PT103452A - POLYPEPTIDES SPECIFICALLY CONNECTED TO THE FIBRONECTIN ED-B DOMAIN WITH SPECIAL SEQUENCES - Google Patents

Abstract

The invention relates to recombinant polypeptides, in particular antibodies or antibody fragments which bind to fibronectin ED-B isoforms and may block their function as well as nucleic acids encoding them. The invention further relates to methods of obtaining such polypeptides, vectors for targeting said nucleic acids, non-human cells and organisms transformed with said nucleic acids or vectors, and to pharmaceutical or diagnostic compositions containing such polypeptides. Also disclosed are the uses of said polypeptides in the prevention, treatment, diagnosis or diagnosis of pre-disposition of diseases associated with ED-B.

Description

MISCELLANEOUS MIGEE »pst p m M tmm m sd b

The invention relates to recombinant polypeptides, in particular antibodies or antibody fragments which bind to the ED-B isoform of fibronectin and may block its function. In addition, the diagnostic and pharmaceutical application of the polypeptides according to the invention is disclosed.

During the development and progression of the tumor, the extracellular matrix (ECM), in which the tumor grows, is modified by proteolytic degradation of preexisting ECM. This process generates a tumor-induced matrix, which is distinguished from ECM that occurs in normal tissue. Tumor-induced ECM appears to be the optimal environment for tumor growth and tumor angiogenesis (1-4).

In tumor angiogenesis, new blood vessels are formed from pre-existing vessels. This process requires ECM proteolysis, the specific growth and differentiation of endothelial cells into new vascular structures, which are essential for further tumor growth (5). resulted in

Fibronectins are an important class of matrix glycoproteins. Their main role is to facilitate cell adhesion to a variety of different extracellular matrices. The presence of fibronectins on the surface of untransformed cells as well as their absence in the case of transformed cells resulted in the identification of fibronectin as important adhesion proteins. They interact with many other different molecules, e.g., collagen, heparan sulfate-proteoglycans, and fibrin, and thereby regulate cell shape and cytoskeleton creation. In addition, they are responsible for cell migration and cell differentiation during embryogenesis. In addition, they are important for wound healing where they make it possible to migrate macrophages and other immune cells into the field in question and in the formation of blood clots, making it possible for blood platelets to adhere to damaged regions of the blood vessels.

Fibronectins are dimers of two similar peptides, each strand being approximately 60-70 nm in length. At least 20 different fibronectin chains have been identified, all of which are produced by alternative splicing of the RNA transcript of a single fibronectin gene.

Fibronectins are high molecular weight glycoproteins, mediators of adhesion, which play an important role in the development of the vascular system. In addition, fibronectins chemotactically act on endothelial cells, modulate the action of growth factors, and support the linear growth of endothelial cells during angiogenesis (6-9). An analysis of proteolytic cleavage products of fibronectin shows that polypeptides consist of six tightly wound domains, each of which in turn contains so-called repeating sequences (" repeats ") whose similarities with respect to their amino acid sequence permit a three types (types I, II and III). The central region of both dimer chains consists of a section of so-called 111-type repeats, which on average are 90 amino acids in length (10). Structural studies have revealed that each I-type repeat consists of seven beta strands, which are wound on two antiparallel pleated sheets, in which short loop regions are exposed as potential sites of the protein-protein interaction (11).

These I-type repeats make it possible for fibronectin to act as adhesion molecules that interact with cell surface molecules, the so-called " integrins ". The term " integrin " was first used in 1987 in (12) to describe a related group of heterodimeric cell surface molecules that act as mediators between the extracellular matrix and the intracellular cytoskeleton and thus induce cell migration and adhesion. These heterodimeric receptors "" or mediate signals from the extracellular environment with specific cellular functions. To date, 17 beta subunits are known which can interact specifically and non-covalently with more than 20 alpha subunits, particularly to form 20 different families (13). The RGDS sequence, which is found in the tenth type III fibronectin (III-10) repeat, in particular mediates the interaction of fibronectin with at least 8 different integrins. In addition, it has been shown that at least four integrins can interact specifically with fibronectin independently of RGDS (13). In addition to the sequences III7, III8, III9 and III10, the type III repeat sequences group also comprises the EIIIB and EIIIA repeats (ED-B and ED-A). ED-B-fibronectin can not be detected in normal adult tissue (only exception: proliferative endometrium), whereas it is strongly expressed in fetal tissue and tumor growth, in addition to a local stromal expression of ED-B. In addition, ED-B-fibronectin is localized perivascularly around blood vessels that have been formed again during angiogenesis. For this reason, ED-B-fibronectin is a marker protein specific for the process of angiogenesis (tumor) (14). The ED-B domain is a highly conserved type 111 complete homology component consisting of 91 amino acids. The degree of homology between humans and rats is 100%, between humans and chickens 96%. In the literature, very little is known about the function of the ED-B domains. Some publications (15-17) speculate on a general action of adhesion mediation for several cells. No specific action on endothelial cells has yet been shown.

