AU2014200157A1 - Improved anti-serum albumin binding single variable domains - Google Patents

Abstract

The invention relates to improved anti-serum albumin immunoglobulin single variable domains, as well as ligands and drug conjugates comprising such variable domains, compositions, nucleic acids, vectors and hosts.

Description

H:\seg\IVnw-\NRPodblI\DCC\SCG5935936_1 OC-0 1/2014 IMPROVED ANTI-SERUM ALBUMIN BINDING SINGLE VARIABLE DOMAINS The invention relates to improved anti-serum albumin immunoglobulin single variable domains, as well as ligands and drug conjugates comprising such domains, 5 compositions, nucleic acids, vectors and hosts. This is a divisional of Australian Patent Application No. 2010272590, the entire contents of which are incorporated herein by reference. BACKGROUND OF THE INVENTION 10 W004003019 and W02008/096158 disclose anti-serum albumin (SA) binding moieties, such as anti-SA immunoglobulin single variable domains (dAbs), which have therapeutically-useful half-lives. These documents disclose monomer anti-SA dAbs as well as multi-specific ligands comprising such dAbs, eg, ligands comprising an anti-SA dAb and a dAb that specifically binds a target antigen, such as TNFR1. Binding moieties 15 are disclosed that specifically bind serum albumins from more than one species, eg human/mouse cross-reactive anti-SA dAbs. WOO5118642 and W02006/059106 disclose the concept of conjugating or associating an anti-SA binding moiety, such as an anti-SA immunoglobulin single variable domain, to a drug, in order to increase the half-life of the drug. Protein, peptide and NCE 20 (chemical entity) drugs are disclosed and exemplified. W02006/059106 discloses the use of this concept to increase the half-life of insulintropic agents, eg, incretin hormones such as glucagon-like peptide (GLP)-1. Reference is also made to Holt et al, "Anti-Serum albumin domain antibodies for extending the half-lives of short lived drugs", Protein Engineering, Design & Selection, vol 25 21, no 5, pp283-288, 2008. It would be desirable to provide improved heavy chain variable domain dAbs that specifically bind serum albumin, preferably albumins from human and non-human species, which would provide utility in animal models of disease as well as for human therapy and/or diagnosis. It would also be desirable to provide for the choice between WO 2011/006915 PCT/EP2010/I6(112 -2 relatively modest- and high-affinity anti-SA binding moieties (dAbs). Such moieties could be linked to drugs, the anti-SA binding moiety being chosen according to the contemplated end-application. This would allow the drug to be better tailored to treating and/or preventing chronic or acute indications, depending upon the choice of 5 anti-SA binding moiety. It would also be desirable to provide anti-SA dAbs that are monomeric or substantially so in solution. This would especially be advantageous when the anti-SA dAb is linked to a binding moiety, eg, a dAb, that specifically binds a cell-surface receptor, such as TNFR1, with the aim of antagonizing the receptor. The monomeric state of the anti-SA dAb is useful in reducing the chance of receptor cross 10 linking, since multimers are less likely to form which could bind and cross-link receptors (eg, TNFR1) on the cell surface, thus increasing the likelihood of receptor agonism and detrimental receptor signaling. It would also be desirable to provide anti SA dAbs that have relatively high melting temperatures. This is useful for providing stable formulations, eg, storage-stable formulations and variable domains that have a 15 good shelf-life. SUMMARY OF THE INVENTION Aspects of the present invention solve these problems. In one aspect the invention, therefore, there is provided an anti-serum albumin 20 (SA) immunoglobulin single variable domain comprising an amino acid sequence that is at least 80% identical to an amino acid sequence selected from SEQ ID NOs: 97 to 191 and 198 to 203. An aspect of the invention provides an anti-serum albumin (SA) immunoglobulin single variable domain comprising an amino acid sequence having up 25 to 4 amino acid changes compared to an amino acid sequence selected from SEQ ID NOs: 97 to 191 and 198 to 203. An aspect of the invention provides an anti-serum albumin (SA) immunoglobulin single variable domain comprising an amino acid sequence that is WO 2011/006915 PCT/EP21I0/060112 -3 encoded by a nucleotide sequence which is at least 80% identical to a sequence selected from SEQ ID NOs I to 96 and 192-197. An aspect of the invention provides a multispecific ligand comprising an anti SA variable domain of the invention and a binding moiety that specifically binds a 5 target antigen other than SA. An aspect of the invention provides an anti-SA single variable domain of the invention, wherein the variable domain is conjugated to a drug (optionally an NCE drug). An aspect of the invention provides a fusion product, eg, a fusion protein or 10 fusion with a peptide or NCE (new chemical entity) drug, comprising a polypeptide, protein, peptide or NCE drug fused or conjugated (for an NCE) to any anti-SA variable domain of the invention. For example, the variable domain comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 97 to 103 and 198 to 203 (or an amino acid sequence that is at least 95, 96, 97, 98 or 99% identical to the amino acid sequence 15 of any one of SEQ ID NOs: 97 to 103 and 198 to 203). An aspect of the invention provides a composition comprising a variable domain, fusion protein or ligand of the invention and a pharmaceutically acceptable diluent, carrier, excipient or vehicle, An aspect of the invention provides a nucleic acid comprising a nucleotide 20 sequence encoding a variable domain, or a multispecific ligand or fusion protein of the invention. An aspect of the invention provides a nucleic acid comprising a nucleotide sequence that is at least 80% identical to a sequence selected from SEQ ID NOs 1 to 96 and 192-197. 25 An aspect of the invention provides a vector comprising the nucleic acid of the invention. An aspect of the invention provides an isolated host cell comprising the vector of the invention.

WO 2011/006915 PCT/EP2010/060112 -4 An aspect of the invention provides a method of treating or preventing a disease or disorder in a patient, comprising administering at least one dose of a variable domain, or a multispecific ligand or fusion protein of the invention to said patient. Embodiments of any aspect of the invention provide anti-serum albumin single 5 variable domains of good anti-serum albumin affinities. The choice of variable domain can allow for tailoring of half-life according to the desired therapeutic and/or prophylactic setting. For example, in one embodiment, the affinity of the variable domain for serum albumin is relatively high, such that the variable domain would be useful for inclusion in products that find utility in treating and/or preventing chronic or 10 persistent diseases, conditions, toxicity or other chronic indications. In one embodiment, the affinity of the variable domain for serum albumin is relatively modest, such that the variable domain would be useful for inclusion in products that find utility in treating and/or preventing acute diseases, conditions, toxicity or other acute indications, In one embodiment, the affinity of the variable domain for serum albumin is intermediate, such 15 that the variable domain would be useful for inclusion in products that find utility in treating and/or preventing acute or chronic diseases, conditions, toxicity or other acute or chronic indications. It is conceivable that a molecule with an appropriately high affinity and specificity for serum albumin would stay in circulation long enough to have the desired 20 therapeutic effect. (Tomlinson, Nature Biotechnology 22, 521 - 522 (2004)). Here, a high affinity anti-SA variable domain would stay in serum circulation matching that of the species' serum albumin (WO2008096158). Once in circulation, any fused therapeutic agent to the AlbudAb variable domain, be it NCE, peptide or protein, consequently would be able to act longer on its target and exhibit a longer lasting 25 therapeutic effect. This would allow for targeting chronic or persisitent diseases without the need of frequent dosing. A variable domain with moderate affinity, (but specificity to SA) would only stay in serum circulation for a short time (eg, for a few hours or a few days) allowing WO 2011/006915 PCT/EP2010/060112 for the specific targeting of therapeutic targets involved in acute diseases by the fused therapeutic agent. This way it is possible to tailor the anti-SA-containing product to the therapeutic disease area by choosing an anti-SA variable domain with the appropriate albumin 5 binding affinity and/or serum half-life. DETAILED DESCRIPTION OF THE INVENTION Within this specification the invention has been described, with reference to embodiments, in a way which enables a clear and concise specification to be written. It 10 is intended and should be appreciated that embodiments may be variously combined or separated without parting from the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art (e.g., in cell culture, molecular genetics, nucleic acid chemistry, hybridization techniques and 15 biochemistry). Standard techniques are used for molecular, genetic and biochemical methods (see generally, Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. and Ausubel et al., Short Protocols in Molecular Biology (1999) 4 th Ed, John Wiley & Sons, Inc. which are incorporated herein by reference) and chemical methods. 20 As used herein, the term "antagonist of Tumor Necrosis Factor Receptor 1 (TNFR1)" or "anti-TNFR1 antagonist" or the like refers to an agent (e.g., a molecule, a compound) which binds TNFRI and can inhibit a (i.e., one or more) function of TNFR1. For example, an antagonist of TNFRI can inhibit the binding of TNFa to TNFRI and/or inhibit signal transduction mediated through TNFR1. Accordingly, 25 TNFRI-mediated processes and cellular responses (e.g., TNFa-induced cell death in a standard L929 cytotoxicity assay) can be inhibited with an antagonist of TNFR1.

WO 2011/006915 PCT/EP2010/0601 12 -6 A "patient" is any animal, eg, a mammal, eg, a non-human primate (such as a baboon, rhesus monkey or Cynomolgus monkey), mouse, human, rabbit, rat, dog, cat or pig. In one embodiment, the patient is a human. As used herein, "peptide" refers to about two to about 50 amino acids that are 5 joined together via peptide bonds. As used herein, "polypeptide" refers to at least about 50 amino acids that are joined together by peptide bonds. Polypeptides generally comprise tertiary structure and fold into flinctional domains. As used herein an antibody refers to IgG, 1gM, IgA, IgD or IgE or a fragment 10 (such as a Fab , F(ab') 2 , Fv, disulphide linked Fv, scFv, closed conformation multispecific antibody, disulphide-linked scFv, diabody) whether derived from any species naturally producing an antibody, or created by recombinant DNA technology; whether isolated from serum, B-cells, hybridomas, transfectomas, yeast or bacteria. As used herein, "antibody format" refers to any suitable polypeptide structure in 15 which one or more antibody variable domains can be incorporated so as to confer binding specificity for antigen on the structure. A variety of suitable antibody formats are known in the art, such as, chimeric antibodies, humanized antibodies, human antibodies, single chain antibodies, bispecific antibodies, antibody heavy chains, antibody light chains, homodimers and heterodimers of antibody heavy chains and/or 20 light chains, antigen-binding fragments of any of the foregoing (e.g., a Fv fragment (e.g., single chain Fv (scFv), a disulfide bonded Fv), a Fab fragment, a Fab' fragment, a F(ab') 2 fragment), a single antibody variable domain (e.g., a dAb, VH, V 1 11 , VL), and modified versions of any of the foregoing (e.g., modified by the covalent attachment of polyethylene glycol or other suitable polymer or a humanized VHH). 25 The phrase "immunoglobulin single variable domain" refers to an antibody variable domain (VH, VHH, VL) that specifically binds an antigen or epitope independently of different V regions or domains. An immunoglobulin single variable domain can be present in a format (e.g., homo- or hetero-multimer) with other variable regions or variable domains where the other regions or domains are not required for WO 2011/006915 PC/EP20100601 12 -7 antigen binding by the single immunoglobulin variable domain (i.e., where the immunoglobulin single variable domain binds antigen independently of the additional variable domains). A "domain antibody" or "dAb" is the same as an "immunoglobulin single variable domain" as the term is used herein. A "single immunoglobulin variable 5 domain" is the same as an "immunoglobulin single variable domain" as the term is used herein. A "single antibody variable domain" or an "antibody single variable domain" is the same as an "immunoglobulin single variable domain" as the term is used herein. An immunoglobulin single variable domain is in one embodiment a human antibody variable domain, but also includes single antibody variable domains from other species 10 such as rodent (for example, as disclosed in WO 00/29004, the contents of which are incorporated herein by reference in their entirety), nurse shark and Camelid Vim dAbs Camelid Vra are immunoglobulin single variable domain polypeptides that are derived from species including camel, llama, alpaca, dromedary, and guanaco, which produce heavy chain antibodies naturally devoid of light chains. The VHH may be humanized. 15 A "domain" is a folded protein structure which has tertiary structure independent of the rest of the protein. Generally, domains are responsible for discrete functional properties of proteins, and in many cases may be added, removed or transferred to other proteins without loss of function of the remainder of the protein and/or of the domain. A "single antibody variable domain" is a folded polypeptide 20 domain comprising sequences characteristic of antibody variable domains. It therefore includes complete antibody variable domains and modified variable domains, for example, in which one or more loops have been replaced by sequences which are not characteristic of antibody variable domains, or antibody variable domains which have been truncated or comprise N- or C-terminal extensions, as well as folded fragments of 25 variable domains which retain at least the binding activity and specificity of the full length domain. In the instant application, the term "prevention" and "preventing" involves administration of the protective composition prior to the induction of the disease or condition. "Treatment" and "treating" involves administration of the protective WO 2011/006915 PCT/EP2010/060112 -8 composition after disease or condition symptoms become manifest. "Suppression" or 'suppressing" refers to administration of the composition after an inductive event, but prior to the clinical appearance of the disease or condition. As used herein, the term "dose" refers to the quantity of ligand administered to a 5 subject all at one time (unit dose), or in two or more administrations over a defined time interval. For example, dose can refer to the quantity of ligand (e.g., ligand comprising an immunoglobulin single variable domain that binds target antigen) administered to a subject over the course of one day (24 hours) (daily dose), two days, one week, two weeks, three weeks or one or more months (e.g., by a single administration, or by two 10 or more administrations). The interval between doses can be any desired amount of time. The term "pharmaceutically effective" when referring to a dose means sufficient amount of the ligand, domain or pharmaceutically active agent to provide the desired effect. The amount that is "effective" will vary from subject to subject, depending on the age and general condition of the individual, the particular drug or pharmaceutically 15 active agent and the like. Thus, it is not always possible to specify an exact "effective" amount applicable for all patients. However, an appropriate "effective" dose in any individual case may be determined by one of ordinary skill in the art using routine experimentation. Methods for pharmacokinetic analysis and determination of ligand (eg, single 20 variable domain, fusion protein or multi-specific ligand) half-life will be familiar to those skilled in the art. Details may be found in Kenneth, A et al: Chemical Stability of Pharmaceuticals: A Handbook for Pharmacists and in Peters et al, Pharmacokinetc analysis: A Practical Approach (1996). Reference is also made to "Pharmacokinetics", M Gibaldi & D Perron, published by Marcel Dekker, 2 "d Rev. ex edition (1982), which 25 describes pharmacokinetic parameters such as t alpha and t beta half lives and area under the curve (AUC). Optionally, all pharmacokinetic parameters and values quoted herein are to be read as being values in a human. Optionally, all pharmacokinetic parameters and values quoted herein are to be read as being values in a mouse or rat or Cynomolgus monkey.

