150 155 160

Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr Ala Met

165 170 175

Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala

180 185 190

Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr Gly Asp

195 200 205

Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr

210 215 220

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

225 230 235 240

Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg Phe Glu

245 250 255

Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

260 265 270

<210> 599

<211> 271

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 599

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

130 135 140

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu

145 150 155 160

Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr Ala Met

165 170 175

Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala

180 185 190

Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr Gly Asp

195 200 205

Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr

210 215 220

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

225 230 235 240

Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg Phe Glu

245 250 255

Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

260 265 270

<210> 600

<211> 271

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 600

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

130 135 140

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu

145 150 155 160

Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr Ala Met

165 170 175

Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala

180 185 190

Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr Gly Asp

195 200 205

Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr

210 215 220

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

225 230 235 240

Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg Phe Glu

245 250 255

Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

260 265 270

<210> 601

<211> 271

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 601

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

130 135 140

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu

145 150 155 160

Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr Ala Met

165 170 175

Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala

180 185 190

Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr Gly Asp

195 200 205

Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr

210 215 220

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

225 230 235 240

Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg Phe Glu

245 250 255

Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

260 265 270

<210> 602

<211> 271

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 602

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

130 135 140

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu

145 150 155 160

Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr Ala Met

165 170 175

Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala

180 185 190

Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr Gly Asp

195 200 205

Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr

210 215 220

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

225 230 235 240

Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg Phe Glu

245 250 255

Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

260 265 270

<210> 603

<211> 271

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 603

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Lys Ser Ser Gly Asp Ser Thr Arg Tyr Ala Gly Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Ser Arg Val Ser Arg Thr Gly Leu Tyr Thr Tyr Asp Asn Arg