In WO 02/20563, recombinant ED-B has been shown to have a specific pro-angiogenic action in vitro: (i) proliferation of human dermal microvascular endothelial cells stimulated by bFGF (HDMVEc) is enhanced by recombinant ED-B , (ii) the protein mediates HDMVEC adhesion, and (iii) recombinant ED-B stimulates the invasion and differentiation (tube formation) of HDMVEc in collagen gels.

In addition, these ED-B mediated effects could be specifically blocked by synthetic peptides that were derived from ED-B domains. The peptide sequences thus represent the binding region for a specific ED-B receptor on the endothelial cell surface which has been identified by affinity chromatography such as Î ± 2β-integrin. The specific interaction between a2pi-integrin and the ED-B domain has not previously been described in the literature.

Also disclosed in WO 02/20563 are proteins which are specifically regulated through the ED-B-fibronectin domain, which comprise ac-1-integrin, focal adhesion kinase, CD6 ligand (ALCAM), the alpha chain of the vitronectin, the integrated alpha-8 subunit or the precursor of follistatin-related protein. Endothelial cells are expressed by a variety of integrin receptors with partially overlapping properties (lit .: D. G. Stupack and D. A. Cheresh, SciSTKE, 2002 Feb 12; 2002). These expression patterns show that different integrins (e.g., alfavbeta3 and alpha5betal) mediate similar biological phenomena (adhesion, migration and survival) and thus represent redundant systems for endothelial cells that protect their behavior and survival. It was previously known that alpha2betal interacts with its natural ligands, the collagens. Blocking this interaction may result in antiangiogenic action (Y. Funahashi et al., Cancer Res. 62: 6116-6123, 2002).

An object of the present invention has thus been the preparation of binding molecules for function blocking, such as, e.g., antibodies that specifically block ED-B domain receptor binding sites. These binding molecules have antiangiogenic action on endothelial (tumor) cells. In contrast to relatively broadly expressed α2β1-ίηίθςΓίη3, the ED-B domain represents a specific and ideal target molecule for such binding molecules. The ED-B structure makes it difficult to develop monoclonal and polyclonal antibodies since ED-B can thus be expected to have a low in vivo immunogenicity. The BC-1 antibody (J. Cell Biol. 108 (1989), 1139-1148) thus reacts with a cryptic epitope of fibronectin, which is present only in the presence of ED-B and thus not directly with ED-B. L19 antibody (Tarli et al., Blood 94 (1999), 192-198 and WO 01/62800), which has been produced by the use of recombinant ED-B as an immunogen, is in turn biologically inactive, ie, not can recognize cell adhesion to ED-B to a significant extent.

In one surprising manner, it has now been found that function blocking ED-B binding molecules, such as, for example, the ED-B function blocking antibody M0R03255, which strongly inhibit cell adhesion to ED-B and cause a significant reduction of tumor growth in vivo. The blocking of ED-B produced through the binding molecules according to the invention can obviously not be compensated for by collagen-integrin compensatory mechanisms.

Through the HuCAL®-GOLD antibody library - a library with, for example, 1.6 x 10E10 different antibodies in the Fab fragment format, which was generated starting from the HuCAL consensus sequences (WO 97/08320; Knappik , A. Hofer, A. Wolle, J., Plunckthun, A. and Virnekas, B. (2000). ) J. Mol. Biol. 296: 57-86) by diversification corresponding to the diversity of human antibodies in all six CDR areas and is rigorously examined through CysDisplay (WO 01/05950) of a variant of the presentation process of phage-fragments of function blocking Fab antibodies that selectively bind to the ED-B domain have been identified in the tests leading to the present invention. The effectiveness of these antibody fragments could be shown in an in vitro adhesion test that reflects the specific interaction between recombinant ED-B and HDMVEc alone. The binding affinity to the ED-B domain could be considerably improved by a specific change in the binding molecules. It has also been shown in vivo that binding molecules in an animal model inhibit tumor growth.

A first aspect of the invention is thus a polypeptide which (i) binds specifically to the ED-B domain of fibronectin and (ii) inhibits the interaction between the ED-B domain and its receptor. The polypeptide according to the invention is preferably an antibody or antibody fragment. The term " antibody " according to the present invention comprises polyclonal, monoclonal, chimeric, humanized or human antibodies, as well as recombinant antibodies, single chain antibodies, or fragments of antigen binding antibodies, eg, monovalent fragments of antibody fragments, such as, for example, Fab fragments or scFv fragments, or divalent antibody fragments, such as, for example, fragments