WO 2011/006915 PCT/EP2)10/060112 -9 Half lives (tA alpha and t% beta) and AUC can be determined from a curve of serum concentration of ligand against time. The WinNonlin analysis package, eg version 5.1 (available from Pharsight Corp., Mountain View, CA94040, USA) can be used, for example, to model the curve. When two-compartment modeling is used, in a 5 first phase (the alpha phase) the ligand is undergoing mainly distribution in the patient, with some elimination. A second phase (beta phase) is the phase when the ligand has been distributed and the serum concentration is decreasing as the ligand is cleared from the patient. The t alpha half life is the half life of the first phase and the t beta half life is the half life of the second phase. Thus, in one embodiment, in the context of the 10 present invention, the variable domain, fusion protein or ligand has a ta half-life in the range of (or of about) 15 minutes or more. In one embodiment, the lower end of the range is (or is about) 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 10 hours, 11 hours or 12 hours. In addition, or alternatively, the variable domain, fusion protein or ligand according to the invention will have a tct half 15 life in the range of up to and including 12 hours (or about 12 hours). In one embodiment, the upper end of the range is (or is about) 1, 10, 9, 8, 7, 6 or 5 hours. An example of a suitable range is (or is about) I to 6 hours, 2 to 5 hours or 3 to 4 hours. In one embodiment, the present invention provides the variable domain, fusion protein or ligand according to the invention has a to half-life in the range of (or of 20 about) 2.5 hours or more. In one embodiment, the lower end of the range is (or is about) 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 10 hours , 11 hours, or 12 hours. In addition, or alternatively, the tp half-life is (or is about) up to and including 21 or 25 days. In one embodiment, the upper end of the range is (or is about)12 hours, 24 hours, 2 days, 3 days, 5 days, 10 days, 15 days, 19 days 20 days, 21 days or 22 days. For 25 example, the variable domain, fusion protein or ligand according to the invention will have a tp half life in the range 12 to 60 hours (or about 12 to 60 hours). In a further embodiment, it will be in the range 12 to 48 hours (or about 12 to 48 hours). In a further embodiment still, it will be in the range 12 to 26 hours (or about 12 to 26 hours).

WO 2011/006915 PCT/EP2010/0601 12 - 10 As an alternative to using two-compartment modeling, the skilled person will be familiar with the use of non-compartmental modeling, which can be used to determine terminal half-lives (in this respect, the term "terminal half-life" as used herein means a terminal half-life determined using non-compartmental modeling). The WinNonlin 5 analysis package, eg version 5.1 (available from Pharsight Corp., Mountain View, CA94040, USA) can be used, for example, to model the curve in this way. In this instance, in one embodiment the single variable domain, fusion protein or ligand has a terminal half life of at least (or at least about) 8 hours, 10 hours, 12 hours, 15 hours, 28 hours, 20 hours, 1 day, 2 days, 3 days, 7 days, 14 days, 15 days, 16 days, 17 days, 18 10 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days or 25 days. In one embodiment, the upper end of this range is (or is about) 24 hours, 48 hours, 60 hours or 72 hours or 120 hours. For example, the terminal half-life is (or is about) from 8 hours to 60 hours, or 8 hours to 48 hours or 12 to 120 hours, eg, in man. In addition, or alternatively to the above criteria, the variable domain, fusion 15 protein or ligand according to the invention has an AUC value (area under the curve) in the range of (or of about) I mg.min/ml or more. In one embodiment, the lower end of the range is (or is about) 5, 10, 15, 20, 30, 100, 200 or 300 mg.min/ml. In addition, or alternatively, the variable domain, fusion protein or ligand according to the invention has an AUC in the range of (or of about) up to 600 mg.min/ml. In one embodiment, the 20 upper end of the range is (or is about) 500, 400, 300, 200, 150, 100, 75 or 50 mg.min/ml. Advantageously the variable domain, fusion protein or ligand will have an AUC in (or about in) the range selected from the group consisting of the following: 15 to 150 mg.min/ml, 15 to 100 mg.min/ml, 15 to 75 mg.min/ml, and 15 to 50mg.min/ml. "Surface Plasmon Resonance": Competition assays can be used to determine if 25 a specific antigen or epitope, such as human serum albumin, competes with another antigen or epitope, such as cynomolgus serum albumin, for binding to a serum albumin binding ligand described herein, such as a specific dAb, Similarly competition assays can be used to determine if a first ligand such as dAb, competes with a second ligand such as a dAb for binding to a target antigen or epitope. The term "competes" as used WO 2011/006915 PCT/EP2010/060112 - it.

herein refers to substance, such as a molecule, compound, preferably a protein, which is able to interfere to any extent with the specific binding interaction between two or more molecules. The phrase "does not competitively inhibit" means that substance, such as a molecule, compound, preferably a protein, does not interfere to any measurable or 5 significant extent with the specific binding interaction between two or more molecules. The specific binding interaction between two or more molecules preferably includes the specific binding interaction between a single variable domain and its cognate partner or target. The interfering or competing molecule can be another single variable domain or it can be a molecule that that is structurally and/or functionally similar to a cognate 10 partner or target. The term "binding moiety" refers to a domain that specifically binds an antigen or epitope independently of a different epitope or antigen binding domain. A binding moiety may be a domain antibody (dAb) or may be a domain which is a derivative of a non-immunoglobulin protein scaffold, eg, a scaffold selected from the group consisting 15 of CTLA-4, lipocalin, SpA, an adnectin, affibody, an avimer, GroEl, transferrin, GroES and fibronectin, which binds to a ligand other than the natural ligand (in the case of the present invention, the moiety binds serum albumin). See W02008/096158, which discloses examples of protein scaffolds and methods for selecting antigen or epitope specific binding domains from repertoires (see Examples 17 to 25). These specific 20 disclosures of W02008/096158 are expressly incorporated herein by reference as though explicitly written herein and for use with the present invention, and it is contemplated that any part of such disclosure can be incorporated into one or more claims herein). In one embodiment, a variable domain of the invention comprises one or more 25 of the following kinetic characteristics: (a) The variable domain comprises a binding site that specifically binds human SA with a dissociation constant (KD) from (or from about) 0.1 to (or to about) 10000 nM, optionally from (or from about) 1 to (or to about) 6000 nM, as determined by surface plasmon resonance; WO 20111/006915 PCT/EP2010/060112 - 12 (b) The variable domain comprises a binding site that specifically binds human SA with an off-rate constant (Kj) from (or from about) 1.5 x 10-4 to (or to about) 0.1 sec&' , optionally from (or from about) 3 x 10-4 to (or to about) 0.1 sec-' as determined by surface plasmon resonance; 5 (c) The variable domain comprises a binding site that specifically binds human SA with an on-rate constant (K) from (or from about)2 x 106 to (or to about) 1 x 104 M-1sec' , optionally from (or from about) 1 x 106 to (or to about) 2 x 10 4 M~ 1 sec-I as determined by surface plasmon resonance; (d) The variable domain comprises a binding site that specifically binds 10 Cynomolgus monkey SA with a dissociation constant (KD) from (or from about) 0.1 to (or to about) 10000 nM, optionally from (or from abou)t I to (or to about) 6000 nM, as determined by surface plasmon resonance; (e) The variable domain of any preceding claim, wherein the variable domain comprises a binding site that specifically binds Cynomolgus monkey SA with an 15 off-rate constant (Kd) from (or from about) 1.5 x 10 - 4 to (or to about) 0.1 sec-' , optionally from (or from about) 3 x 10- 4 to (or to about) 0.1 sec-' as determined by surface plasmon resonance; (f) The variable domain of any preceding claim, wherein the variable domain comprises a binding site that specifically binds Cynomolgus monkey SA with an 20 on-rate constant (Ka) from (or from about) 2 x 106 to (or to about) 1 x 10 4

M

Ise- , optionally from (or from about) 1 x 106 to (or to about) 5 x 10 3 M-1see' as determined by surface plasmon resonance; (g) The variable domain comprises a binding site that specifically binds rat SA with a dissociation constant (KD) from (or from about) I to (or to about) 10000 nM, 25 optionally from (or from about) 20 to (or to about) 6000 nM, as determined by surface plasmon resonance; WO 2011/006915 PCT/EP2010/060112 - 13 (h) The variable domain comprises a binding site that specifically binds rat SA with an off-rate constant (K) from (or from about) 2 x 10 3 to (or to about) 0.15 sec-' , optionally from (or from about) 9 x 10-3 to (or to about) 0.14 sec-' as determined by surface plasmon resonance; 5 (i) The variable domain comprises a binding site that specifically binds rat SA with an on-rate constant (Ka) from (or from about) 2 x 106 to (or to about) I x 10 4 M~ t sec- , optionally from (or from about) 1 x 106 to (or to about) 3 x 10 4 M-1sec- 1 as determined by surface plasmon resonance; () The variable domain comprises a binding site that specifically binds mouse SA 10 with a dissociation constant (KD) from (or from about) 1 to (or to about) 10000 nM as determined by surface plasmon resonance; (k) The variable domain comprises a binding site that specifically binds mouse SA with an off-rate constant (Kj) from (or from about) 2 x 10-3 to (or to about) 0.15 sec' as determined by surface plasmon resonance; and/or 15 (1) The variable domain comprises a binding site that specifically binds mouse SA with an on-rate constant (Ka) from (or from about) 2 x 106 to (or to about) 1 x 10 4 M-sec~ 1 , optionally from (or from about) 2 x 106 to (or to about) 1.5 x 10 4 M'isec' as determined by surface plasmon resonance. Optionally, the variable domain has 20 I: a KD according to (a) and (d), a Kd according to (b) and (e), and a Ka according to (c) and (f); or II: a KD according to (a) and (g), a K 3 according to (b) and (h), and a Ka according to (c) and (i); or 111: a KD according to (a) and (), a Kd according to (b) and (k), and a Ka according 25 to (c) and (1); or WO 2011/006915 PCT/EP2010/060112 -14 IV: kinetics according to I and II; or V: kinetics according to I and III; or VI: kinetics according to I, II and II. The invention also provides a ligand comprising a variable domain of any 5 preceding aspect or embodiment of the invention. For example, the ligand can be a dual-specific ligand (see W004003019 for examples of dual-specific ligands). In one aspect, the invention provides a multispecific ligand comprising an anti-SA variable domain of any preceding aspect or embodiment of the invention and a binding moiety that specifically binds a target antigen other than SA. The binding moiety can be any 10 binding moiety that specifically binds a target, eg, the moiety is an antibody, antibody fragment, scFv, Fab, dAb or a binding moiety comprising a non-immunoglobulin protein scaffold. Such moieties are disclosed in detail in W02008/096158 (see examples 17 to 25, which disclosure is incorporated herein by reference). Examples of non-immunoglobulin scaffolds are CTLA-4, lipocallin, staphylococcal protein A (spA), 15 AffibodyTM, AvimersTM, adnectins, GroEL and fibronectin. In one embodiment, a linker is provided between the anti-target binding moiety and the anti-SA variable domain, the linker comprising the amino acid sequence AST, optionally ASTSGPS. Alternative linkers are described in W02007085814 (incorporated herein by reference) and W02008/096158 (see the passage at page 135, 20 line 12 to page 140, line 14, which disclosure and all sequences of linkers are expressly incorporated herein by reference as though explicitly written herein and for use with the present invention, and it is contemplated that any part of such disclosure can be incorporated into one or more claims herein). In one embodiment of the multispecific ligand, the target antigen may be, or be 25 part of, polypeptides, proteins or nucleic acids, which may be naturally occurring or synthetic. In this respect the ligand of the invention may bind the target antigen and act as an antagonist or agonist (e.g., EPO receptor agonist). One skilled in the art will appreciate that the choice is large and varied. They may be for instance, human or WO 2011/006915 PCT/EP2010/060112 - 15 animal proteins, cytokines, cytokine receptors, where cytokine receptors include receptors for cytokines, enzymes, co-factors for enzymes or DNA binding proteins. Suitable cytokines and growth factors include, but are preferably not limited to: ApoE, Apo-SAA, BDNF, Cardiotrophin-1, EGF, EGF receptor, ENA-78, Eotaxin, Eotaxin- 2 , 5 Exodus-2, EpoR, FGF-acidic, FGF-basic, fibroblast growth factor-10, FLT3 ligand, Fractalkine (CX3C), GDNF, G-CSF, GM-CSF, GF-P 1, insulin, IFN-y, IGF-I, IGF-II, IL-la, IL-13, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8 (72 a.a.), IL-8 (77 a.a.), IL-9, IL 10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18 (IGIF), Inhibin a, Inhibin P, IP-10, keratinocyte growth factor-2 (KGF-2), KGF, Leptin, LIF, Lymphotactin, Mullerian 10 inhibitory substance, monocyte colony inhibitory factor, monocyte attractant protein, M-CSF, MDC (67 a.a.), MDC (69 a.a.), MCP-1 (MCAF), MCP-2, MCP-3, MCP-4, MDC (67 a.a.), MDC (69 a.a.), MIG, MIP-ia, MIP-1j, MIP-3a, MIP-3, MIP-4, myeloid progenitor inhibitor factor-I (MPIF- 1), NAP-2, Neurturin, Nerve growth factor, p-NGF, NT-3, NT-4, Oncostatin M, PDGF-AA, PDGF-AB, PDGF-BB, PF-4, 15 RANTES, SDFl a, SDF1P, SCF, SCGF, stem cell factor (SCF), TARC, TGF-a, TGF p, TGF-p2, TGF-p3, tumour necrosis factor (TNF), TNF-a, TNF-P, TNF receptor I, TNF receptor II, TNIL-1, TPO, VEGF, VEGF receptor 1, VEGF receptor 2, VEGF receptor 3, GCP-2, GRO/MGSA, GRO-p, GRO-y, HCCJ, 1-309, HER 1, HER 2, HER 3 and HER 4, CD4, human chemokine receptors CXCR4 or CCR5, non-structural 20 protein type 3 (NS3) from the hepatitis C virus, , TNF-alpha, IgE, IFN-gamma, MMP 12, CEA, H. pylori, TB, influenza, Hepatitis E, MMP-12, internalizing receptors that are over-expressed on certain cells, such as the epidermal growth factor receptor (EGFR), ErBb2 receptor on tumor cells, an intemalising cellular receptor, LDL receptor, FGF2 receptor, ErbB2 receptor, transferrin receptor, PDGF receptor, VEGF 25 receptor, Ps mAr, an extracellular matrix protein, elastin, fibronectin, laminin, al antitrypsin, tissue factor protease inhibitor, PDKI, GSK1, Bad, caspase-9, Forkhead, an antigen of Helicobacter pylori, an antigen of Mycobacterium tuberculosis, and an antigen of influenza virus. It will be appreciated that this list is by no means exhaustive.