100 105 110

Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

130 135 140

Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu

145 150 155 160

Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn Tyr Ala Met

165 170 175

Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala

180 185 190

Ile Thr Arg Ser Gly Val Arg Ser Gly Val Ser Ala Ile Tyr Gly Asp

195 200 205

Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr

210 215 220

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr

225 230 235 240

Tyr Cys Ala Ala Ser Ala Ile Gly Ser Gly Ala Leu Arg Arg Phe Glu

245 250 255

Tyr Asp Tyr Ser Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

260 265 270

<210> 604

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 604

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Thr Val Ser Ser Ala

370 375

<210> 605

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 605

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Lys Val Ser Ser Ala

370 375

<210> 606

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 606

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Gln Val Ser Ser Ala

370 375

<210> 607

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 607

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Thr Val Ser Ser Ala

370 375

<210> 608

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 608

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Lys Val Ser Ser Ala

370 375

<210> 609

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 609

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Gln Val Ser Ser Ala

370 375

<210> 610

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 610

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Thr Val Ser Ser Ala

370 375

<210> 611

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 611

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Lys Val Ser Ser Ala

370 375

<210> 612

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 612

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Gln Val Ser Ser Ala

370 375

<210> 613

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 613

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Thr Val Ser Ser Ala

370 375

<210> 614

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 614

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Lys Val Ser Ser Ala

370 375

<210> 615

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 615

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Gln Val Ser Ser Ala

370 375

<210> 616

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 616

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Thr Val Ser Ser Ala

370 375

<210> 617

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 617

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Lys Val Ser Ser Ala

370 375

<210> 618

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 618

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Gln Val Ser Ser Ala

370 375

<210> 619

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 619

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Thr Val Ser Ser Ala

370 375

<210> 620

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 620

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Lys Val Ser Ser Ala

370 375

<210> 621

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 621

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Gln Val Ser Ser Ala

370 375

<210> 622

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 622

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Thr Val Ser Ser Ala

370 375

<210> 623

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 623

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Lys Val Ser Ser Ala

370 375

<210> 624

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 624

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Gln Val Ser Ser Ala

370 375

<210> 625

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 625

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Thr Val Ser Ser Ala

370 375

<210> 626

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 626

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Lys Val Ser Ser Ala

370 375

<210> 627

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 627

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Gln Val Ser Ser Ala

370 375

<210> 628

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 628

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Thr Val Ser Ser Ala

370 375

<210> 629

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 629

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Lys Val Ser Ser Ala

370 375

<210> 630

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 630

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Gln Val Ser Ser Ala

370 375

<210> 631

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 631

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Thr Val Ser Ser Ala

370 375

<210> 632

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 632

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Lys Val Ser Ser Ala

370 375

<210> 633

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 633

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Gln Val Ser Ser Ala

370 375

<210> 634

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 634

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Thr Val Ser Ser Ala

370 375

<210> 635

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 635

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Lys Val Ser Ser Ala

370 375

<210> 636

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 636

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Gln Val Ser Ser Ala

370 375

<210> 637

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 637

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Thr Val Ser Ser Ala

370 375

<210> 638

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 638

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Lys Val Ser Ser Ala

370 375

<210> 639

<211> 377

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 639

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Gly Gly Leu Asn

20 25 30

Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val

35 40 45

Ala Gly Ile Phe Gly Val Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Arg

85 90 95

Met Ser Ser Val Thr Arg Gly Ser Ser Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu

115 120 125

Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser

130 135 140

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly

145 150 155 160

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

165 170 175

Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys

180 185 190

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

195 200 205

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr

210 215 220

Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val

225 230 235 240

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val

245 250 255

Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

260 265 270

Cys Ala Ala Ser Gly Arg Thr Tyr Tyr Leu Asn Ala Met Gly Trp Phe

275 280 285

Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Asp Trp

290 295 300

Ser Glu Gly Asn Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr

305 310 315 320

Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser

325 330 335

Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp Thr Pro

340 345 350

Pro Trp Gly Pro Leu Ile Tyr Ile Glu Ser Tyr Asp Ser Trp Gly Gln

355 360 365

Gly Thr Leu Val Gln Val Ser Ser Ala

370 375

<210> 640

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 640

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360

<210> 641

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 641

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360

<210> 642

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 642

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360

<210> 643

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 643

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360

<210> 644

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 644

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360

<210> 645

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 645

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360

<210> 646

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 646

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360

<210> 647

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 647

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360

<210> 648

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 648

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360

<210> 649

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 649

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360

<210> 650

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 650

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360

<210> 651

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 651

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360

<210> 652

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 652

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360

<210> 653

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 653

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360

<210> 654

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 654

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360

<210> 655

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 655

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360

<210> 656

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 656

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360

<210> 657

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 657

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360

<210> 658

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 658

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360

<210> 659

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 659

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360

<210> 660

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 660

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360

<210> 661

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 661

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360

<210> 662

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 662

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360

<210> 663

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 663

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360

<210> 664

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 664

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360

<210> 665

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 665

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360

<210> 666

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 666

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360

<210> 667

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 667

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360

<210> 668

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 668

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360

<210> 669

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 669

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360

<210> 670

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 670

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360

<210> 671

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 671

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360

<210> 672

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 672

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360

<210> 673

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 673

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

355 360

<210> 674

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 674

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

355 360

<210> 675

<211> 364

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 675

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Glu Ile Asn Thr Asn Gly Leu Ile Thr Lys Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ser Gly Phe Asn Arg Gly Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Asp Tyr Trp Met Tyr Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ser Glu Ile Asn Thr Asn Gly Leu

290 295 300

Ile Thr Lys Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Arg Ser Pro Ser Gly Phe Asn

340 345 350

Arg Gly Gln Gly Thr Leu Val Gln Val Ser Ser Ala

355 360

<210> 676

<211> 250

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 676

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Pro Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Ala

245 250

<210> 677

<211> 250

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 677

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Pro Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Lys Val Ser Ser Ala

245 250

<210> 678

<211> 250

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 678

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Pro Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Gln Val Ser Ser Ala

245 250

<210> 679

<211> 250

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 679

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Pro Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Ala