In this context, it is essential for the invention that the antibodies contain one or more antigen binding sites that meet the above requirements, ie, specific binding to the ED-B domain and inhibition of the interaction between the ED-B domain and its receptor, especially its receptor on endothelial cells. These antigen binding properties are preferably achieved by combining a V H and V L region, whereby these regions are constructed from the thus mentioned framework regions (FR 1, FR 2, FR 3 and FR 4) as well as the CDR regions that mediate the binding of the antigen (H-CDR1, H-CDR2, H-CDR3 to the VH region and L-CDR1, L-CDR2, L-CDR3 to the VL region). The polypeptide according to the invention preferably has an affinity for the ED-B domain which corresponds to a value of KD 5, 1 and m, preferably? 100 nM, especially preferably? 10 nM, even more preferably 1 nM and most preferably, S < 0.1 nM, wherein the affinity can be determined as indicated in the examples by a test in the Bladec® system. The polypeptide according to the invention is distinguished in that it specifically binds to the ED-B domain of fibronectin , eg, binds with a significantly lower affinity to other fibronectin domains, in particular to the fibronectin domain 6 (FN6) and / or the 7-8-9 domains of fibronectin (7-8-9). In a preferred embodiment, the polypeptide according to the invention and the ED-B domain of fibronectin bind with an affinity which is higher by at least a factor of 2 - in particular by at least one factor of 5, and particularly preferably at least a factor of 10 - than that of FN6 and / or 7-8-9, as may be determined, for example, by the binding test which is indicated in examples.

In another preferred embodiment, the polypeptide according to the invention exhibits an inhibition of the adhesion of recombinant ED-B to HDMVEc cells in vitro, preferably at least 50% inhibition, and especially preferably of , at least 75% at a concentration of 10 æg / ml in each case.

In addition, it is preferred that the polypeptide according to the invention exhibits inhibition of tumor growth in vivo that is produced by implantation of F9-teratocarcinoma cells (ATCC CRL-1720) in test animals, e.g. fur. The polypeptide according to the invention is preferably selected from antibodies and antibody fragments which comprise

(a) a VH (1) region encoded by a nucleic acid sequence SEQ ID NO: 1 (MOR 02610), SEQ ID NO 5 (MOR 02611), SEQ ID NO 9 (MOR 02613), SEQ ID NO: (MOR 02614), SEQ ID NO: 29 (SEQ ID NO: 21), SEQ ID NO: 21 (SEQ ID NO: 21) SEQ ID NO: 41 (MOR 02721), SEQ ID NO: 45 (MOR 02722) or at least one H-CDR 1 -, H- CDR-2 and / or H-CDR3 of one of the abovementioned VH regions, or (ii) Derived from a VH region according to (i), by a change in at least one H-CDR region and / or

(b) A VL region (i) encoded by a nucleic acid sequence SEQ ID NO. 3 (MOR 02610), SEQ ID NO. 7 (MOR 02611), SEQ ID NO. 11 (MOR 02613), SEQ ID NO. 15 (MOR 02614), SEQ ID NO. 19 (MOR 02616), SEQ ID NO. 23 (MOR 02618), SEQ ID NO. 27 (MOR 02619), SEQ ID NO. 31 (MOR 02622), SEQ ID NO. 35 (MOR 02715), SEQ ID NO. 39 (MOR 02718), SEQ ID NO. 43 (MOR 02721), SEQ ID NO. 47 (MOR 02722) or at least one L-CDR 1, L-CDR 2 - and / or L-CDR 3 - region of one of the abovementioned VL regions or (ii) Derived from a VL region according to ( i), by a change in at least one L-CDR region. Changes in the L-CDR3 region in the VL region and / or changes in the H-CDR2 region in the VH region are preferred.

For example, the polypeptide according to the invention has a VL region which is derived from the VL region and which is encoded by the nucleic acid sequence SEQ ID NO. 27 (MOR 02619) or SEQ ID NO. 35 (MOR 02715). Especially preferred is a polypeptide comprising a VH (I) region encoded by the nucleic acid sequence SEQ ID NO. 25 (MOR 02619) or SEQ ID NO. 33 (MOR 02715) or at least one H-CDR 1, H-CDR-2 and / or H-CDR 3 region of one of the abovementioned VH regions, or (ii) Derived from a VH region according to ( i) by a change in at least one H-CDR region. The polypeptide preferably has a VH region which is derived by a change in the H-CDR2 region and is encoded through a VH region from the nucleic acid sequence SEQ ID NO. 25 (MOR 02619) or SEQ ID NO. 33 (MOR 02715). Especially preferred in this case is a polypeptide comprising

(a) a VH (i) region encoded by the nucleic acid sequence SEQ ID NO. 63 (MOR 03243), SEQ ID NO. 67 (MOR 03245), SEQ ID NO. 71 (MOR 03246), SEQ ID NO. 75 (MOR 03251), SEQ ID NO. 79 (MOR 03252), SEQ ID NO. 81 (MOR 03253), SEQ ID NO. 83 (MOR 03255), SEQ ID NO. 85 (MOR 03257), SEQ ID NO. 87 (MOR 03258) or at least the H-CDR2 region of one of the abovementioned VH regions or (ii) Derived from a VH region according to (i), by a change in at least one H-CDR region and / or