WO 2011/006915 PCT/EP2010/060112 - 16 In one embodiment, the multispecific ligand comprises an anti-SA dAb variable domain of the invention and an anti-TNFR1 binding moiety, eg, an anti-TNFR1 dAb. Optionally, the ligand has only one anti-TNFR1 binding moiety (eg, dAb) to reduce the chance of receptor cross-linking. In one embodiment, the anti-SA dAb comprises or 5 consists of the amino acid sequence of any one of SEQ ID NOs: 97 to 103 and 198 to 203 (or an amino acid sequence that is at least 95, 96, 97, 98 or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 97 to 103 and 198 to 203). In one embodiment, the anti-TNFR1 binding moiety is DOMlh-131-206 disclosed in W02008149148 (the amino acid sequence of which and the nucleotide 10 sequence of which, as disclosed in that PCT application, are expressly incorporated herein by reference as though explicitly written herein and for use with the present invention, and it is contemplated that any part of such disclosure can be incorporated into one or more claims herein). In one embodiment, the multispecific ligand comprises or consists of the amino acid sequence of DOMlh-131-206 and the amino acid 15 sequence of any one of SEQ ID NOs: 97 to 103 and t98 to 203 (or an amino acid sequence that is at least 95, 96, 97, 98 or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 97 to 103 and 198 to 203). In one embodiment, the anti-TNFR1 binding moiety or dAb is any such moiety or dAb disclosed in co-pending application USSN 61/153,746, the disclosure of which 20 is incorporated herein by reference. In one embodiment, the anti-TNFRI binding moiety comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of DOM lh-574-156, DOMlh-574-72, DOMlh-574-109, DOMI1h-57 4 138, DOMlh-574-162 or DOMlh-574-180 or the amino acid sequence of any anti TNFR1 dAb dis closed herein. In one embodiment, the multispecific ligand comprises 25 or consists of the amino acid sequence of DOMlh-574-156 and the amino acid sequence of any one of SEQ ID NOs: 97 to 103 and 198 to 203 (or an amino acid sequence that is at least 95, 96, 97, 98 or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 97 to 103 and 198 to 203).

WO 2011/006915 PCT/EP2010/060112 - 17 In one embodiment, the ligand of the invention is a fusion protein comprising a variable domain of the invention fused directly or indirectly to one or more polypeptides. For example, the fusion protein can be a "drug fusion" as disclosed in W02005/118642 (the disclosure of which is incorporated herein by reference), 5 comprising a variable domain of the invention and a polypeptide drug as defined in that PCT application. As used herein, "drug" refers to any compound (e.g., small organic molecule, nucleic acid, polypeptide) that can be administered to an individual to produce a beneficial, therapeutic or diagnostic effect through binding to and/or altering the 10 function of a biological target molecule in the individual. The target molecule can be an endogenous target molecule encoded by the individual's genome (e.g. an enzyme, receptor, growth factor, cytokine encoded by the individual's genome) or an exogenous target molecule encoded by the genome of a pathogen (e. g. an enzyme encoded by the genome of a virus, bacterium, fungus, nematode or other pathogen). Suitable drugs for 15 use in fusion proteins and conjugates comprising an anti-SA dAb domain of the invention are disclosed in W02005/118642 and W02006/059106 (the entire disclosures of which are incorporated herein by reference, and including the entire list of specific drugs as though this list were expressly written herein, and it is contemplated that such incorporation provides disclosure of specific drugs for inclusion in claims herein). For 20 example, the drug can be glucagon-like peptide 1 (GLP- 1) or a variant, interferon alpha 2b or a variant or exendin-4 or a variant. In one embodiment, the invention provides a drug conjugate as defined and disclosed in W02005/118642 and W02006/059106, wherein the conjugate comprises a variable domain of the invention. In one example, the drug is covalently linked to the 25 variable domain (eg, the variable domain and the drug are expressed as part of a single polypeptide). Alternatively, in an example, the drug is non-covalently bonded or associated with the variable domain. The drug can be covalently or noncovalently bonded to the variable domain directly or indirectly (e.g., through a suitable linker and/or noncovalent binding of complementary binding partners (e.g., biotin and WO 2011/006915 PCT/EP2010/060112 - 18 avidin)). When complementary binding partners are employed, one of the binding partners can be covalently bonded to the drug directly or through a suitable linker moiety, and the complementary binding partner can be covalently bonded to the variable domain directly or through a suitable linker moiety. When the drug is a 5 polypeptide or peptide, the drug composition can be a fusion protein, wherein the polypeptide or peptide, drug and the polypeptide binding moiety are discrete parts (moieties) of a continuous polypeptide chain. As described herein, the polypeptide binding moieties and polypeptide drug moieties can be directly bonded to each other through a peptide bond, or linked through a suitable amino acid, or peptide or 10 polypeptide linker. A ligand which contains one single variable domain (eg, monomer) of the invention or more than one single variable domain (multimer, fusion protein, conjugate, and dual specific ligand as defined herein) which specifically binds to serum albumin, can further comprise one or more entities selected from, but preferably not limited to a 15 label, a tag, an additional single variable domain, a dAb, an antibody, and antibody fragment, a marker and a drug. One or more of these entities can be located at either the COOH terminus or at the N terminus or at both the N terminus and the COOH terminus of the ligand comprising the single variable domain, (either immunoglobulin or non immunoglobulin single variable domain). One or more of these entities can be located 20 at either the COOH terminus, or the N terminus, or both the N terminus and the COOH terminus of the single variable domain which specifically binds serum albumin of the ligand which contains one single variable domain (monomer) or more than one single variable domains (multimer, fusion protein, conjugate, and dual specific ligand as defined herein), Non-limiting examples of tags which can be positioned at one or both 25 of these termini include a HA, his or a myc tag. The entities, including one or more tags, labels and drugs, can be bound to the ligand which contains one single variable domain (monomer) or more than one single variable domain (multimer, fusion protein, conjugate, and dual specific ligand as defined herein), which binds serum albumin, either directly or through linkers as described above.

WO 2011/006915 PCT/EP2010/060112 - 19 An aspect of the invention provides a fusion product, eg, a fusion protein or fusion with a peptide or conjugate with an NCE (new chemical entity) drug, comprising a polypeptide drug fused or conjugated (for an NCE) to any variable domain as described above, optionally wherein the variable domain comprises or consists of the 5 amino acid sequence of any one of SEQ ID NOs: 97 to 103 and 198 to 203 (or an amino acid sequence that is at least 95, 96, 97, 98 or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 97 to 103 and 198 to 203). The invention provides a composition comprising a variable domain, fusion protein, conjugate or ligand of any aspect of the invention and a pharmaceutically 10 acceptable diluent, carrier, exipient or vehicle. Also encompassed herein is an isolated nucleic acid encoding any of the variable domain, fusion proteins, conjugates or ligands described herein, e.g., a ligand which contains one single variable domain (eg, monomer) of the invention or more than one single variable domain (e.g., multimer, fusion protein, conjugate, and dual specific 15 ligand as defined herein) which specifically binds to serum albumin, or which specifically binds both human serum albumin and at least one non-human serum albumin, or functionally active fragments thereof. Also encompassed herein is a vector and/or an expression vector, a host cell (eg, a non-human host cell or a host cell that is not isolated from a human or human embryo) comprising the vector, e.g., a plant or 20 animal cell and/or cell line transformed with a vector, a method of expressing and/or producing one or more variable domains, fusion proteins or ligands which contains one single variable domain (monomer) or more than one single variable domains (e.g., multimer, fusion protein, conjugate, and dual specific ligand as defined herein) which specifically binds to serum albumin, or fragment(s) thereof encoded by said vectors, 25 including in some instances culturing the host cell so that the one or more variable domains, fusion proteins or ligands or fragments thereof are expressed and optionally recovering the ligand which contains one single variable domain (monomer) or more than one single variable domain (e.g., multimer, fusion protein, conjugate, and dual specific ligand as defined herein) which specifically binds to serum albumin, from the WO 2011/006915 PCT/EP2010/060112 -20 host cell culture medium. Also encompassed are methods of contacting a ligand described herein with serum albumin, including serum albumin and/or non-human serum albumin(s), and/or one or more targets other than serum albumin, where the targets include biologically active molecules, and include animal proteins, cytokines as 5 listed above, and include methods where the contacting is in vitro as well as administering any of the variable domains, fusion proteins or ligands described herein to an individual host animal or cell in vivo and/or ex vivo. Preferably, administering ligands described herein which comprises a single variable domain (immunoglobulin or non-immunoglobulin) directed to serum albumin and/or non-human serum albumin(s), 10 and one or more domains directed to one or more targets other than serum albumin, will increase the half life, including the T beta and/or terminal half life, of the anti-target ligand. Nucleic acid molecules encoding the domains, fusion proteins or single domain containing ligands or fragments thereof, including functional fragments thereof, are contemplated herein. Vectors encoding the nucleic acid molecules, including but 15 preferably not limited to expression vectors, are contemplated herein, as are host cells from a cell line or organism containing one or more of these expression vectors. Also contemplated are methods of producing any domain, fusion protein or ligand, including, but preferably not limited to any of the aforementioned nucleic acids, vectors and host cells. 20 An aspect of the invention provides a nucleic acid comprising a nucleotide sequence encoding a variable domain according to the invention or a multispecific ligand of the invention or fusion protein of the invention. An aspect of the invention provides a nucleic acid comprising the nucleotide sequence selected from any one of SEQ ID NOs: I to 96 and 192-197, or a nucleotide 25 sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to said selected sequence. An aspect of the invention provides a vector comprising the nucleic acid of the invention. An aspect of the invention provides an isolated host cell comprising the vector.

WO 2011/006915 PCT/EP2010/060112 -21 Reference is made to W02008/096158 for details of library vector systems, combining single variable domains, characterization of dual specific ligands, structure of dual specific ligands, scaffolds for use in constructing dual specific ligands, uses of anti-serum albumin dAbs and multispecific ligands and half- life-enhanced ligands, and 5 compositions and formulations of comprising anti-serum albumin dAbs. These disclosures are incorporated herein by reference to provide guidance for use with the present invention, including for domains, ligands, fusion proteins, conjugates, nucleic acids, vectors, hosts and compositions of the present invention. 10 SEQUENCES OF ANTI-SERUM ALBUMIN VH SINGLE VARIABLE DOMAINS All variable domains bind at least one species of serum albumin as determined by SPR.. 15 Nucleotide sequences: DOM7h-112 SEQ ID NO: 1 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 20 CCTCCGGATTCACCTTTGGGGGGTATGTGATGGGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAGCTATTAATAGGTTTGGTTCGTCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAGGTAGTTTGCGGCATTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAG C 25 DOM7h-98 SEQ ID NO; 2 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGGTAATTATGCGATGGCGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATCGATTGATATGGTTGGTATTAAGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 30 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAGGTTTTCGTATTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC DOM7r-29 SEQ ID NO: 3 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 35 CCTCCGGATTCACCTTTAAGGATTATGATATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAATGATTTCTTCGTCGGGTCTTTGGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAGGTTTTAGGCTGTTTCCTCGGACTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCGAGCG 40 DOM7r-35 SEQ ID NO: 4 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CC TCCGGATTCACCTTTTCGCTGTATAGGATGGTGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAG TG WO 2011/006915 PCT/EP2010/060112 -22 GGTCTCAATGATTTCTCAGT TTGGTAATCAGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAGTTAGGTCTTGGGATCAGACTGGTGGTCGTCGTACTTTTGACTACTGGGGTCAGGG AACCCTGGTCACCGTCTCGAGC 5 DOM7r-36 SEQ ID NO: 5 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTAATCATTATACGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATTGATTCATCCGAGTGGTACGGTGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 10 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAATGGAGTTCGAGGGCGTTTGACTACTG GGGTCAGGGAACCCTGGTCACCGTCTCGAGC DOM7r-38 SEQ ID NO: 6 15 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGATAATAATGCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACTATTAGTGCGAATGGTAATGCGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGGACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAGGGTTTCGTCGGTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC 20 DOM7r31 SEQ ID NO: 7 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTACAG CCTCCGGATTCACCTTTAGGCATTATCGTATGGGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATGGATTCGTCCGGATGGTACGTTTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 25 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAATCTTATATGGGTGATAGGTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTC GAGCG DOM7h-32 SEQ ID NO: 8 30 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGCGCAG CCTCCGGATTCACCTTTGGTAATTATCCGATGACGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTGGAGTG GGTCTCAACTATTAGTTATGGTGGTCTTGCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAATGGCGATTAATGGTGTTAGGCCTAGGCGGTTTGACTACTGGGGTCAGGGAACCCT 35 GGTCACCGTCTCGAGC DOM7h-33 SEQ ID NO: 9 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTATGGCGTATCAGATGGCTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG 40 GGTCTCAACTATTCATCAGACGGGTTTTTCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGATACCGCGGTAT ATTACTGTGCGAAAGTGCGTTCTATGCGTCCTTATAAGTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCGAGC 45 DOM7h-34 SEQ ID NO; 10 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGGTGATAAGGCAATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACGATTAGTGCTCCTGGTAACCGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 50 ATTACTGTGCGAAAGGTTTTCGGAATTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC DOM7h-83 SEQ ID NO: 11 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG

CCTCCGGATTCACCTTTGATGGGATGCGTATGGGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG

WO 2011/006915 PCT/EP2010/060112 -23 GGTCTCAGCTATTGAGGTGAATGGTCAGCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAATGGCTCATCCTCAGTCGGGGGTGGCTTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCGAGC 5 DOM7h-84 SEQ ID NO: 12 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTACGCCTGATGCTATGGCGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATCGATTGGTGTGAATGGTTCTCCGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 10 TCCCGCGACAATTCCAGGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAATGGCTCATCCTCAGTCGGGGGTGGCTTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCGAGC DOM7h-85 SEQ ID NO: 13 15 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTTATCAGTCGGATATGTCTTGGGTCCGCCAGGCTCCAGGGAAAGGTCTAGAGTG GGTCTCATCTATTTCTTCTCAGGGTCGTTCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAATGGCTCATCCTCAGTCGGGGGTGGCTTTTGACTACTGGGGTCAGGGAACCCTGGT 20 CACCGTCTCGAGC DOM7h-86 SEQ ID NO: 14 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTACAG CCTCCGGATTCACCTTTGCGGCGAGGGATATGAGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTGGAGTG 25 GGTCTCAAGTATTTCTGCTCAGGGTGCTCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACGATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGATACCGCGGTAT ATTACTGTGCGAAACCTCGGCATCCTCAGGGGGGGGTTACTTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCGAGC 30 DOM7h-87 SEQ ID NO: 15 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGATAATGGGGATATGGTTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAGGGATTGCGCATAATGGTCGTAATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 35 ATTACTGTGCGAAAAATTTGGGTCAGGGTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAG C DOM7h-88 SEQ ID NO: 16 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCACCTGTGCAG 40 CCTCCGGATTCACCTTGAATGGTACGTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAGGATCTAGAGTG GGTCTCATCTATTATGCCTGTGGGTTCTCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAATGGCTCATCCTCAGTCGGGGGTGGCTTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCGAGC 45 DOM7h-89 SEQ ID NO: 17 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGATCATGCGCCTATGAAGTGGGCCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATATATTGGGTCGGCGGGTAATATGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 50 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAGATGAGGGGCCGTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC DOM7h-90 SEQ ID NO: 18 WO 2011/006915 PCT/EP2010/060112 - 24 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTACAG CCTCCGGATTCACCTTTGATGGGATGGATATGAGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAAGTATTTCTACGACTGGTGGGACTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 5 ATTACTGTGCGAAACCTCGGCATCCTCAGGGGGGGGTTACTTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCGAGC DOM7h-91 SEQ ID NO: 19 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 10 CCTCCGGATTCACCTTTGAGGCGGAGACGATGGCTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACTATTCATTCGGAGGGTTCTCGGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAACCTCGGCATCCTCAGGGGGGGGTTACTTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCGAGC 15 DOM7h-92 SEQ ID NO: 20 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTAGTACTGGGGAGATGGCTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATCTATTAGTTCGAGTGGTGCTACGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 20 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAACCTCGGCATCCTCAGGGGGGGGTTACTTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCGAGC DOM7h-93 SEQ ID NO: 21 25 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTCCTAGTGCTGATATGGTTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCACGTATTTCGCCTGAGGGTAATCATACATACTACGCAGACTCCGTGAAGGGTCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGATACCGCGGTAT ATTACTGTGCGGAACGGCCTCCTTCGGATTATGTTTCTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC 30 CGTCTCGAGC DOM7h-94 SEQ ID NO: 22 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGCGAATGCGACTATGTCGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG 35 GGTCTCAGATATTGATCAGGTGGGTCATGCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAATATTCGTGGCATCCGGATCTGTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGT CTCGAGC 40 DOM7h-95 SEQ ID NO: 23 GAGGTGCGGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTAAGGATTATGGGATGAATTGGGTCCGCCAGGCTCCAGGGAAGGGTC TAGAGTG GGTCTCACGGATTAGTAGGAATGGTACTGTTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAACTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 45 ATTACTGTGCGAAATTGGCTGCTCCGGTTCGTCAGAAGGGGATGGATTTTGACTACTGGGGTCAGGGAAC CCTGGTCACCGTCTCGAGC DOM7h-96 SEQ ID NO: 24 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 50 CCTCCGGATTCACCTTTGAGTGGTATAATATGTCGTGGGTCCGCCAGGCTCCAGGGAAGGATCTGGAGTG GGTCTCATCGATTTCTCATGATGGTTGGAATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGC GGTAT

ATTACTGTGCGAAAGGGATGATTGGTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC

WO 2011/006915 PCT/EP2010/060112 -25 DOM7h-97 SEQ ID NO: 25 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGATATTTATACGATGCATTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACTATTGTTCCGCAGGGTACTCCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 5 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAATCTAAGCGTAGGTTTCTTAAGAGGTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCGAGC DOM7h-99 SEQ ID NO: 26 10 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGCTAGGTATGATATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATCGATTAAGAGTAATGGTATGAAGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAGCTAGTATGTGGACGTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAA 15 C DOM7h-100 SEQ ID NO: 27 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTATGTTGTATCATATGGGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG 20 GGTCTCAGCTATTACCGGGGGGGGTTATCCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAACTGGGGCTTCGGGGTGTGCTGTGGCGGAGGAGGTTTGACTACTGGGGTCAGGGAAC CCTGGTCACCGTCTCGAGC 25 DOM7h-101 SEQ ID NO: 28 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGGTGCTTATTCTATGATGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCACGGATTAGTAGGAATGGTACTGTTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 30 ATTACTGTGCGAAAATTAGGTGGAATACTGCTCAGGTGCCTGTGTTTGACTACTGGGGTCAGGGAACTCT GGTCACCGTCTCGAGC DOM7h-102 SEQ ID NO: 29 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 35 CCTCCGGATTCACCTTTGGTCCGTATTGGATGGCTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACGATTACGCCTTCGGGTCGTGGGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGATACCGCGGTAT ATTACTGTGCGAAAGGGCGTCCTCGTGTTGGTTTGTGGAGGTCGGGGTTTGACTACTGGGGTCAGGGAAC CCTGGTCACCGTCTCGAGC 40 DOM7h-103 SEQ ID NO: 30 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGGGCAGTATGCTATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATCTATTAATATTACTGGTTCTACTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 45 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAGATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAGGTTTTAGGTCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC DOM7h-106 SEQ ID NO: 31 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 50 CCTCCGGATTCACCTTTGCTGGTTATACGATGTCGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACGATTTCGGGTTTTGGTTGGACTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGC TGTATCTGCAAATGAACAGCCTGCGTGC CGAGGATACCGCGGTAT ATTACTGTGC GAAAAGGCTGGGGATGCGTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTC TCGAG

C

WO 2011/006915 PCT/EP2010/060112 - 26 DOM7h-109 SEQ ID NO: 33 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 5 CCTCCGGATTCACCTTTGGTCCGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATTTATTCATTCTGATGGTCGTCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAAAGACGCCTTATAGGTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAG C 10 DOM7h-111 SEQ ID NO: 34 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGGGCAGTATGCTATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATCTATTAATATTACTGGTTCTACTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 15 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAGATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAGGTTTTAGGTCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC DOM7h-114 SEQ ID NO: 35 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 20 CCTCCGGATTCACCTTTAGGCGGTATGCGATGTCTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACGATTTCGCCTTATGGTCCTGTTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAATAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAGCTTATTATGGTGGGTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAG C 25 DOM7r-34 SEQ ID NO: 36 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGATGCTTATGCTATGGGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAAAGATTGATTCTCCTGGTTGGAGGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 30 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAATCGGCTCGGATGCGTTCTCGGCATTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCGAGC DOM7r-37 SEQ ID NO: 37 35 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTAAGGATTATGGGATGAATTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCACGGATTAGTAGGAATGGTACTGTTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAATTAGGTGGAATACTGCTCAGGTGCCTGTGTTTGACTACTGGGGTCAGGGAACTCT 40 GGTCACCGTCTCGAGC DOM7r-39 SEQ ID NO: 38 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAA 45 CCTCCGGATTCACCTTTCCGTCTTATACGATGGGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCACGTATTTCTCGTACTGGGAATTATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGATACCGCGGTAT AT TACTGTGCGAAACCTATGTATAATAGGGGGTCTTCGTATTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCGAGC 50 DOM7r-40 SEQ ID NO: 39 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTTCGCAGTATCAGATGTCGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATCGATTTCGCCTACGGGTATTCAGACATACTACGCAGACTCCGTGAAGGGCCGGT TCACCATC WO 2011/006915 PCT/EP2010/160112 -27 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAAGGCTTATTGGGATGCCGTATGTTGAGGATACTTTTGACTACTGGGGTCAGGGAAC CCTGGTCACCGTCTCGAGC 5 DOM7r-41 SEQ ID NO: 40 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTATGGAGTATGAGATGGAGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAGGTATTACTAATTCTGGTTCTGGGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAACTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 10 ATTACTGTGCGATAATGCAGCATCCTCAGGCGACTGGGGGGAGGGTTGGGTTTGACTACTGGGGTCAGGG AACCCTGGTCACCGTCTCGAGC DOM7r-42 SEQ ID NO: 41 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 15 CCTCCGGATTCACCTTTCCGAGGTATACTATGAAGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATCGATTGATAGGACGGGTCGTAAGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGATACCGCGGTAT ATTACTGTGCGAAAGAGTCGTTGGTTTCGTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAG C 20 DOM7r-43 SEQ ID NO: 42 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGGTGGTTATACGATGCCTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACTATTTCTCGTGATGGTAATTATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 25 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAGATATTGGTATGGGTTTTGACTACGGGGGGCGGGGAACCCTGGTCACCGTCTCGAG C DOM7r-44 SEQ ID NO: 43 30 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGAGATTTATGCGATGCATTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACGATTAGTTCGGGTGGTAAGGGGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAATCGCGTACTATGTATTTTCGTGTTAGGGAGGCTTTTGACTACTGGGGTCAGGGAAC 35 CCTGGTCACCGTCTCGAGC DOM7r-45 SEQ ID NO: 44 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTCGTGCTTATAGGATGATGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTGGAGTG 40 GGTCTCATCTATTGATCCTGATGGTGCGGTTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGGAACATTTTGATCTTGCGATGCCGAATCCGAATGCGAAGTTTGACTACTGGGGTCAGGG AACCCTGGTCACCGTCTCGAGC 45 DOM7r-46 SEQ ID NO; 45 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGCCTCTCCTGTGCAG CCTCCGGATTCACCTTTTCTCGTTATCAGATGTCTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTGGAGTG GGTCTCATCTATTAAGTCGAATGGTTCTTCGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 50 ATTACTGTGCGAAACCTAGTCGGCAGAGTTTTCAGTATCCGAGTTTTGACTACTGGGGTCAGGGAACCCT GGTCACCGTCTCGAGC DOM7r-47 SEQ ID NO: 46 WO 2011/006915 PCT/EP2010/060112 -28 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGGGCGTTATAAGATGGGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATCTATTTCGCCTACGGGTTCGTCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 5 ATTACTGTGCGAAAACTGGGTATGTTATGGTTGAGCATTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCGAGC DOM7r-48 SEQ ID NO: 47 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 10 CCTCCGGATTCACCTTTAGTGATTATCCGATGAAGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTGGAGTG GTCTCAACTATTAATTCTTCGGGTACGATTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAACCGTTGTTGCCGTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC 15 DOM7r-49 SEQ ID NO: 48 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGCTAGGTATAGGATGTGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATGTATTCGGGATCCGGGTTTTCCGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 20 ATTACTGTGCGAAATGTTCGCCGTCTTCTACGCAGTGTACGGGGCTTTTTGACTACTGGGGTCAGGGAAC CCTGGTCACCGTCTCGAGC DOM7r-50 SEQ ID NO: 49 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 25 CCTCCGGATTCACCTTTAGGTTTTATGGGATGGCGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCACTTATTGATCCTCCTGGTGGGGCGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAATGGAGAGGCGGCATCTTAAGAGTGGTCATAAGGGGTTTGACTACTGGGGTCAGGG AACCCTGGTCACCGTCTCGAGC 30 DOM7r-51 SEQ ID NO: 50 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTACGGAGTATGATATGATGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATCTATTAGTCATAGGGTGAGAAGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 35 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAGATAAGCGTTATCGGGGGTCTCAGCATTATTTTGACTACTGGGGTCAGGGAACCCT GGTCACCGTCTCGAGC DOM7r-52 SEQ ID NO: 51 40 GAGGTGCAGCTGTTGGAGTCTGGGGOAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTCGGAGTTATGATATGGGTTGGGCCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACTATTGGGTCGAATGGTGCTAATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAACTTATGGGTATGTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC 45 DOM7r-53 SEQ ID NO: 52 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGAGCGTTATTCTATGAGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACGATTGGTTCGACGGGTAAGTGGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 50 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAGGGCGTGGGTTGGTTTCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTC GAGC DOM7r-54 SEQ ID NO: 53 WO 2011/006915 PCT/EP2010/060112 -29 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTAGGCGTTATTCGATGTCTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATCTATTGATCGGTCTGGTAGGATGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 5 ATTACTGTGCGAAATCTCGGCTGTCTTCGACGGGTTCTGAGGGTCATAATTTTGACTACTGGGGTCAGGG AACCCTGGTCACCGTCTCGAGC DOM7r-55 SEQ ID NO: 54 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 10 CCTCCGGATTCACCTTTAAGTGGTATCCGATGAAGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACTATTGCTTATGATGGTGTTCAGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAATTGGGTCCGACTAGTCGTGTGTTTGCTGCTACTGATTTTGACTACTGGGGTCAGGG AACCCTGGTCACCGTCTCGAGC 15 DOM7r-56 SEQ ID NO: 55 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTCCGAATTATGCGATGAAGTGGGGCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACTATTGATACGAGTGGTAGTACTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 20 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAACTTACTCATCCTATGGCGCCGCGTCCGGCTTTTGACTACTGGGGTCAGGGAACCCT GGTCACCGTCTCGAGC DOM7r-57 SEQ ID NO: 56 25 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGATCTTACGGAGATGGAGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTGGAGTG GGTCTCATCGATTGGGCCTTGGGGTACTCCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAATTTCGCATCCTCAGGCGATGTATCATACGTTTGACTACTGGGGTCAGGGAACCCT 30 GGTCACCGTCTCGAGC DOM7r-58 SEQ ID NO: 57 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGCGCATCAGGATATGACGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG 35 GGTCTCAGATATTGATCATTCGGGTTCGTATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAATGGTGGCATCCGCAGGGGGGGACTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCGAGC 40 DOM7r-59 SEQ ID NO: 58 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGGTTCTAAGGATATGTCGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACGATTGGGGCGAATGGTAAGGCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 45 ATTACTGTGCGGAAGCGGGTCATCCTCAGGCGCCGTCTTTTAAGAGTTTTGACTACTGGGGTCAGGGAAC CCTGGTCACCGTCTCGAGC DOM7r-60 SEQ ID NO: 59 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 50 CCTCCGGATTCACCTTTCTGAATGCGGAGATGAGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACTATTGATCGGGATGGTGCTAATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGT GCGAAAC TTCCTCCGCCGATGTCGCCGAAGAAGTTTGAC TACTGGGGTCAGGGAACCCTGGT