245 250

<210> 680

<211> 250

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 680

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Pro Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Lys Val Ser Ser Ala

245 250

<210> 681

<211> 250

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 681

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Pro Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Gln Val Ser Ser Ala

245 250

<210> 682

<211> 250

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 682

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Pro Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Thr Val Ser Ser Ala

245 250

<210> 683

<211> 250

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 683

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Pro Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Lys Val Ser Ser Ala

245 250

<210> 684

<211> 250

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 684

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Asp Tyr Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Leu Cys Ile Asp Ala Ser Asp Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Thr Pro Ile Gly Leu Ser Ser Ser Cys Leu Leu Glu Tyr Asp Tyr

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly

130 135 140

Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

145 150 155 160

Phe Thr Phe Arg Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

165 170 175

Lys Gly Pro Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr

180 185 190

Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

195 200 205

Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

210 215 220

Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser

225 230 235 240

Gln Gly Thr Leu Val Gln Val Ser Ser Ala

245 250

<210> 685

<211> 249

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 685

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Ala

245

<210> 686

<211> 249

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 686

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Lys Val Ser Ser Ala

245

<210> 687

<211> 249

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 687

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Gln Val Ser Ser Ala

245

<210> 688

<211> 249

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 688

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Ala

245

<210> 689

<211> 249

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 689

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Lys Val Ser Ser Ala

245

<210> 690

<211> 249

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 690

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Gln Val Ser Ser Ala

245

<210> 691

<211> 249

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 691

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Ala

245

<210> 692

<211> 249

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 692

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Lys Val Ser Ser Ala

245

<210> 693

<211> 249

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 693

Asp Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asp Asp Tyr

20 25 30

Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Gly Val

35 40 45

Ser Ser Ile Ser Ser Thr Tyr Gly Leu Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Thr Pro Ile Gly Leu Ile Gly Leu Asp Ala Tyr Glu Tyr Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Gln Val Ser Ser Ala