(b) a VL region (i) encoded by the nucleic acid sequence SEQ ID NO. 65 (MOR 03243), SEQ ID NO. 69 (MOR 03245), SEQ ID NO. 73 (MOR 03246), SEQ ID NO. 77 (MOR 03251, as well as MOR 03252, MOR 03253, MOR 03255 and MOR 03257), SEQ ID NO. 89 (MOR 03258) or at least the L-CDR 1, L-CDR 2 or L-CDR 3 region of one of the aforementioned VL regions, or (ii) Derived from a VL region according to (i), through of a change in at least one L-CDR region.

Specific examples of the polypeptide according to the invention are as follows:

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 1 and the VL region which is encoded by SEQ ID NO. 3 (MOR 02610) or at least one H-CDR1, H-CDR2, HCDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 5 and the VL region which is encoded by SEQ ID NO. 7 (MOR 02611) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 9 and the VL region which is encoded by SEQ ID NO. 11 (MOR 02613) or at least one H-CDR1, H-CDR2, HCDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 13 and the VL region which is encoded by SEQ ID NO. 15 (MOR 02614) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 17 and the VL region which is encoded by SEQ ID NO. 19 (MOR 02616) or at least one H-CDR1, H-CDR2, HCDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 21 and the VL region which is encoded by SEQ ID NO. 23 (MOR 02618) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 25 and the VL region which is encoded by SEQ ID NO. 27 (MOR 02619) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 29 and the VL region which is encoded by SEQ ID NO. 31 (MOR 02622) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 33 and the VL region which is encoded by SEQ ID NO. (MOR 02715) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 37 and the VL region which is encoded by SEQ ID NO. 39 (MOR 02718) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 41 and the VL region which is encoded by SEQ ID NO. 43 (MOR 02721) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 45 and the VL region which is encoded by SEQ ID NO. 47 (MOR 02722) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 25 and the VL region which is encoded by SEQ ID NO. 49 (MOR 03055) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 25 and the VL region which is encoded by SEQ ID NO. 51 (MOR 03066) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 25 and the VL region which is encoded by SEQ ID NO. 53 (MOR 03075) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. 13

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 25 and the VL region which is encoded by SEQ ID NO. 55 (MOR 03069) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 25 and the VL region which is encoded by SEQ ID NO. 57 (MOR 03071) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 33 and the VL region which is encoded by SEQ ID NO. 59 (MOR 03064) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 33 and the VL region which is encoded by SEQ ID NO. 61 (MOR 03062) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 63 and the VL region which is encoded by SEQ ID NO. 65 (MOR 03243) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 67 and the VL region which is encoded by SEQ ID NO. 69 (MOR 03245) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 71 and the VL region which is encoded by SEQ ID NO. 73 (MOR 03246) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 75 and the VL region which is encoded by SEQ ID NO. 77 (MOR 03251) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 79 and the VL region which is encoded by SEQ ID NO. 77 (MOR 03252) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 81 and the VL region which is encoded by SEQ ID NO. 77 (MOR 03253) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 83 and the VR region which is encoded by SEQ ID NO. 77 (MOR 03255) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 85 and the VR region which is encoded by SEQ ID NO. 77 (MOR 03257) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof.

A polypeptide comprising the VH region which is encoded by SEQ ID NO. 87 and the VR region which is encoded by SEQ. ID NO. 89 (MOR 03258) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. The creation of the V H and V R chains of the polypeptides according to the invention is as follows:

Chain VH: vs · The structure of region 1 extends from nt 1-78 (i.e., 26 aa); The last codon (aa) of FR1 is always: TCC (Cys). &Quot; CDR1 region " can be of two different lengths, 30 nt (10 aa) (possible in VH1A, VH1B, 3, 4 and 5 families), or 36 nt (12 aa) (possible in VH2, VH4 and VH6 families).

- > The structure of region 2 always shows 33 nt (ie, 11 aa); the first codon (aa) of FR2 is always: TGG (Trp); the last two codons are always CTC.GAG (LeuGlu). - > &Quot; CDR2 region " can be of three different lengths; 57 nt (19 aa) (possible in VH2 and VH4 families), 60 nt (20 aa) (possible in VH1A, VH1B, 3 and 5 families); or 63 nt (21 aa) (possible in the VH6 family).