CACCGTCTCGAGC

WO 2011/006915 PCT/EP2011/060112 -30 DOM7r-61 SEQ ID NO: 60 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGAGAGGGAGGGTATGATGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG 5 GGTTTCAACTATTGATCGTATGGGTAGGTATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAAGGGATTCGCATCCTATGGGGTTTGACTACCGGGGTCAGGGAACCCTGGTCACCGT CTCGAGC 10 DOM7r-62 SEQ ID NO: 61 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGGTTCACCTTTGAGAATGAGAAGATGAGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATCGATTGGTCCTACGGGTAGTGGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 15 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAACTCCTCATCCGCAGGTTTCTAGTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCGAGC DOM7r-63 SEQ ID NO: 62 20 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGAGATTGATCATATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAGAGATTGCGCCTTCGGGTGATCGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGATACCGCGGTAT ATTACTGTGCGAAAGTGATTTGTCAGAATCAGTGTCTGTTTGACTACTGGGGTCAGGGAACCCTGGTCAC 25 CGTCTCGAGC DOM7r-64 SEQ ID NO: 63 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTAGGGATTCTGAGATGTCGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG 30 GGTCTCATTTATTACTTCTGATGGTCGGGATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAACCTAGTCTGCCTCATGTTACGGCTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCGAGC 35 DOM7r-65 SEQ ID NO: 64 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGAGGATGAGACGATGAGTTGGGCCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATCGATTGGGGATGCTGGTATGCCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 40 ATTACTGTGCGAAAGGGGAGCCGATTTATGTTCATACGACTCATTTTGACTACTGGGGTCAGGGAACCCT GGTCACCGTCTCGAGC DOM7r-66 SEQ ID NO: 65 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 45 CCTCCGGATTCACCTTTCCGCATGGTAAGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATGGATTGCTGGGTCTGGTGATATGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAATTGGGTCATCCTCAGCGGGGTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGT CTCGAGC 50 DOM7r-67 SEQ ID NO: 66 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGGGACTTCTGATATGTCGTGGGTCCGCCAGGCCCCAGGGAAGGGTCTAGAGTG

GGTCTCAACTATTGATTCTGGGGGTAGTTTTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC

WO 2011/006915 PCT/EP2010/060112 -31 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAACCTCGGCATCCTCAGGGGGGGGTTACTTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCGAGC 5 DOM~r-68 SEQ ID NO: 68 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGG GGGGTCCCTGCGTCTCTCCTOTGCAG CCTCCGGATTCACCTTTGAGCATGTTCCTATGGCTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCACGGATTAGTGAGCAGGGTAGTAATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 10 ATTACTGTGCGAAAGTGCAGCATCCTATGTCTCCGCATGAGTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCGAGC DOM7r-69 SEQ ID NO: 69 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 15 CCTCCGGATTCACCTTTGAGCAGGGTATGATGTCGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATCGATTAATCCTGGTGGTCAGTTTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAGGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGGAAGATCTGGGGCCGGGTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAG C 20 DOM7r-70 SEQ ID NO: 70 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGAGCGTTGGCCTATGTCTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACTATTGATAGGTCTGGTAATACTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 25 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGATACCGCGGTAT ATTACTGTGCGAAAGTTTTGCATCCTCAGGCGGGGTCTGCTTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCGAGC DOM7r-71 SEQ ID NO: 71 30 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTCGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGGGGGTAGTGATATGGGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATATATTGATAATCAGGGTTATAATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAATATAAGCTTCTGGGTCCGTCTACTGAGTTTGACTACTGGGGTCAGGGAACCCTGGT 35 CACCGTCTCGAGC DOM7r-72 SEQ ID NO; 72 GAGGTGCAGCTGTTGGAGTCAGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTAGTAGTGATGTTATGTCTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG 40 GGTCTCAAGTATTACGAGGTCGGGTATGCAGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAATATGCGCATCCTCAGTCGGCTGTTGAGTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCGAGC 45 DOM7r-73 SEQ ID NO: 73 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTCGTAATGAGCCGATGAGTTGGGTGCGCCAGGCTCCAGTGAAGGGTCTAGAGTG GGTCTCAACTATTTCGCCTGATGGTAGTGGGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 50 ATTACTGTGCGAAACATGGTCATCCTCAGGGGGCTCGTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCGAGC DOM7r-74 SEQ ID NO: 74 WO 2011/006915 PCT/EP2010/06(1112 - 32 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTTTGAATAGTGAGATGTCGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTGGAGTG GGTCTCAACTATTGGGTATGCGGGTACTCCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 5 ATTACTGTGCGAAACCTCGGCATCCTCAGGGGGGGGTTACTTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCGAGC DOM7r-75 SEQ ID NO: 75 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 10 CCTCCGGATTCACCTTTGCTCGGGGGCCTATGTCTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACTATTACGAATGATGGTACGTCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGGAACCGCCTCATAGTGGTAGGCCTATGTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCGAGC 15 DOM7r-76 SEQ ID NO: 76 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CC TCCGGATTCACCTTTCAGCGGACTGCTATGTCTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTTGAGTG GGTCTCATCTATTGAGGC TTCGGGTCGGTATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC 20 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAACAGTCGCATCCTCAGAATGGTCGTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCT CGAGC DOM7r-77 SEQ ID NO: 77 25 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGATGCGTCGGAGATGGCTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAAGTATTACGGTTTATGGTGATAGGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAACCTCGGCATCCTCAGGGGGGGGTTACTTTTGACTACTGGGGTCAGGGAACCCTGGT 30 CACCGTCTCGAGC DOM7r-78 SEQ ID NO: 78 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCT TGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGATGATTCGCATATGGCTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG 35 GGTCTCAAGGATTTCGAGGGAGGGTAAGGCGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACK TGTGCGGCACCGAATGATCAGTCGGCGGCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGT CTCGAGC 40 DOM7r-79 SEQ ID NO: 79 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGATATGAGTGAGATGTCGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAGCTATTACTTCGGATGGTAGTTCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 45 ATTACTGTGCGAAACCTAGTCTGCCTCATGTTACGGCTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCGAGC DOM7r-B0 SEQ ID NO: 80 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 50 CCTCCGGATTCACCTTTGAGAGGTCTACTATGCATTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAGAGATTGATGCTCTGGGTACGGATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAATCGTCTGATCATCCTCAGAATAGTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC

CGTCTCGAGC

WO 2011/006915 PCT/EP2010/060112 -33 DOM7r-81 SEQ ID NO: 81 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGAGCCTCGTGAGATGTATTGGGCCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG 5 GGTCGCACGGATTGGTTGGGATGGTCATACGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAACAGCTGGGTCAGTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC DOM7r-82 SEQ ID NO: 82 10 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGATGCTTATAGTATGATGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAACTATTGGTAGGTGGGGTGAGATTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGATACCGCGGTAT ATTACTGTGCGAAACGTCGTTATATTGGGCCTTATATGCTTTCGGGTCGTTTTGACTACTGGGGTCAGGG 15 AACCCTGGTCACCGTCTCGAGC DOM7r-83 SEQ ID NO: 83 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTATGCGGTATCCTATGGTGTGGGTCCGCCAGGCTCCAGGGAGGGGTCTAGAGTG 20 GGTCTCATCTATTTCTCCTGCTGGTTATGGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAGGTCATGAGATTAGTCGGTTTTCTCGTTGGTCTTCTTTTGACTACTGGGGTCAGGG AACCCTGGTCACCGTCTCGAGC 25 DOM7r-84 SEQ ID NO: 84 GAGGTGCAGCTGTTGGAGTCTGGGGGGGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTCGGAAGTATAGGATGTCGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATCTATTGCGAGGAATGGTCGTTCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 30 ATTACTGTGCGAAAACTACGTCTGGGTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC DOM7r-85 SEQ ID NO: 85 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTAATAAGAAGGAGATGGGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG 35 GGTCTCATCTATTGATGTGAGTGGTAATGTTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAATGGCTCATCCTCAGTCGGGGGTGGCTTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCGAGC 40 DOM7r-88 SEQ ID NO: 86 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTCGGATGTATGATATGGCGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAAAGTG GGTCTCAACTATTCTGTCTTCTGGTAAGGGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT 45 ATTACTGTGCGAAATTGGCTCATCCTCAGAAGGGTAGTATTTTTGACTACCGGGGTCAGGGAACCCTGGT CACCGTCTCGAGC DOM7r-89 SEQ ID NO: 87 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG 50 CCTCCGGATTCACCTTTCATCAGGGTCCTATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATGGATTCAGGCTACGGGTGGTGCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAGGGATGCATCCTCAGAGTGGTACTCTTTTTGACTACTGGGGTCAGGGAACCCTGGT

CACCGTCTCGAGC

WO 2011/00)6915 PCT/EPZOIO/0601 12 - 34 DON7r-90 SEQ ID NO: 88 GAGOTOCAGO TGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGATGTTGCGGATATGGATTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG 5 GGTCTCAGGGATTTCGTCGTCGGGTGGTTATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACAC GCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGATACCGCGGTAT ATTACTGTGC GAAAAATTTGGGTCAGGGTTTTGACTAC TGGGGTCAGGGAACCCTGGTCACCGTCTCGAG c 10 DON7r-92 SEQ ID NO: 89 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CC TCCGGATTCACCTTTGATACGAGTAGTATGTTGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAGTTATTCATCAGAGTGGTACGCCTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAAQAC GCTGTATCTGCAAATGAACAGCCTGC GTGCCGAGGACACCGCGGTAT 15 ATTACTGTGCGAAATTTCCGTTTACTCATGGTAAGTTTGACTACTGGGGTCAGGGuV2CCTGGTCACCGT CT CGAG C DOM7r-93 SEQ ID NO: 90 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGT CCCTGCGTCTCTCCTGTGCAG 20 CCTCCGGATTCACCTTTAATAATTATACGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCATTGATTCATACGAGTGGTACGGTGACATAC TACGCAGACTCCGTGAAGGGCCGGT TOACCATO TCCCGCGACAATTCCAAGAJ\CACGCTGTATCTGCAAATGAACAGC CTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAATGGAGTTCGAGGGCGTTTGAC TACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAG C 25 DONI7r-94 SEQ TD NO: 91 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CC TCCGGATTCACCTTTGGGAATTATAGGATGACTTGGGTCCGCCAGGCTCCAGGGA&GGGTCTAGAGTG GGTCTCAACTATTTCTCCTTTGGGTACGTATACATACTACGCAGACTCCGTGM\GGGCCGGTTCACCA TC 30 TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGC GGTAT ATTACTGTGCGAAAGGGCGTTGGTCGATTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAG C DO7r-95 SEQ ID NO: 92 35 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CC TCCGGATTCACCTTTGGTAGTTATCCTATGGGTTGGGTCCGCCAGGCTCCAGGGAAGGGT CTGGAGTG GGTCTCATGGATTCGTGGGAGGGGTCTTGCTACATACTACGCAGACTCCGTGM\GGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACAC GCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACAC CGCGCTAT ATTACTGTGCGAAATATTTTCATGGTAAGTTTGACTACTGGGGTCAGGGAACCCTGGTCAcC GTC TCGAG 40 C DO7r-96 SEQ ID NO: 93 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTC CTGTGCAG C CTCCGGATTCACCTTTAGTGC TTATGTGATGGGTTGGGTACGCCAGGCTCCAGGGAAGGGTC TAGAGTG 45 GGTCTCATCGATTCGGATGCCGGGTTATCTGAC-ATAC-TAC-GCAGAC-TCCrGTGAAGGGCCrGGTTC-ACCATC TCCCGCGACAA T TCCALAGAACACGCTGTATCTGCAAAT GAACAGC CT GC GTGCC GAGGACACCGCG GTAT ATTACTGTGCGAAACGTACTCCTTTTTTTGACTAC TGGGGTCAGGGAACCCTGGTCACCGTC TCGAGC DOM7r-97 SEQ IED NO: 94 50 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTGAGCATTATTCGATGGGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAGAGATTGATCCGGATGGTATTATGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACAC GCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT WO 2011/006915 PCT/EP2010/060112 -35 ATTACTGTGCGAAAGCGCCGGGGGTTCTTGAGATGTGGATTACGCATTTTGACTACTGGGGTCAGGGAAC CCTGGTCACCGTCTCGAGC DOM7r-98 SEQ ID NO: 95 5 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTCGTCATTATGTGATGGGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG GGTCTCAGCTATTTCTGCGCATGGTAATCGOACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAATCTTATAGCCTTGCTCTGACTCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC 10 CGTCTCGAGC DOM7r-99 SEQ ID NO: 96 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAG CCTCCGGATTCACCTTTACTGTGTATGAGATGAAGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTG 15 GGTCTCAGCGATTTCTGCTGGGGGTAAGTATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATC TCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTAT ATTACTGTGCGAAAGAGATTCGGCATCTTGATAATGCGGTTGAGTTTGACTACTGGGGTCAGGGAACCCT GGTCACCGTCTCGAGC 20 Amino acid sequences: DOM7h-112 SEQ ID NO: 97 EVQLLESGGGLVQPGGSLRLSCAASGFTFGGYVMGWVRQAPGKGLEWVSA INRFGSSTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKGSLRHFDYWGQGTLVTVSS 25 DOM7h-98 SEQ ID NO: 98 EVQLLESGGGLVQPGGSLRLSCAASGFTFGNYAMAWVRQAPGKGLEWVSSIDMVGIKTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKGFRI FDYWGQGTLVTVSS 30 DOM7r-29 SEQ ID NO: 99 EVQLLESGGGLVQPGGSLRLSCAASGFTFKDYDMTWVRQAPGKGLEWVSMISSSGLWTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKGFRLFPRTFDYWGQGTLVTVSS DOM7r-35 SEQ ID NO: 100 35 EVQLLESGGGLVQPGGSLRLSCAASGFTFSLYRMVWVRQAPGKGLEWVSMISQFGNQTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKVRSWDQTGGRRTFDYWGQGTLVTVSS DOM7r-36 SEQ ID NO: 101 EVQLLESGGGLVQPGGSLRLSCAASGFTFNHYTMGWVRQAPGKGLEWVSLIHPSGTVTYYADSVKGRFTI 40 SRDNSKNTLYLQMNSLRAEDTAVYYCAKWSSRAFDYWGQGTLVTVSS DOM7r-38 SEQ ID NO: 102 EVQLLESGGGLVQPGGSLRLSCAASGFTFDNNAMGWVRQAPGKGLEWVSTISANGNATYYADSVKGRFTI SRDNSKDTLYLQMNSLRAEDTAVYYCAKGFRRFDYWGQGTLVTVSS 45 DOM7r31 SEQ ID NO: 103 EVQLLESGGGLVQPGGSLRLSCTASGFTFRHYRMGWVRQAPGKGLEWVSW IRP DGTFTYYADSVKGRFT I SRDNSKNTLYLQMNSLRAEDTAVYYCAKSYMGDRFDYWGQGTLVTVSS 50 DOM7h-32 SEQ ID NO: 104 EVQLLESGGGLVQPGGSLRLSCAASGFTFGNY PMTWVRQAPGKGLEWVSTISYGGLATYYADSVKGRFTI SR DNSKNTLYLQMNSLRAEDTAVYYCAKMAINGVRPRRFDYWGQGTLVTVSS DOM7h-33 SEQ ID NO: 105 WO 20111/006915 PCT/EP2010/060112 -36 EVQLLESGGGLVQPGGSLRLSCAASGFTFMAYQMAWVRQAPGKGLEWVSTIHQTGFSTYYADSVKGRFTT SRDNSKNTLYLQMNSLRAEDTAVYYCAKVRSMRPYKFDYWGQGTLVTVSS DOM7h-34 SEQ ID NO: 106 5 EVQLLESGGGLVQPGGSLRLSCAASGFTFGDKAMGWVRQAPGKGLEWVSTISAPGNRTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKGFRNFDYWGQGTLVTVSS DOM7h-83 SEQ ID NO: 107 EVQLLESGGGLVQPGGSLRLSCAASGFTFDGMRMGWVRQAPGKGLEWVSAIEVNGQHTYYADSVKGRFTI 10 SRDNSKNTLYLQMNSLRAEDTAVYYCAKMAHPQSGVAFDYWGQGTLVTVSS DOM7h-84 SEQ ID NO: 108 EVQLLESGGGLVQPGGSLRLSCAASGFTFTPDAMAVRQAPGKGLEWVSSIGVNGSPTYYADSVKGRFTI SRDNSRNTLYLQMNS LRAEDTAVYYCAKMAHPQSGVAFDYWGQGTLVTVSS 15 DOM7h-85 SEQ ID NO: 109 EVQLLESGGGLVQPGGSLRLSCAASGFTFYQSDMSWVRQAPGKGLEWVSSISSQGRSTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKMAHPQSGVAFDYWGQGTLVTVSS 20 DOM7h-86 SEQ ID NO: 110 EVQLLESGGGLVQPGGSLRLSCTASGFTFAARDMSWVRQAPGKGLEWVSSISAQGAHTYYADSVKGRFTI SRDDSKNTLYLQMNSLRAEDTAVYYCAKPRHPQGGVTFDYWGQGTLVTVSS DOM7h-87 SEQ ID NO: 111 25 EVQLLESGGGLVQPGGSLRLSCAASGFTFDNGDMVWVRQAPGKGLEWVSGIAHNGRNTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKNLGQGFDYWGQGTLVTVSS DOM7h-88 SEQ ID NO: 112 EVQLLESGGGLVQPGGSLRLTCAASGFTLNGTSMGWVRQAPGKDLEWVSSIMPVGSHTYYADSVKGRFTI 30 SRDNSKNTLYLQMNSLRAEDTAVYYCAKMARPQSGVAFDYWGQGTLVTVSS DOM7h-89 SEQ ID NO: 113 EVQLLESGGGLVQPGGSLRLSCAASGFTFDHAPMKWARQAPGKGLEWVSYIGSAGNMTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKDEGPFDYWGQGTLVTVSS 35 DOM7h-90 SEQ ID NO: 114 EVQLLESGGGLVQPGGSLRLSCTASGFTFDGMDMSWVRQAPGKGLEWVSSISTTGGTTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKPRHPQGGVTFDYWGQGTLVTVSS 40 DOM7h-91 SEQ ID NO: 115 EVQLLESGGGLVQPGGSLRLSCAASGFTFEAETMAWVRQAPGKGLEWVSTIHSEGSRTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKPRHPQGGVTFDYWGQGTLVTVSS DOM7h-92 SEQ ID NO: 116 45 EVQLLESGGGLVQPGGSLRLSCAASGFTFSTGEMAWVRQAPGKGLEWVSSISSSGATTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKPRHPQGGVTFDYWGQGTLVTVSS DOM7h-93 SEQ ID NO: 117 EVQLLESGGGLVQPGGSLRLSCAASGFTFPSADMVWVRQAPGKGLEWVSRISPEGNHTYYADSVKGRFTI 50 SRDNSKNTLYLQMNSLRAEDTAVYYCAERPPSDYVSFDYWGQGTLVTVSS DOM7h-94 SEQ ID NO: 118 EVQLLESGGGLVQPGGSLRLSCAASGFTFANATMSWVRQAPGKGLEWVSDIDQVGHATYYADSVKGRFTI