245

<210> 694

<211> 386

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 694

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

130 135 140

Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser

145 150 155 160

Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro

165 170 175

Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp

180 185 190

Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

195 200 205

Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu

210 215 220

Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser

225 230 235 240

Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

245 250 255

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

260 265 270

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

275 280 285

Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg

290 295 300

Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala

305 310 315 320

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn

325 330 335

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

340 345 350

Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp

355 360 365

Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

370 375 380

Ser Ala

385

<210> 695

<211> 386

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 695

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

130 135 140

Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser

145 150 155 160

Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro

165 170 175

Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp

180 185 190

Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

195 200 205

Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu

210 215 220

Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser

225 230 235 240

Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

245 250 255

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

260 265 270

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

275 280 285

Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg

290 295 300

Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala

305 310 315 320

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn

325 330 335

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

340 345 350

Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp

355 360 365

Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser

370 375 380

Ser Ala

385

<210> 696

<211> 386

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 696

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

130 135 140

Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser

145 150 155 160

Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro

165 170 175

Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp

180 185 190

Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

195 200 205

Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu

210 215 220

Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser

225 230 235 240

Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

245 250 255

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

260 265 270

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

275 280 285

Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg

290 295 300

Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala

305 310 315 320

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn

325 330 335

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

340 345 350

Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp

355 360 365

Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser

370 375 380

Ser Ala

385

<210> 697

<211> 386

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 697

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

130 135 140

Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser

145 150 155 160

Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro

165 170 175

Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp

180 185 190

Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

195 200 205

Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu

210 215 220

Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser

225 230 235 240

Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

245 250 255

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

260 265 270

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

275 280 285

Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg

290 295 300

Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala

305 310 315 320

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn

325 330 335

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

340 345 350

Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp

355 360 365

Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

370 375 380

Ser Ala

385

<210> 698

<211> 386

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 698

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

130 135 140

Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser

145 150 155 160

Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro

165 170 175

Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp

180 185 190

Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

195 200 205

Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu

210 215 220

Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser

225 230 235 240

Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

245 250 255

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

260 265 270

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

275 280 285

Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg

290 295 300

Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala

305 310 315 320

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn

325 330 335

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

340 345 350

Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp

355 360 365

Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser

370 375 380

Ser Ala

385

<210> 699

<211> 386

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 699

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

130 135 140

Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser

145 150 155 160

Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro

165 170 175

Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp

180 185 190

Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

195 200 205

Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu

210 215 220

Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser

225 230 235 240

Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

245 250 255

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

260 265 270

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

275 280 285

Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg

290 295 300

Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala

305 310 315 320

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn

325 330 335

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

340 345 350

Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp

355 360 365

Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser

370 375 380

Ser Ala

385

<210> 700

<211> 386

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 700

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

130 135 140

Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser

145 150 155 160

Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro

165 170 175

Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp

180 185 190

Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

195 200 205

Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu

210 215 220

Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser

225 230 235 240

Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly

245 250 255

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

260 265 270

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

275 280 285

Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg

290 295 300

Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala

305 310 315 320

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn

325 330 335

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

340 345 350

Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp

355 360 365

Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

370 375 380

Ser Ala

385

<210> 701

<211> 386

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 701

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

130 135 140

Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser

145 150 155 160

Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro

165 170 175

Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp

180 185 190

Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

195 200 205

Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu

210 215 220

Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser

225 230 235 240

Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly

245 250 255

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

260 265 270

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

275 280 285

Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg

290 295 300

Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala

305 310 315 320

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn

325 330 335

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

340 345 350

Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp

355 360 365

Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser

370 375 380

Ser Ala

385

<210> 702

<211> 386

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 702

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

130 135 140

Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser

145 150 155 160

Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro

165 170 175

Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp

180 185 190

Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

195 200 205

Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu

210 215 220

Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser

225 230 235 240

Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly

245 250 255

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

260 265 270

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

275 280 285

Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg

290 295 300

Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala

305 310 315 320

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn

325 330 335

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

340 345 350

Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp

355 360 365

Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser

370 375 380

Ser Ala

385

<210> 703

<211> 386

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 703

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

130 135 140

Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser

145 150 155 160

Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro

165 170 175

Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp

180 185 190

Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

195 200 205

Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu

210 215 220

Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser

225 230 235 240

Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly

245 250 255

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

260 265 270

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

275 280 285

Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg

290 295 300

Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala

305 310 315 320

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn

325 330 335

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

340 345 350

Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp

355 360 365

Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

370 375 380

Ser Ala

385

<210> 704

<211> 386

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 704

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

130 135 140

Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser

145 150 155 160

Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro

165 170 175

Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp

180 185 190

Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

195 200 205

Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu

210 215 220

Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser

225 230 235 240

Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly

245 250 255

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

260 265 270

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

275 280 285

Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg

290 295 300

Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala

305 310 315 320

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn

325 330 335

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

340 345 350

Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp

355 360 365

Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser

370 375 380

Ser Ala

385

<210> 705

<211> 386

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 705

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp Tyr Arg Lys

100 105 110

Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

115 120 125

Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

130 135 140

Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser

145 150 155 160

Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro

165 170 175

Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp

180 185 190

Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

195 200 205

Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu

210 215 220

Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser

225 230 235 240

Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly

245 250 255

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

260 265 270

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

275 280 285

Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg

290 295 300

Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala

305 310 315 320

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn

325 330 335

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu

340 345 350

Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr Tyr Leu Ser Arg Asp

355 360 365

Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser

370 375 380

Ser Ala

385

<210> 706

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 706

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Thr Val Ser Ser Ala

370 375

<210> 707

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 707

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Lys Val Ser Ser Ala

370 375

<210> 708

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 708

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Gln Val Ser Ser Ala

370 375

<210> 709

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 709

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Thr Val Ser Ser Ala

370 375

<210> 710

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 710

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Lys Val Ser Ser Ala

370 375

<210> 711

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 711

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Gln Val Ser Ser Ala

370 375

<210> 712

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 712

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Thr Val Ser Ser Ala

370 375

<210> 713

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 713

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Lys Val Ser Ser Ala

370 375

<210> 714

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 714

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Gln Val Ser Ser Ala

370 375

<210> 715

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 715

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Thr Val Ser Ser Ala

370 375

<210> 716

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 716

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Lys Val Ser Ser Ala

370 375

<210> 717

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 717

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Gln Val Ser Ser Ala

370 375

<210> 718

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 718

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Thr Val Ser Ser Ala

370 375

<210> 719

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 719

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Lys Val Ser Ser Ala

370 375

<210> 720

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 720

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Gln Val Ser Ser Ala

370 375

<210> 721

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 721

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Thr Val Ser Ser Ala

370 375

<210> 722

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 722

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Lys Val Ser Ser Ala

370 375

<210> 723

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 723

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Gln Val Ser Ser Ala

370 375

<210> 724

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 724

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Thr Val Ser Ser Ala

370 375

<210> 725

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 725

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Lys Val Ser Ser Ala

370 375

<210> 726

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 726

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Lys Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Gln Val Ser Ser Ala

370 375

<210> 727

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 727

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Thr Val Ser Ser Ala

370 375

<210> 728

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 728

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Lys Val Ser Ser Ala

370 375

<210> 729

<211> 375

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 729

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Gln Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Ser Ser Tyr Pro Met Gly Trp Phe Arg Gln Ala

275 280 285

Pro Gly Lys Gly Arg Glu Phe Val Ser Ser Ile Thr Gly Ser Gly Gly

290 295 300

Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

305 310 315 320

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

325 330 335

Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Tyr Ile Arg Pro Asp Thr

340 345 350

Tyr Leu Ser Arg Asp Tyr Arg Lys Tyr Asp Tyr Trp Gly Gln Gly Thr

355 360 365

Leu Val Gln Val Ser Ser Ala

370 375

<210> 730

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 730

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 731

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 731

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

370 375 380

<210> 732

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 732

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 733

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 733

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 734

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 734

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

370 375 380

<210> 735

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 735

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 736

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 736

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 737

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 737

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

370 375 380

<210> 738

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 738

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 739

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 739

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 740

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 740

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

370 375 380

<210> 741

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 741

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 742

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 742

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 743

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 743

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

370 375 380

<210> 744

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 744

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 745

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 745

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 746

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 746

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

370 375 380

<210> 747

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 747

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 748

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 748

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 749

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 749

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

370 375 380

<210> 750

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 750

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 751

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 751

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 752

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 752

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

370 375 380

<210> 753

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 753

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 754

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 754

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 755

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 755

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

370 375 380

<210> 756

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 756

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 757

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 757

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 758

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 758

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

370 375 380

<210> 759

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 759

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 760

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 760

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 761

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 761

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

370 375 380

<210> 762

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 762

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Lys Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 763

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 763

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 764

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 764

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Lys Val Ser Ser Ala

370 375 380

<210> 765

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 765

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Leu

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Leu Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Gln Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<210> 766

<211> 382

<212>PRT

<213> Artificial Sequence

<220>

<223> Nanobody construct

<400> 766

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val His Ser Gly Pro Thr Phe Arg Thr Asp

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val

35 40 45

Ala Ala Val Thr Trp Asn Ser Gly Arg Ile Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ala His Arg Phe Val Val Gly Gly Asn Arg Val Glu Asp Trp Arg

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

130 135 140

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

145 150 155 160

Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

165 170 175

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu

180 185 190

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

195 200 205

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

210 215 220

Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln

225 230 235 240

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly

260 265 270

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Asn

275 280 285

Tyr Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe

290 295 300

Val Ala Ala Val Ser Arg Ser Gly Val Ser Thr Tyr Tyr Ala Asp Ser

305 310 315 320

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val

325 330 335

Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr

340 345 350

Cys Ala Ala Ala Tyr Arg Gly Thr Ala Ile Asn Val Arg Arg Ser Tyr

355 360 365

Ser Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

370 375 380

<---

Claims (50)