The structure of region 3 is always 96 nt (ie, 32 aa); the third codon (aa) of FR3 is always: ACC (thr); the last five codons are always TAT.TAT.TGC.GCG.CGT (Tyr Tyr Cys Ala Arg). &Quot; CDR3 region " can be of several different lengths: from 12-69 nt (4-23 aa) (in all VH2 and VH4 families), 60 nt (20 aa) (possible in VH1A, 16 VH1B, 3 and 5 families), or 63 nt (21 aa) (possible in the VH6 family). - > The structure of region 4 is always 33 nt (ie, 11 aa) and is identical in all 7 families: and Vytli, and Xi and ACiC. STCs and. AUls and «AGG TCÂ

VL kappa chain: - > The structure of region 1 extends from nt 1-69 (i.e., 23 aa); the last codon (aa) of FR1 is always: TGC (Cys). > 4 · A " CDR1 region " can be of four different lengths: 24 nt (8 aa) (possible in Vkl and

Vk3), 27 nt (9 aa) (possible in the Vk3 family), 39 nt (13 aa) (possible in the Vk2 family), or 42 nt (14 aa) (possible in the Vk4 family); the first codon (aa) is always AGA (Arg); the penultimate codon (aa) of the CDR1 region is always: CTG (Leu). Η * The structure of region 2 always shows 33 nt (ie, 11 aa); the first two codons (aa) of FR2 are always: TGG.TAC (Trp Tyr); the penultimate codon is always CCG (Pro). &Quot; CDR2 region " always shows 33 nt (ie, 11 aa), where the first three codons (aa) are always CTA.TTA.ATT (LeuLeuIle). The structure of region 3 is always 96 nt (ie, 32 aa); the first three codons (aa) of FR3 are always: GGG.GTC.CCG (Gly Vai Pro); the last three codons are always TAT.TAT.TGC (Tyr Tyr Cys). - A " CDR3 region " always has 24 nt (i.e., 8 aa), where the second codon (aa) is always CAG (Gin). The structure of region 4 is always 39 nt (ie, 13 aa) and is identical in all four families: ACC.TTT.GGC.CAG.GGT.ACG.AAA.GTT.GAA.ATT.AAA.CGT.ACG .

VL lambda chain: - The structure of region 1 extends from nt 1-66 (i.e., 22 aa); The last codon (aa) of FR1 is always: TGT (Cys). - " " CDR1 region " can be present in three different lengths: 33 nt (11 aa) (possible in the V13 family), 39 nt (13 aa) (possible in the Vil family) or 42 nt (14 aa) (possible in Vil and V12 families). - > The structure of region 2 always shows 33 nt (ie, 11 aa); the first two codons (aa) of FR2 are always: TGG.TAC (Trp Tyr); the third last codon is always GCG (Ala). - " " CDR2 region " always shows 33 nt (ie, 11 aa), where the third codon (aa) is always ATT (Ile) and the last three codons are always CGT.CCC.TCA (Arg Pro Ser). - > The structure of region 3 is always 96 nt (i.e. 32 aa), where the first codon (aa) of FR3 is always: GGC (Gly), and the last four codons are always GAT.TAT.TAT.TGC ( Asp Tyr Tyr Cys). - A " CDR3 region " can have three different lengths: 24 nt (8 aa), 27 nt (9 aa), or 30 nt (10 aa). - »The structure of region 4 always shows 39 nt (ie 13 aa) and is identical and all 3 families: GTG.TTT.GGC.GGC.GGC.ACG.AAG.TTA.ACC.GTT.CTT.GGC .CAG.

For therapeutic or diagnostic purposes, e.g., for in vitro or in vivo diagnosis, the polypeptide according to the invention may be used.

For therapeutic applications, the polypeptide according to the invention may be present in the form of a conjugate with a therapeutically active ingredient, selected, for example, from radiotherapy agents or chemotherapy agents, eg, low molecular weight active ingredients or biologically cytostatic or cytotoxic. Conjugation of the therapeutically active ingredient into the polypeptide may be carried out according to known methods, preferably through a covalent attachment to the amino, carboxyl, hydroxyl and / or thiol reactive groups of the protein, optionally with the use of heterobifunctional linkers , according to known methods.

In addition, the polypeptide may also be present in the form of a fusion protein which, in addition to the antibody, eg, in the form of an IgG molecule or a fragment thereof, eg, contains a fused cytokine, eg, IL2, IL12 or TNFÎ ± -polypeptide. In addition, the fusion protein may be present in the form of a bispecific antibody, wherein in addition to the binding to the ED-B domain, a binding to another antigen is preferred. Other bispecific antibody antibody specificities are diagnostic and therapeutically relevant binding domains for radionuclide chelators, eg, α, β or γ emitters, such as, for example, NIR (diagnostic near infrared) dyes, therapeutically effective dyes, molecules (eg, NK cells, cytotoxic T cells or NKT cells), integrins relevant to angiogenesis, in particular binding domains that block their function (eg, og, β3 / α *, 9¾¾), inactivating domains anti-VEGF binding and inactivating binding domains against VEGF 1, 2 and 3 receptors.