SRDNSKNTLYLQMNSLRAEDTAVYYCAKYSWHPDLFDYWGQGTLVTVSS

WO 2011/006915 PCT/EP2010/060112 -37 DOM7h-95 SEQ ID NO: 119 EVRLLESGGGLVQPGGSLRLSCAASGFTFKDYGMNWVRQAPGKGLEWVSRISRNGTVTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKLAAPVRQKGMDFDYWGQGTLVTVSS 5 DOM7h-96 SEQ ID NO: 120 EVQLLESGGGLVQPGGSLRLSCAASGFTFEWYNMSWVRQAPGKDLEWVSSISHDGWNTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKGMIGFDYWGQGTLVTVSS 10 DOM7h-97 SEQ ID NO: 121 VQLLESGGGLVQPGGSLRLSCAASGFTFDIYTMHWVRQAPGKGLEWVSTIVPQGTPTYYADSVKGRFTIS RDNSKNTLYLQMNSLRAEDTAVYYCAKSKRRFLKRFDYWGQGTLVTVSS DOM7h-99 SEQ ID NO: 122 15 EVQLLESGGGLVQPGGSLRLSCAASGFTFARYDMQWVRQAPGKGLEWVSSIKSNGMKTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKASMWTFDYWGQGTLVTVSN DOM7h-100 SEQ ID NO: 123 EVQLLESGGGLVQPGGSLRLSCAASGFTFMLYHMGWVRQAPGKGLEWVSAITGGGYPTYYADSVKGRFTI 20 SRDNSKNTLYLQMNSLRAEDTAVYYCAKLGLRGVLWRRRFDYWGQGTLVTVSS DOM7h-101 SEQ ID NO: 124 EVQLLESGGGLVQPGGSLRLSCAASGFTFGAYSMMWVRQAPGKGLEWVSRISRNGTVTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKIRWNTAQVPVFDYWGQGTLVTVSS 25 DOM7h-102 SEQ ID NO: 125 EVQLLESGGGLVQPGGSLRLSCAASGFTFGPYWMAWVRQAPGKGLEWVSTITPSGRGTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKGRPRVGLWRSGFDYWGQGTLVTVSS 30 DOM7h-103 SEQ ID NO: 126 EVQLLESGGGLVQPGGSLRLSCAASGFTFGQYAMQWVRQAPGKGLEWVSSINITGSTTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKGFRSFDYWGQGTLVTVSS DOM7h-106 SEQ ID NO: 127 35 VQLLESGGGLVQPGGSLRLSCAASGFTFAGYTMSWVRQAPGKGLEWVSTISGFGWTTYYADSVKGRFTIS RDNSKNTLYLQMNSLRAEDTAVYYCAKRLGMRFDYWGQGTLVTVSS DOM7h-109 SEQ ID NO: 129 40 EVQLLESGGGLVQPGGSLRLSCAASGFTFGPYSMGWVRQAPGKGLEWVSFIHSDGRHTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKKTPYRFDYWGQGTLVTVSS DOM7h-111 SEQ ID NO: 130 EVQLLESGGGLVQPGGSLRLSCAASGFTFGQYAMQWVRQAPGKGLEWVSSINITGSTTYYADSVKGRFTI 45 SRDNSKNTLYLQMNSLRAEDTAVYYCAKGFRSFDYWGQGTLVTVSS DOM7h-114 SEQ ID NO: 131 EVQLLESGGGLVQPGGSLRLSCAASGFTFRRYAMSWVRQAPGKGLEWVSTISPYGPVTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKAYYGGFDYWGQGTLVTVSS 50 DOM7r-34 SEQ ID NO: 132 EVQLLESGGGLVQPGGSLRLSCAASGFTFDAYAMGWVRQAPGKGLEWVSKDSPGWRTYYADSVKGRFTI

SRDNSKNTLYLQMNSLRAEDTAVYYCAKSARMRSRHFDYWGQGTLVTVSS

WO 2011/006915 PCT/EP2010/064)112 -38 DOM7r-37 SEQ ID NO: 133 EVQLLESGGGLVQPGGSLRLSCAASGFTFKDYGMNWVRQAPGKGLEWVSRI SRNGTVTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKIRWNTAQVPVFDYWGQGTLVTVSS 5 DOM7r-39 SEQ ID NO: 134 EVQLLESGGGLVQPGGSLRLSCATSGFTFPSYTMGWVRQAPGKGLEWVSRISRTGNYTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKPMYNRGSSYFDYWGQGTLVTVSS DOM7r-40 SEQ ID NO: 135 10 EVQLLESGGGLVQPGGSLRLSCAASGFTFSQYQMSWVRQAPGKGLEWVSSISPTGIQTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKRLIGMPYVEDTFDYWGQGTLVTVSS DOM7r-41 SEQ ID NO: 136 EVQLLESGGGLVQPGGSLRLSCAASGFTFMEYEMEWVRQAPGKGLEWVSGI TNSGSGTYYADSVKGRFTI 15 SRDNSKNTLYLQMNSLRAEDTAVYYCAIMQHPQATGGRVGFDYWGQGTLVTVSS DOM7r-42 SEQ ID NO: 137 EVQLLESGGGLVQPGGSLRLSCAASGFTFPRYTMKWVRQAPGKGLEWVSSIDRTGRKTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKESLVSFDYWGQGTLVTVSS 20 DOM7r-43 SEQ ID NO: 138 EVQLLESGGGLVQPGGSLRLSCAASGFTFGGYTMPWVRQAPGKGLEWVSTISRDGNYTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKDIGMGFDYGGRGTLVTVSS 25 DOM7r-44 SEQ ID NO: 139 EVQLLESGGGLVQPGGSLRLSCAASGFTFETYAMBWVRQAPGKGLEWVSTISSGGKGTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKSRTMYFRVREAFDYWGQGTLVTVSS DOM7r-45 SEQ ID NO: 140 30 EVQLLESGGGLVQPGGSLRLSCAASGFTFRAYRMMWVRQAPGKGLEWVSSIDPDGAVTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAEHFDLAMPNPNAKFDYWGQGTLVTVSS DOM7r-46 SEQ ID NO: 141 EVQLLESGGGLVQPGGSLRLSCAASGFTFSRYQMSWVRQAPGKGLEWVSSIKSNGSSTYYADSVKGRFTI 35 SRDNSKNTLYLQMNSLPAEDTAVYYCAKPSRQSFQYPSFDYWGQGTLVTVSS DOM7r-47 SEQ ID NO: 142 EVQLLESGGGLVQPGGSLRLSCAASGFTFGRYKMGWVRQAPGKGLEWVSSISPTGSSTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKTGYVMVEHFDYWGQGTLVTVSS 40 DOM7r-48 SEQ ID NO: 143 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYPMKWVRQAPGKGLEWVSTINSSGTITYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKPLLPFDYWGQGTLVTVSS 45 DOM7r-49 SEQ ID NO: 144 EVQLLESGGGLVQPGGSLRLSCAASGFTFARYRMCWVRQAPGKGLEWVSCIRDPGFPTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKCSPSSTQCTGLFDYWGQGTLVTVSS DOM7r-50 SEQ ID NO: 145 50 VQLLESGGGLVQPGGSLRLSCAASGFTFRFYGMAWVRQAPGKGLEWVSLIDPPGGATYYADSVKGRFTIS RDNSKNTLYLQMNSLRAEDTAVYYCAKMERRHLKSGHKGFDYWGQGTLVTVSS DOM7r-51 SEQ ID NO: 146 WO 2011/006915 PCT/EP2010/060112 -39 EVQLLESGGGLVQPGGSLRLSCAASGFTFTEYDMMWVRQAPGKGLEWVSS ISHRGEKTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKDKRYRGSQHYFDYWGQGTLVTVSS DOM7r-52 SEQ ID NO: 147 5 VQLLESGGGLVQPGGSLRLSCAASGFTFRSYDMGWARQAPGKGLEWVSTIGSNGANTYYADSVKGRFTIS RDNSKNTLYLQMNSLRAEDTAVYYCAKLMGMFDYWGQGTLVTVSS DOM7r-53 SEQ ID NO: 148 EVQLLESGGGLVQPGGSLRLSCAASGFTFERYSMRNVRQAPGKGLEWVSTIGSTGKWTYYADSVKGRFTI 10 SRDNSKNTLYLQMNSLRAEDTAVYYCAKGRGLVSFDYWGQGTLVTVSS DOM7r-54 SEQ ID NO: 149 EVQLLESGGGLVQPGGSLRLSCAASGFTFRRYSMSWVRQAPGKGLEWVSSIDRSGRMTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKSRLSSTGSEGHNFDYWGQGTLVTVSS 15 DOM7r-55 SEQ ID NO: 150 VQLLESGGGLVQPGGSLRLSCAASGFTFKWYPMKWVRQAPGKGLEWVSTIAYDGVQTYYADSVKGRFTIS RDNSKNTLYLQMNSLRAEDTAVYYCAKLGPTSRVFAATDFDYWGQGTLVTVSS 20 DOM7r-56 SEQ ID NO: 151 EVQLLESGGGLVQPGGSLRLSCAASGFTFPNYAMKWGRQAPGKGLEWVSTIDTSGSTTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKLTHPMAPRPAFDYWGQGTLVTVSS DOM7r-57 SEQ ID NO: 152 25 EVQLLESGGGLVQPGGSLRLSCAASGFTFDLTEMEWVRQAPGKGLEWVSSIGPWGTPTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKISHPQAMYHTFDYWGQGTLVTVSS DOM7r-58 SEQ ID NO: 153 EVQLLESGGGLVQPGGSLRLSCAASGFTFAHQDMTWVRQAPGKGLEWVSDIDHSGSYTYYADSVKGRFTI 30 SRDNSKNTLYLQMNSLRAEDTAVYYCAKWWHPQGGTFDYWGQGTLVTVSS DOM7r-59 SEQ ID NO: 154 EVQLLESGGGLVQPGGSLRLSCAASGFTFGSKDMSWVRQAPGKGLEWVSTIGANGKATYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAEAGHPQAPSFKSFDYWGQGTLVTVSS 35 DOM7r-60 SEQ ID NO: 155 EVQLLESGGGLVQPGGSLRLSCAASGFTFLNAEMSWVRQAPGKGLEWVSTIDRDGANTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKLPPPMSPKKFDYWGQGTLVTVSS 40 DOM7r-61 SEQ ID NO: 156 EVQLLESGGGLVQPGGSLRLSCAASGFTFEREGMMWVRQAPGKGLEWVSTIDRMGRYTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKRDSHPMGFDYRGQGTLVTVSS DOM7r-62 SEQ ID NO: 157 45 EVQLLESGGGLVQPGGSLRLSCAASGFTFENEKMSWVRQAPGKGLEWVSSIGPTGSGTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKTPHPQVSSFDYWGQGTLVTVSS DOM7r-63 SEQ ID NO: 15B EVQLLESGGGLVQPGGSLRLSCAASGFTFEIDHMGWVRQAPGKGLEWVSEIAPSGDRTYYADSVKGRFTI 50 SRDNSKNTLYLQMNSLRAEDTAVYYCAKVICQNQCLFDYWGQGTLVTVSS DOM7r-64 SEQ ID NO: 159 EVQLLESGGGLVQPGGSLRLSCAASGFTFRDSEMSWVRQAPGKGLEWVSFITSDGRDTYYADSVKGRFTI