1. A single immunoglobulin heavy chain variable domain (ISVD) representing a co-VHH domain, a humanized VHH domain, or an overblown VH domain that is directed against TNF, in which (i) position 112 is K or Q; or (ii) position 110 is K or Q and position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v); wherein the polypeptide has reduced binding to pre-existing antibodies present in samples from subjects suffering from SLE, compared to a polypeptide containing VHH, humanized VHH or overblown VH without amino acid residues (i) 112 K or Q; (ii) 110 K or Q and 11 V; (iii) 89T; (iv) 89L and 110 K or Q; or (v) 11B and 89L; where the positions of amino acid residues are designated by Kabat numbering. 2. Heavy chain ISVD according to claim 1, wherein: - the amino acid residue at position 11 is preferably selected from L, V or K (and most preferably is V); And the amino acid residue at position 14 is preferably suitably selected from A or P; And - the amino acid residue at position 41 is preferably suitably selected from A or P; And - the amino acid residue at position 89 is preferably suitably selected from T, V or L; And - the amino acid residue at position 108 is preferably suitably selected from Q or L; And the amino acid residue at position 110 is preferably suitably selected from T, K or Q; And the amino acid residue at position 112 is preferably suitably selected from S, K or Q; so that either (i) position 112 is K or Q; or (ii) position 110 is K or Q and position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v) thereof. 3. The heavy chain ISVD of claim 1 or 2, wherein the amino acid residue at position 112 is K or Q. 4. The heavy chain ISVD of claim 1 or 2, wherein the amino acid residue at position 110 is K or Q and the amino acid residue at position 11 is V. 5. The heavy chain ISVD of claim 1 or 2, wherein the amino acid residue at position 89 is T. 6. The heavy chain ISVD of claim 1 or 2, wherein the amino acid residue at position 89 is L and the amino acid residue at position 110 is K or Q. 7. The heavy chain ISVD of claim 1 or 2, wherein the amino acid residue at position 11 is V and the amino acid residue at position 89 is L. 8. The heavy chain ISVD of any one of the preceding claims, which further comprises (i) a P14A substitution or an A14P substitution and/or (ii) a Q108L substitution. 9. A heavy chain ISVD as claimed in any one of the preceding claims, which comprises a C-terminal extension (X) _n , wherein (i)n is 1-10, preferably 1-5, such as 1, 2, 3, 4 or 5 ( preferably 1 or 2, for example 1); and each (ii) X is an amino acid residue (preferably naturally occurring) which is independently selected, and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) and isoleucine (I). 10. Heavy chain ISVD according to any one of paragraphs. 1-9, which contains (i) a CDR1 sequence that is the sequence of SEQ ID NO: 317 or which is an amino acid sequence that differs from the sequence of SEQ ID NO: 317 in only one amino acid; (ii) a CDR2 sequence that is the sequence of SEQ ID NO: 318 or that is an amino acid sequence that differs from the sequence of SEQ ID NO: 318 in only one or two amino acids; and (iii) a CDR3 sequence that is the sequence of SEQ ID NO: 319 or that is an amino acid sequence that differs from the sequence of SEQ ID NO: 319 in only one or two amino acids. 11. The heavy chain ISVD of claim 10, wherein (i) CDR1 is SEQ ID NO: 317; (ii) CDR2 is SEQ ID NO: 318 and (iii) CDR3 is SEQ ID NO: 319. 12. A heavy chain ISVD that is directed against TNF that has a degree of sequence identity to SEQ ID NO: 316 of at least 90%, wherein: - the amino acid residue at position 11 is preferably selected from L, V or K (and most preferably is V); And - the amino acid residue at position 14 is preferably suitably selected from A or P; And - the amino acid residue at position 41 is preferably suitably selected from A or P; And - the amino acid residue at position 89 is preferably suitably selected from T, V or L; And - the amino acid residue at position 108 is preferably suitably selected from Q or L; And - the amino acid residue at position 110 is preferably suitably selected from T, K or Q; And - the amino acid residue at position 112 is preferably suitably selected from S, K or Q; so that either (i) position 112 is K or Q; or (ii) position 110 is K or Q and position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any suitable combination of (i)-(v). 