For diagnostic applications, the polypeptide may be present in the form of a conjugate of a diagnostically detectable marker group, e.g., a marker group for in vitro or in vivo diagnosis. Examples of marker groups are radioactive labeling groups, NMR, coloring, enzymatic and fluorescence marker groups (e.g., near-infrared range fluorescence).

For therapeutic applications, the polypeptide is preferably formulated as a pharmaceutical composition containing the active ingredient, the polypeptide according to the invention, optionally additional active ingredients, as well as pharmaceutically acceptable carriers, adjuvants and / or diluents. The pharmaceutical composition contains the active ingredient in a therapeutically effective dose which can be determined by a person skilled in the art, simply by in vitro tests, for example in suitable cell cultures or in animal models. Administration of the composition is preferably performed by injection or infusion, but other types of administration are also conceivable. Intravenous and / or subcutaneous administration is preferably performed. The dose of the active ingredient administered depends on the type and severity of the disease, as well as the condition of the patient being treated. The therapeutic composition is preferably administered several times over a prolonged period of, for example, at least 2-4 weeks. In this context, reference is made to known methods for administering antibodies or antibody conjugates, as described in, for example, Ferarra, N. et al., Nature Reviews Drug Discovery, Volume 3, May 2004, 391-400 and Salgaller , ML, Current Opinion in Molecular Therapeutics 2003 5 (6): 657-667, or to existing administration procedures for pharmaceutical antibodies, such as Rituximab, CAMPATH, Remicade, etc.

Another object of the invention is a diagnostic composition comprising a polypeptide according to the invention as a diagnostic reagent. In addition, the diagnostic composition may further contain additional diagnostically common reagents, vehicles, adjuvants and / or diluents. The diagnostic composition contains the polypeptide in an amount sufficient to make diagnostic detection possible in the respective format, e.g., in a diagnostic format in vivo or in vitro. In this context, reference is made to known methods for in vivo and in vitro diagnosis with the use of labeled antibodies.

The pharmaceutical and diagnostic compositions may be used for therapy and diagnosis of all diseases which are accompanied by ED-B expression, for example a stromal and / or perivascular expression of ED-B. Examples of such diseases are hyperproliferative diseases, eg diseases which are associated with angiogenesis, in particular cancer, ocular diseases, hypertrophic scars, etc., diseases which are associated with a malfunction of myofibroblast, eg, endometriosis, atherosclerotic plaque, etc., or inflammatory diseases, eg, psoriasis, Crohn's disease, rheumatoid arthritis or multiple sclerosis. The pharmaceutical or diagnostic composition according to the invention may contain one or more active polypeptides, e.g., a combination of polypeptides, which bind to different areas of the ED-B domain. The compositions are suitable for use in human and veterinary medicine.

Another object of the invention is a nucleic acid encoding a fusion peptide or polypeptide according to the invention. This nucleic acid may be a single- or double-stranded DNA or an RNA. The nucleic acid is preferably operably linked to an expression monitoring sequence, which makes expression possible in a suitable host cell or in a suitable host organism. The nucleic acid may be present in a vector that is suitable for introduction into a host cell or host organism. The vector may be, for example, a prokaryotic vector, suitable for introduction into prokaryotic cells, e.g., a plasmid or bacteriophage. In contrast, the vector may also be a eukaryotic vector, suitable for introduction into host cells or eukaryotic host organisms, e.g., a plasmid, an artificial chromosome or a viral vector. Suitable vectors are known to the person skilled in the art, for example, from Sambrook et al. (1989), Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory

Press, and Ausubel et al. (1989), Current Protocols in Molecular Biology, John Wiley and Sons.

Still another object of the invention is a cell, e.g., a prokaryotic cell or a eukaryotic cell, such as, for example, a human cell, which is transformed with a nucleic acid according to the invention or a vector according to the invention. Another object of the invention is a non-human organism, e.g., a transgenic animal, which is transformed with a nucleic acid according to the invention or a vector according to the invention. In this case, the term " transformation " within the scope of the present invention contains all possibilities for introducing foreign nucleic acids into a cell or organism, including transfection or infection. The polypeptide according to the invention may be produced by culturing a cell according to the invention or a non-human organism according to the invention under conditions in which an expression of the polypeptide is performed, and then the expressed polypeptide , eg, from the cell, culture medium, organism or excretory products of the organism.

In addition, the invention is to be explained by the following figures and examples: Figure 1 shows the schematic implementation of an inhibition test to identify functionally active antibodies.

Human endothelial cells, which were obtained from skin microvessels (human dermal microvessel endothelial cells, HDMVEc), were incubated together with ED-B specific antibody Fab fragments. The number of bound cells is made visible by staining with crystal violet and measured on a photometer. A high color intensity means many adherent cells and no binding blocking antibodies. A low color intensity means poor adhesion and a binding blocking antibody. Figure 2 shows a screening diagram for identifying blocking antibodies to ED-B-fibronectin function through a presentation of Fab fragments.