SRDNSKNTLYLQMNSLRAEDTAVYYCAKPSLPHVTAFDYWGQGTLVTVSS

WO 2011/006915 PCT/EP2010/060112 -40 DOM7r-65 SEQ ID NO: 160 EVQLLESGGGLVQPGGSLRLSCAASGFTFEDETMSWARQAPGKGLEWVSSIGDAGMPTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKGEPIYVHTTHFDYWGQGTLVTVSS 5 DOM7r-66 SEQ ID NO: 161 EVQLLESGGGLVQPGGSLRLSCAASGFTFPHGKMGWVRQAPGKGLEWVSWIAGSGDMTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKLGHPQRGFDYWGQGTLVTVSS 10 DOM7r-67 SEQ ID NO: 162 EVQLLESGGGLVQPGGSLRLSCAASGFTFGTSDMSWVRQAPGKGLEWVSTIDSGGSFTYYADSVKGRETI SRDNSKNTLYLQMNSLRAEDTAVYYCAKPRHPQGGVTFDYWGQGTLVTVSS DOM7r-68 SEQ ID NO: 163 15 EVQLLESGGGLVQPGGSLRLSCAASGFTFEHVPMAWVRQAPGKGLEWVSRISEQGSNTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKVQBPMSPHEFDYWGQGTLVTVSS DOM7r-69 SEQ ID NO: 164 EVQLLESGGGLVQPGGSLRLSCAASGFTFEQGMMSWVRQAPGKGLEWVSSINPGGQFTYYADSVKGRFTI 20 SRDNSRNTLYLQMNSLRAEDTAVYYCAEDLGPGFDYWGQGTLVTVSS DOM7r-70 SEQ ID NO: 165 EVQLLESGGGLVQPGGSLRLSCAASGFTFERWPMSWVRQAPGKGLEWVSTIDRSGNTTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKVLHPQAGSAFDYWGQGTLVTVSS 25 DOM7r-71 SEQ ID NO: 166 EVQLLESGGGSVQPGGSLRLSCAASGFTFGGSDMGWVRQAPGKGLEWVSYIDNQGYNTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKYKLLGPSTEFDYWGQGTLVTVSS 30 DOM7r-72 SEQ ID NO: 167 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSDVMSWVRQAPGKGLEWVSSITRSGMQTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKYAHPQSAVEFDYWGQGTLVTVSS DOM7r-73 SEQ ID NO: 168 35 EVQLLESGGGLVQPGGSLRLSCAASGFTFRNEPMSWVRQAPVKGLEWVSTISPDGSGTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKHGHPQGARFDYWGQGTLVTVSS DOM7r-74 SEQ ID NO: 169 EVQLLESGGGLVQPGGSLRLSCAASGFTFLNSEMSWVRQAPGKGLEWVSTIGYAGTPTYYADSVKGRFTI 40 SRDNSKNTLYLQMNSLRAEDTAVYYCAKPRHPQGGVTFDYWGQGTLVTVSS DOM7r-75 SEQ ID NO: 170 EVQLLESGGGLVQPGGSLRLSCAASGFTFARGPMSWVRQAPGKGLEWVSTITNDGTSTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAEPPHSGRPMFDYWGQGTLVTVSS 45 DOM7r-76 SEQ ID NO: 171 EVQLLESGGGLVQPGGSLRLSCAASGFTFQRTAMSWVRQAPGKGLEWVSSIEASGRYTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKQSPQNGRFDYWGQGTLVTVSS 50 DOM7r-77 SEQ ID NO: 172 EVQLLESGGGLVQPGGSLRLSCAASGFTFDASEMAWVRQAPGKGLEWVSSITVYGDRTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKPRHPQGGVTFDYWGQGTLVTVSS DOM7r-78 SEQ ID NO: 173 WO 2011/006915 PCT/EP2i10/0611 12 -41 EVQLLESGGGLVQPGGSLRLSCAASGFTFDDSHMAWVRQAPGKGLEWVSRISREGKATYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAAPNDQSAAFDYWGQGTLVTVSS DOM7r-79 SEQ ID NO: 174 5 EVQLLESGGGLVQPGGSLRLSCAASGFTFDMSEMSWVRQAPGKGLEWVSAITSDGSSTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKPSLPHVTAFDYWGQGTLVTVSS DOM7r-80 SEQ ID NO: 175 EVQLLESGGGLVQPGGSLRLSCAASGFTFERSTMHWVRQAPGKGLEWVSEIDALGTDTYYADSVKGRFTI 10 SRDNSKNTLYLQMNSLRAEDTAVYYCAKSSDHPQNSFDYWGQGTLVTVSS DOM7r-81 SEQ ID NO: 176 EVQLLESGGGLVQPGGSLRLSCAASGFTFEPREMYWARQAPGKGLEWVARIGWDGHTTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKQLGQFDYWGQGTLVTVSS 15 DOM7r-82 SEQ ID NO: 177 EVQLLESGGGLVQPGGSLRLSCAASGFTFDAYSMMWVRQAPGKGLEWVSTIGRWGEYTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKRRYIGPYMLSGRFDYWGQGTLVTVSS 20 DOM7r-83 SEQ ID NO: 178 EVQLLESGGGLVQPGGSLRLSCAASGFTFMRYPMVWVRQAPGRGLEWVSSISPAGYGTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKGHEISRFSRWSSFDYWGQGTLVTVSS DOM7r-84 SEQ ID NO: 179 25 EVQLLESGGGLVQPGGSLRLSCAASGFTFRKYRMSWVRQAPGKGLEWVSSIARNGRSTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKTTSGFDYWGQGTLVTVSS DOM7r-85 SEQ ID NO: 180 EVQLLESGGGLVQPGGSLRLSCAASGFTFNKKEMGVRQAPGKGLEWVSSIDVSGNVTYYADSVKGRFTI 30 SRDNSKNTLYLQMNSLRAEDTAVYYCAKMAHPQSGVAFDYWGQGTLVTVSS DOM7r-88 SEQ ID NO: 181 EVQLLESGGGLVQPGGSLRLSCAASGFTFRMYDMAWVRQAPGKGLKWVSTILSSGKGTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKLAHPQKGSIFDYRGQGTLVTVSS 35 DOM7r-89 SEQ ID NO: 182 EVQLLESGGGLVQPGGSLRLSCAASGFTFHQGPMGNVRQAPGKGLEWVSWIQATGGATYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKGMEPQSGTLFDYWGQGTLVTVSS 40 DOM7r-90 SEQ ID NO: 183 EVQLLESGGGLVQPGGSLRLSCAASGFTFDVADMDWVRQAPGKGLEWVSGISSSGGYTYYADSVKGRFTT SRDNSKNTLYLQMNSLRAEDTAVYYCAKNLGQGFDYWGQGTLVTVSS DOM7r-92 SEQ ID NO: 184 45 EVQLLESGGGLVQPGGSLRLSCAASGFTFDTSSMLWVRQAPGKGLEWVSVIHQSGTPTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKFPFTHGKFDYWGQGTLVTVSS DOM7r-93 SEQ ID NO: 185 EVQLLESGGGLVQPGGSLRLSCAASGFTFNNYTMGWVRQAPGKGLEWVSLIHTSGTVTYYADSVKGRFTI 50 SRDNSKNTLYLQMNSLRAEDTAVYYCAKWSSRAFDYWGQGTLVTVSS DOM7r-94 SEQ ID NO: 186 EVQLLESGGGLVQPGGSLRLSCAASGFTFGNYRMTWVRQAPGKGLEWVSTISPLGTYTYYADSVKGRFTI