13. A heavy chain ISVD as claimed in any one of the preceding claims, which is a VHH domain, a humanized VHH domain, or a _VH domain overblown. 14. A heavy chain ISVD that is directed against TNF, having an amino acid sequence that is selected from the amino acid sequences of SEQ ID NOs: 320, 321 and 324-333. 15. Heavy chain ISVD according to any one of paragraphs. 1-9, which includes (i) a CDR1 sequence that is the sequence of SEQ ID NO: 335 or that is an amino acid sequence that differs from the sequence of SEQ ID NO: 335 in only one amino acid; (ii) a CDR2 sequence that is the sequence of SEQ ID NO: 336 or that is an amino acid sequence that differs from the sequence of SEQ ID NO: 336 in only one or two amino acids; and (iii) a CDR3 sequence that is the sequence of SEQ ID NO: 337 or that is an amino acid sequence that differs from the sequence of SEQ ID NO: 337 in only one or two amino acids. 16. The heavy chain ISVD of claim 15, wherein: (i) CDR1 is SEQ ID NO: 335; (ii) CDR2 is SEQ ID NO: 336 and (iii) CDR3 is SEQ ID NO: 337. 17. A heavy chain ISVD that is directed against TNF that has a degree of sequence identity to SEQ ID NO: 334 of at least 90%, in which: the amino acid residue at position 11 is preferably selected from L, V or K (and most preferably is V); And the amino acid residue at position 14 is preferably selected from A or P; And the amino acid residue at position 41 is preferably selected from A or P; And the amino acid residue at position 89 is preferably selected from T, V or L; And the amino acid residue at position 108 is preferably selected from Q or L; And the amino acid residue at position 110 is preferably selected from T, K or Q; And the amino acid residue at position 112 is preferably selected from S, K or Q; so that either (i) position 112 is K or Q; or (ii) position 110 is K or Q and position 11 is V; or (iii) position 89 is T; or (iv) position 89 is L and position 110 is K or Q; or (v) position 11 is V and position 89 is L; or any combination of (i)-(v). 18. Heavy chain ISVD according to any one of paragraphs. 15-17, which is a VHH domain, a humanized VHH domain, or an overblown VH domain. 19. A heavy chain ISVD directed against TNF, having an amino acid sequence that is selected from the amino acid sequences of SEQ ID NO: 338, 339 and 342-351. 20. A polypeptide directed against TNF, which includes at least one VH domain according to any one of claims. 1-19 and which contains: (i) a single immunoglobulin variable domain that binds serum albumin; and/or (ii) a C-terminal extension (X)n, wherein (i) n is from 1 to 10, preferably from 1 to 5, for example 1, 2, 3, 4 or 5 (and preferably 1 or 2, for example 1 ); and (ii) each X is an amino acid residue (preferably naturally occurring) that is independently selected and preferably independently selected from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). 21. The polypeptide of claim 20, which has a half-life (expressed as t1/2 beta) in a human subject of at least 1 day, preferably at least 3 days, more preferably at least 7 days, such as at least 10 days. 22. An anti-TNF polypeptide having an amino acid sequence that is selected from the amino acid sequences of SEQ ID NOs: 640-675. 23. A composition directed against TNF, comprising a therapeutically effective amount of ISVD heavy chain according to any one of paragraphs. 1-19 or a polypeptide according to any one of paragraphs. 20-22 and a pharmaceutically acceptable carrier. 24. The composition according to claim 23, which is a pharmaceutical composition.

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