In a first step, a screening procedure is performed with recombinant ED-B. Antibody fragments that are obtained in this way are subjected to a specificity (ELISA) test, a functional adhesion test, as well as an immunohistochemical study. Then, the affinity of the antibodies carrying out these tests is determined. Thereafter, changes in CDR domains are performed to improve affinity, where affinity maturation 1 means a change in the L-CDR3 domain and affinity maturation 2 means a change in the H-CDR2 domain.

After the antibodies obtained by affinity maturation pass through the tests mentioned above, then the in vivo efficacy is tested. Figure 3 shows the results of an ELISA specificity test with antibody-Fab fragments which are produced by screening with recombinant ED-B.

ED-B means binding to recombinant ED-B, 6-FN means binding to domain 6 of recombinant fibronectin, domain 7-8-9 means binding to 7-8-9 domains of recombinant fibronectin (without ED-B) , and 7-EDB-8-9 domain means binding to the 7-8-9 domains of recombinant fibronectin with ED-B. The ratio of ED-B to 6-FN or 7-8-9 produces the specificity of the antibody under study. AP-39 means a covalently dimer of the biologically inactive anti-ED-B sc19 L-scFv antibody. Figure 4 shows the result of a adhesion test with the antibodies under study.

Inhibition of HDMVEc cell adhesion to ED-B coated plates was examined by the indicated Fab fragments at concentrations of 25 pg / ml or 0.4 pg / ml Fab. The values given are the result of three determinations. Figure 5 shows the immunohistochemical reaction pattern of binding blocking anti-ED-B Fab fragments in the example of MOR 02616. Results are shown in Figures 5A and 5C, the results with a negative control (HuCAL-Fab negative), and Figures 5B and 5D, the results with the MOR 02616 antibody on iRM-human neuroblastoma cell xenografts (Figures 5A and 5B) as well as murine F9-teratocarcinoma cells (Figures 5C and 5D).

Cryo-cells (thickness: 10 μm) were air dried and then held in ice-cold acetone for 10 minutes. The cuts were then washed in PBS and incubated for 60 minutes with 2 μg / ml MOR 02616 or negative controls at room temperature. As a secondary antibody, a peroxidase-labeled goat polyclonal human antiserum (1: 100 diluted in PBS, Dianova) in combination with diaminobenzidine (Sigma Chemicals) was used as a chromogenic substrate. Figure 6 shows the results of an ELISA specificity test with antibody Fab fragments that are optimized by maturation. The test run was as described in Figure 3. Figure 7 shows the immunohistochemical reaction pattern of the MOR 03255 antibody Fab fragments, optimized for maturation, in cryosomes of F9-teratocarcinoma cells (Figure 7A) and in xenotransplants of SKMEL-28 human melanoma cell in hairless mice (Figure 7B). The test run was as described in Figure 5. Figure 8 shows the result of a adhesion test with the antibody Fab fragments according to the invention relative to the comparative antibodies L19 and Ly6 0.3. Testing was essentially described in Figure 4. Antibody concentrations were 1 Âμg / ml, 10 Âμl / well or 20 Âμl / ml. Figure 9 shows the stability of antibody Fab fragments according to the invention after incubation for 4 hours in human plasma or PBS at 37 ° C. Immune reactivity was determined in the ELISA at concentrations in the range of 0.039 to 5 pg / ml. The 0.62 pg / ml signal in human plasma without incubation was set to a value of 100%. Figure 10 shows the therapeutic efficacy of binding blocking anti-ED-B antibody Fab fragments in the example of MOR 03255. Figure 11 shows the nucleotide sequences coding for the V H and V L regions of the antibodies according to the invention .

The ED-B (His) s domain of fibronectin, domain 6 of fibronectin (6FN), domain 7-8-9 of fibronectin and domain 7-ED-B-8-9, The purified recombinants were produced according to standard procedures (eg, Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press).

Mouse antibodies against purified ED-B receptors were also produced according to conventional procedures by administration of 50æg of purified receptor in complete Freund's adjuvant to one mouse, 3 weeks later administration of 25æg of purified Freund's incomplete adjuvant, and after another 3 weeks all applications are administered intraperitoneally in incomplete adjuvant. The blood was then removed by retro-orbital puncture 14 days after immunization. Plasma fibronectin was ordered from Sigma.