SRDNSKNTLYLQMNSLRAEDTAVYYCAKGRWSIFDYWGQGTLVTVSS

WO 2011/006915 PCT/EP21I0/060112 -42 DOM7r-95 SEQ ID NO: 187 EVQLLESGGGLVQPGGSLRLSCAASGFTFGSYPMGWVRQAPGKGLEWVSWIRGRGLATYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKYFHGKFDYWGQGTLVTVSS 5 DOM7r-96 SEQ ID NO: 188 EVQLLESGGGLVQPGGSLRLSCAASGFTFSAYVMGWVRQAPGKGLEWVSSIRMPGYLTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKRTPFFDYWGQGTLVTVSS 10 DOM7r-97 SEQ ID NO: 189 EVQLLESGGGLVQPGGSLRLSCAASGFTFEHYSMGWVRQAPGKGLEWVSEIDPDGIMTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKAPGVLEMWITHFDYWGQGTLVTVSS DOM7r-98 SEQ ID NO: 190 15 EVQLLESGGGLVQPGGSLRLSCAASGFTFRHYVMGWVRQAPGKGLEWVSAISAHGNRTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKSYSLALTPFDYWGQGTLVTVSS DOM7r-99 SEQ ID NO: 191 EVQLLESGGGLVQPGGSLRLSCAASGFTFTVYEMKWVRQAPGKGLEWVSAISAGGKYTYYADSVKGRFTI 20 SRDNSKNTLYLQMNSLRAEDTAVYYCAKEIRHLDNAVEFDYWGQGTLVTVSS EXEMPLIFICATION 25 Example 1 Biophysical Characterisation: 30 The routine bacterial expression level in 2.5L shake flasks was determined following culture in Onex media at 30'C for 48hrs at 250rpm. The biophysical characteristics were determined by SEC MALLS and DSC, SEC MALLS (size exclusion chromatography with multi-angle-LASER-light scattering) is a non-invasive technique for the characterizing of macromolecules in 35 solution. Briefly, proteins (at concentration of lmg/mL in buffer Dulbecco's PBS) are separated according to their hydrodynamic properties by size exclusion chromatography (column: TSK3000; S200). Following separation, the propensity of the protein to scatter light is measured using a multi-angle-LASER-light-scattering (MALLS) detector. The intensity of the scattered light while protein passes through the detector is 40 measured as a function of angle. This measurement taken together with the protein WO 2011/006915 PCT/EP2010/060112 - 43 concentration determined using the refractive index (RI) detector allows calculation of the molar mass using appropriate equations (integral part of the analysis software Astra v.5.3.4.12). The highest concentration at the mid-point of the eluting peak is about 8 1OuM and this consequently is the concentration at which MALLS determines the in 5 solution state of the protein. DSC (Differential Scanning Calorimetry): briefly, the protein is heated at a constant rate of 180 degrees C/hrs (at 1mg/mL in PBS) and a detectable heat change associated with thermal denaturation measured. The transition midpoint (appTm) is determined, which is described as the temperature where 50% of the protein is in its 10 native conformation and the other 50% is denatured. Here, DSC determined the apparent transition midpoint (appTm) as most of the proteins examined do not fully refold. The higher the Tm, the more stable the molecule. The software package used was OriginR v7.0383. 15 Characteristics of the VH dAbs are summarised in Table 1 below. Cross reactivity of the AlbudAbsTM (ie, anti-serum albumin dAbs) was determined against human, Cynomolgus monkey (cyno), rat and mouse serum albumin ("4AGs" in the table) using surface plasmon resonance (SPR). In this case, BiacoreTM was used. The epitope mapping to domain 1, 2 and/or 3 (D1,2,3) of human serum albumin (HSA) was 20 performed using SPR and purified individual domains of HSA (in-house) covalently coupled to a CM5 chip (amine coupling). The expression was in 2.5L baffled glass flasks in a volume of 500mL in OverNight ExpressTM at 30C, 250rpm. MALLS results: A single VH AlbudAb is l4kDa in size. Any value between 14 and 28kDa as determined by MALLS is indicative of varying degrees of self 25 association or dimer formation (i.e L6kDa predominately monomeric under the conditions tested whereas 22kDa indicates a strong propensity to dimerise under MALLS conditions). DSC results: The concentration of protein in a DSC experiment is much higher at lmg/mL in the actual reaction cell compared to MALLS. This higher concentration 30 could explain in part the presence of two appTms for some AlbudAbs as seen in table 1; WO 2011/006915 PCT/EP2010/060112 - 44 the first Tm constitutes the dissociation of the dimeric complex, whereas the second Tm represents the unfolding of the actual AlbudAb protein. Table 1 -~ ~ ~P %~ ~BUnding to x.. 01/K30f RiC . i * reacivit MALSjDCC Exrsin IS (Ecoli) mg/L in shake (4AGs) [kDa] appTm ppTm2 flasks SPR no human; yes other 3 DOM7h 112 antigens 16 62 66 46.6 No binding DOM7h-98 yes 14.7 65 28.3 D2 DOM7r-29 yes 16.9 62.5 21 D2 DOM7r-35 yes 21.8 58.7 61.8 33.5 D2 DOM7r-36 yes 98 /45 /16 67.4 69.9 31.5 02 DOM7r-38 yes 14.8 61.3 64.5 61.5 D2 DOM7r-31 yes 15 67.9 74.5 25 D2 5 *: precise in-solution affinities of the leads will be determine by ITC, equilibrium dialysis or fluorescence polarisation Apart from DOM7h-1 12, all above AlbudAbs leads are fully cross-reactive between the four species of serum albumin. All identified AlbudAbs bind Domain2 of HSA and 10 express reasonably well in shake flasks under non-optimised conditions. 5 out of 7 AlbudAbs are monomeric as determined by MALLS, whereas DOM7r-35 shows a significant propensity to dimerise under the MALLS conditions. Monomeric state is advantageous because it avoids dimerisation and the risk of products that may cross-link targets such as cell-surface receptors. 15 DOM7r-36 shows some degree of aggregate formation (less than 10% when quantified on MALLS). For 5 out of 7 AlbudAbs, 2 appTms can be detennined. This is due to the higher experimental concentration in DSC experiments and slightly different in-solution state of the dAb at this elevated concentration (for details, see explanation also above). 20 WO 2011/006915 PCT/EP2010/060112 -45 Example 2 Determination of serum half life in rat AlbudAbs were cloned into the pDOM5 vector. The pDOM5 vector is a pUC1 19-based 5 expression vector where protein expression is driven by the LacZ promoter. A GASI leader sequence (see WO 2005/093074) ensures secretion of isolated, soluble dAbs into the periplasm and culture supernatant of K coli. dAbs are cloned SalI/Not] in this vector, which appends a myc tag at the C-terminus of the dAb. For each AlbudAb, 20 50mg quantities were expressed in E. coli and purified from bacterial culture 10 supernatant using protein A affinity resin and eluted with 100mM glycine pH2. The proteins were concentrated to greater than 1mg/ml, buffer exchanged into PBS and endotoxin depleted using using Q spin columns (Vivascience). For Rat pharmacokinetic (PK) analysis, AlbudAbs were dosed as single i.v injections at 2.5mg/kg using 3 rats per compound. Serum samples were taken at 0.16, 1, 4, 12, 24,48, 72, 96, 120, 168hrs. 15 Analysis of serum levels was by anti-myc capture followed by anti-VH detection ELISA as per the method described below. Results are shown in table 2. All tested AlbudAbs show a serum-half life extending ability (negative control HEL4 dAb with T1/2 of 20mins in rat) to varying degrees; this trend can also be seen in the calculated AUC being the highest value for 20 the longest tl/2. The longest serum half-life with 34.5hrs approximates the serum half life of rat serm albumin. The specific affinities of the AlbudAbs to RSA will need to be determined. 25 Table 2 VH dAb T %* AUC 0-inf [hr] [hr*ug/mL] DOM7h-98 13.5 577.5 DOM7r-29 21.9 697.6 WO 2011/006915 PCT/EP2010/060112 -46 DOM7r-35 34.4 1249.6 DOM7r-36 26.5 910.8 DOM7r-38 8.8 203.4 DOM7r-31 11 239 *The serum half-life of rat serum albumin is 35hrs. T /2 is a measure of the circulation time of the molecule in the subjects. AUC=area under the curve, which is a PK profile parameter 5 Anti-mye ELISA method using MSD The AlbudAb concentration in serum was measured by anti- myc ELISA. Briefly, goat anti- myc polyclonal antibody (1:500; Abcam, catalogue number ab9132) was coated overnight onto Nunc 96-well Maxisorp plates and blocked with 5% 10 BSA/PBS + 1% TWEENTM. Serum samples were added at a range of dilutions alongside a standard at known concentrations, Bound myc-tagged AlbudAb was then detected using a rabbit polyclonal anti-VH directly labelled with the MSD sulfo-tag. Each dAb was diluted in assay buffer containing 10% control rat serum (1:1000; in-house reagent,) (method DM222). MSD (MesoScaleDiscovery; 15 MesoScale.com) utilizes electrochemituminescence detection of the sulfo-tag after electrochemi cal stimulus. From the raw ELISA data, the concentration of unknown samples was established by interpolation against the standard curve taking into account dilution factors. The mean concentration result from each time point was determined from 20 replicate values and entered into WinNonLin analysis package (eg version 5.1 (available from Pharsight Corp., Mountain View, CA94040, USA). The data was fitted using a non-compartmental model, where PK parameters were estimated by the software to give terminal half-lives. Dosing information and time points were selected to reflect the terminal phase of each PK profile. 25 Example 3: Affinity maturation of naive VH AlbudAbsTM WO 2011/006915 PCT/EP2010/060112 -47 12 VH AlbudAb leads isolated from naive selection were taken forward for affinity maturation. Individual error prone libraries (EP) of DOM7r-36, DOM7r-35, DOM7r-31, DOM7h-98, DOM7h-1 12, DOM7r-38 and DOM7r-29 were made, whereas the following parental clones were pooled and combined in a single EP library and screened 5 together: DOM7r-83, DOM7r-85, DOM7r-92, DOM7r-94 and DOM7r-95. All libraries were greater than 2x 10 9 CFU/mL. Selections were performed in 4 rounds on soluble antigen (biotin-HSA; biotin-RSA; blocking with 2% Marvel) by cross over-selection with decreasing concentration of 10 antigen: Round1 at I pM (HSA or RSA), Round 2 at 1pM (RSA or HSA), followed by 2 further rounds of selection at 1OOnM and 1OnM, respectively, with the same antigen as in Round2. Ca. 3000 samples from both, R3 and R4 outputs were screened by supernatant BlAcore and clones ranked according to their off-rate only, Eight-point dilution kinetic affinity measurements were performed on improved clones (data 15 below). Table 3 Improved clone From round DOM7r-31-14 R4 DOM7r-201 R3 DOM7r-36-2 R4 DOM7r-36-8 R4 DOM7r-92-4 R4 DOM7h-98-4 R3 20 Table 4 - Kinetic data: RSA HSA CSA MSA KD(M) KD(M) KD(M) KD(M) DOM7r-201 2.4E-07 6.OE-8 5.8E-08 2.BE-07 DOM7r-36-2 1.9E-07 1.5E-07 1.8E-07 5.2E-07 DOM7r-36-8 2.1E-07 6.7E-08 9.2E-08 5.2E-07 DOM7r-92-4 2.6E-07 1.3E-07 9,8E-08 1.1E-07 WO 2011/006915 PCT/EP2010/1060112 -48 DOM7h-98-4 5.8E-07 2.OE-06 3.6E-06 8.1E-07 DOM7r-31-14 4.6E-08 5.8E-08 3.1E-05 6.0E-09 Table 5 - Sequence alignment: 5 5 15 25 35 45 55 A EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSA ISGSGGSTYY B EVQLLESGGG LVQPGGSLRL SCAASGFTFN HYTMGWVRQA PGKGLEWVSL IBPSGTVIYY C EVQLLESGGG LVQPGGSLRL SCAASGFTFN HYTMGWVRQA PGKGREWVSL IBPSGTVTYY D EVQLLESGGG LVQPGGSLRL SCAASGFTFN HYTMGWVRQA PGKGLEWVSL IBPSGTVIYY 10 E EVQLLESGGG LVQPGGSLRL SCAASGFTFD TSSMLWVRQA PGKGLEWVSV IHQSGTPTYY F EVQLLESGGG LVQPGGSLRL SCAASGFTFG NYAMAWVRQA PGKGLEWVSS IDMVGIKTYY G EVQLLESGGG LVQPGGSLRL SCTASGFTFR HYRMGWVRQA PGKGLEWVSW IRPDGTFTYY 65 . 75 85 95 105 115 15 A ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKSY GA-~~FDYWG QGTLVTVSS B ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKWS SRA~~FDYWG QGTLVTVSS C ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKWS SRA--FDYWG QGTLVTVSS D ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARWS SRA--FDYWG QGTLVTVSS E ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKFP STHGKFDYWG QGTLVTVSS 20 F ADSVKGRFTN SRDNSKNTLY LQMNSLRAED TAVYYCARGF RI--FDYWG QGTLVTVSS G ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKSY MADR-FDYWG QGTLVTVSS A= VH dummy B= DOM7r-201 25 C= DOM7r-36-2 D= DOM7r-36-8 E= DOM7r-92-4 F= DOM7h-98-4 G= DOM7r-31-1 30 The CDRs are underlined; sequences are shown N- to C-terminus;"~" denote gaps introduced for alignment 35 Nucleotide sequences DOM7r-201 SEQ ID NO: 192 GAGGTGCAACTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTC CCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAATCATTATACGA 40 TGGGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCATTG ATTCATCCGAGTGGTACGGTGATATACTACGCAGACTCCGTGAAGGGCCG GTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGA ACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAAATGGAGT TCGAGGGCATTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCTAG 45 C DOM7r-36-2 SEQ ID NO: 193 WO 2011/006915 PCT/EP2010/060112 -49 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTC CCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAATCATTATACGA TGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCGAGAGTGGGTCTCATTG ATTCATCCGAGTGGTACGGTGACATACTACGCAGACTCCGTGAAGGGCCG 5 GTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGA ACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAAATGGAGT TCGAGGGCGTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAG C 10 DOM7r-36-8 SEQ ID NO: 194 GAGGTGCAACTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTC CCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAATCATTATACGA TGGGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCATTG ATTCATCCGAGTGGTACGGTGATATACTACGCAGACTCCGTGAAGGGCCG 15 GTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGA ACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAGATGGAGT .TCGAGGGCGTTTGACTACTGGGGTCAGGGGACCCTGGTCACCGTCTCGAG C 20 DOM7r-92-4 SEQ ID NO: 195 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTC CCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGATACGAGTAGTA TGTTGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCAGTT ATTCATCAGAGTGGTACGCCTACATACTACGCAGACTCCGTGAAGGGCCG 25 GTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGA ACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAAATTTCCG TCTACTCATGGTAAGTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGT CTCGAGC 30 DOM7h-98-4 SEQ ID NO: 196 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTC CCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGGTAATTATGCGA TGGCGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCATCG ATTGATATGGTTGGTATTAAGACATACTACGCAGACTCCGTGAAGGGCCG 35 GTTCACCAATTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGA ACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAGAGGTTTT CGTATTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC DOM7r-31-14 SEQ ID NO: 197 40 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTC CCTGCGTCTCTCCTGTACAGCCTCCGGATTCACCTTTAGGCATTATCGTA TGGGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCATGG ATTCGTCCGGATGGTACGTTTACATACTACGCAGACTCCGTGAAGGGCCG GT TCACCATCT CCCGCGACAATTCCAAGAACACGCTGTATC TGCAAATGA 45 ACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAAATCTTAT ATGGCTGATAGGTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTC GAGC Amino Acid Sequences 50 DOM7r-201 SEQ ID NO: 198 EVQLLESGGGLVQPGGSLRLSCAASGFTFNHYTMGWVRQAPGKGLEWVSL

IHPSGTVIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKWS

-50 SRAFDYWGQGTLVTVSS DOM7r-36-2 SEQ ID NO: 199 EVQLLESGGGLVQPGGSLRLSCAASGFTFNHYTMGWVRQAPGKGREWVSL I8 PSGTVTYYADSVIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKWS SRAFDYWGQGTLVTVSS DOM7r-36-8 SEQ ID NO: 200 EVQLLESGGGLVQPGGSLRLSCAASGFTFNHTMGWVRQAPGKGLEWVSL IHPSGTVIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARWS SRAFDYWGQGTLVTVSS DOM7r-92-4 SEQ ID NO: 201 EVQLLESGGGLVQPGGSLRLSCAASGFTFDTSSMLWVRQAPGKGLEWVSV IHQSGTPTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKFP STHGKFDYWGQGTLVTVSS DOM7h-98-4 SEQ ID NO; 202 EVQLLESGGGLVQPGGSLRLSCAASGFTFGNYAMAWVROAPGKGLEWVSS IDMVGIKTYYADSVKGRFTNSRDNSKNTLYLQMNSLPAEDTAVYYCARGF RIFDYWGQGTLVTVSS DOM7r-31-14 SEQ ID NO: 203 EVQLLESGGGLVQPGGSLRLSCTASGFTFRHYRMGWVRQAPGKGLEWVSW IRPDGTFTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSY MADRFDYWGQGTLVTVSS Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (15)

1. An anti-serum albumin (SA) immunoglobulin single variable domain 5 comprising an amino acid sequence that is at least 80% identical to an amino acid sequence selected from SEQ ID NOs: 97 to 191 and 198 to 203.

2. An anti-serum albumin (SA) immunoglobulin single variable domain comprising an amino acid sequence having up to 4 amino acid changes 10 compared to an amino acid sequence selected from SEQ ID NOs: 97 to 191 and 198 to 203.

3. An anti-serum albumin (SA) immunoglobulin single variable domain comprising an amino acid sequence that is encoded by a nucleotide sequence 15 which is at least 80% identical to a sequence selected from SEQ ID NOs I to 96 and 192 to 197.

4. The variable domain of any preceding claim, wherein the variable domain comprises the amino acid sequence of any one of SEQ ID NOs: 97 to 103 and 20 198 to203.

5. The variable domain of any preceding claim, comprising a binding site that specifically binds human SA with a dissociation constant (KD) of from about 0.1 to about 10000 nM, optionally from about 1 to about 6000 nM, as determined by surface plasmon resonance. 25 6. The variable domain of any preceding claim, comprising a binding site that specifically binds human SA with an off-rate constant (Kd) of from about 1.5 x

10-4 to about 0.1 sec- , optionally from about 3 x 10-4 to about 0.1 sec-' as determined by surface plasmon resonance. WO 2011/006915 PCT/EP2010/060112 - 52 7. The variable domain of any preceding claim, comprising a binding site that specifically binds human SA with an on-rate constant (Ka) of from about 2 x 106 to about l x 10 4 M-'sec- 1 , optionally from about I x 106 to about 2 x 10 4 M-'sec as determined by surface plasmon resonance. 5 8. The variable domain of any preceding claim, comprising a binding site that specifically binds Cynomolgus monkey SA with a dissociation constant (KD) of from about 0.1 to about 10000 nM, optionally from about I to about 6000 nM, as determined by surface plasmon resonance. 10 9. The variable domain of any preceding claim, comprising a binding site that specifically binds Cynomolgus monkey SA with an off-rate constant (Kd) of from about 1.5 x 10~ 4 to about 0.1 sec- , optionally from about 3 x 104 to about 0.1 sec- as determined by surface plasmon resonance. 15 10. The variable domain of any preceding claim, comprising a binding site that specifically binds Cynomolgus monkey SA with an on-rate constant (Ka) of from about 2 x 106 to about I x 10 4 M'sec- 1 , optionally from about I x 106 to about 5 x 103 M- 1 sec as determined by surface plasmon resonance. 20

11. The variable domain of any preceding claim, wherein the variable domain has a melting temperature (Tm) of at least 55 degrees centigrade, optionally 55 < Tm 5 75 degrees centigrade, as determined by DSC (differential scanning calorimetry). 25

12. The variable domain of any preceding claim, wherein the variable domain is substantially monomeric as determined by SEC-MALLS (size exclusion chromatography with multi-angle-LASER-light-scattering). WO 2011/006915 PCT/EP2010/060112 - 53 13. A multispecific ligand comprising an anti-SA variable domain of any preceding claim and a binding moiety that specifically binds a target antigen other than SA, optionally wherein the binding moiety is an TNFR1 antagonist. 5 14. An anti-SA single variable domain of any one of claims I to 12, wherein the variable domain is conjugated to a drug (optionally an NCE drug), optionally wherein the selected variable domain is according to claim 4.

15. A fusion protein comprising a polypeptide or peptide drug fused to a variable 10 domain according to any one of claims I to 12, optionally wherein the selected variable domain is according to claim 4.

16. A composition comprising a variable domain, fusion protein or ligand of any preceding claim and a pharmaceutically acceptable diluent, carrier, excipient or 15 vehicle.

17. A nucleic acid comprising a nucleotide sequence encoding a variable domain according to any one of claims I to 12 and 14, or a multispecific ligand of claim 13 or fusion protein of claim 15. 20

18. A nucleic acid comprising a nucleotide sequence that is at least 80% identical to a sequence selected from SEQ ID NOs I to 96 and 192-197.

19. A vector comprising the nucleic acid of claim 17 or 18. 25

20. An isolated host cell comprising the vector of claim 19.

21. A method of treating or preventing a disease or disorder in a patient, comprising administering at least one dose of a variable domain according to any one of WO 2011/006915 PCT/EP2010/060112 - 54 claims I to 12 and 14, or a multispecific ligand of claim 13 or fusion protein of claim 15 to said patient.