1.2 Selection of Specific ED-B Phage Selection was performed according to the HuCAL® Gold Phage selection protocol. The HuCAL® Gold library was subdivided into six specific groups of structure. The specific ED-B phages were concentrated in three successive rounds of recombinant protein selection immobilized on 96-well plates (Maxisorb, Nunc, Rochester, NY, USA). For screening A, the plate was coated with 1 Âμg / well ED-B (His5) (10 Âμg / ml for 2 hours at 37Â ° C. For screen B, the plate was coated with ED-B on the same concentration in PBS (pH 7.2 with 1 mmol of 1 mmol giOil overnight at 4Â ° C. Plates were blocked with 5% lean milk powder in PBS, 0.05% Tween20 ( Sigma, St. Louis, MO, USA) (blocking buffer) and incubated with 1 x 1013 HuCAL® Gold phages, which had been preincubated with one volume of blocking buffer.For screening B, the phages were pre- incubated additionally with 0.5 pg / ml fibronectin domain 6 so as to reduce the selection of binding molecules that are specific for the conserved structure of a fibronectin type 3 repeat domain After an incubation with the phages for 2 hours at room temperature, the wells were washed 5x with PBS, 0.05% Tween20 and 5x with PBS.The remaining phages were eluted with 20 mmol dithiothreitol (DTT) in 10 mmol tris / HCl (pH 8.0) for 10 minutes at room temperature. Then an incubation with E. coli TG-1 (Stratagene, = 0.5) was performed for infection. The wells were then incubated with E. coli TG-1 as an additional elution step. 1.3 Phagemid Recovery, Fagic Amplification and

Purification

HuCAL® Gold phages were amplified in 2x TY medium with 34 pg / ml chloramphenicol and 1% Glucose (2x TY-CG). After infection with a helper phage (VCSM13) at 37øC and a 0¾½ of about 0.5, centrifugation and resuspension in 2x TY-CG / 50æg / ml kanamycin, the cells were induced with 0.25 mmol of IPTG and grown overnight at 22 ° C. Phage were precipitated from the supernatant with polyethylene glycol (Ausubel et al. (1998), Current Protocols of Microbiology), resuspended in PBS and used for subsequent rounds of selection. 1.4 Subcloning of Selected Fab Fragments and Expression of Soluble Fab Fragments

Inscriptions encoding Fab of HuCAL® Gold phages

selected were subcloned into the pM0RPHx9-FS expression vector. The plasmid DNA preparation of the selected HuCAL® GOLD clone was cleaved with XbalI / EcoRI restriction enzymes, whereby the insertion encoding Fab was cut (ompA-VL and phoA-Fd). Fab molecules which are expressed in this vector contain two C-terminal and Strep-tag-1 tags for detection and purification. 1.5 Expression and Purification of Antibodies & Gold & Gold in E. coli Expression of TG-1F cells in Fab fragments encoded by pMORPHx9-FS in E.coli was performed on cultures in vials with agitation with 0.75 L of 2xTY medium and 34 pg / mL of

> N X- " > chloramphenicol. After induction with 0.75æl of IPTG, the cells were cultured for 16 hours at 30 ° C. As an alternative, the Fab clones, which had been obtained from the second maturation group 2, were induced with 0.1 mmol IPTG and then grown at 22 " Periplasmic extracts were produced from cell precipitates by osmotic shock, and the Fab fragments were isolated by Strep-Taetiii® chromatography (IBA, Gottingen, Germany). Apparent molecular weights were determined by size exclusion chromatography (SEC) with calibration standards. Concentrations were determined by UV spectrometry. 1.6 Identification of Fab fragments binding to ED-B by ELISA.

The 96-well Maxisorb ELISA plates were coated with 100 μl of ED-B solution (10 μg / ml in coating buffer (PBS pH 7.4, 1 mmol of CaSg, 1 mmol of MgCl 2) overnight at 4 ° C. Raw lysates or purified Fab molecules were added; unbound Fab molecules were removed by washing 5x with wash buffer (PBS pH 7.4, 0.05%

Tween20). Fab fragments were detected by incubation with peroxidase-conjugated human anti-Fab antibodies (Dianova), followed by development with a peroxidase-soluble substrate (Roche) and determination at 370 nm. Clones expressing specific ED-B Fab molecules were

identified by a positive ELISA signal in immobilized ED-B against little or no signal in 6FN.

1.7 Determination of Plasma Stability under Physiological Temperature Conditions by ELISA

The ED-B coating (2.5 pg / ml) was performed essentially as described above. The Fab fragments were incubated for 4 hours at 37Â ° C and at a concentration of 50 Âμg / ml in human plasma (German Red Cross, lot 9985550). After incubation, the Fab molecules were diluted to the ELISA Test at concentrations of 5.0, 2.5, 1.25, 0.62, 0.31, 0.156, 0.078 and 0.039 pg / ml in PBS with 1% of bovine serum albumin to determine the linear area of the signal intensity. Functional Fab molecules were determined with the anti-Flag M2 antibody (Sigma F3165) and a secondary alkaline-conjugated mouse anti-mouse antibody, followed by development with Attophos (Roche) and by determination at 535 nm. 1.8 Culture of HDMVEc Cells and Cell Adhesion Test

Human dermal microvascular endothelial cells (HDMVEc), isolated from juvenile foreskins, were cultured in EGM-MV medium (Clonetics, Inc.) with addition of 10% fetal calf serum, 2 mmol glutamine, 20æg / ml heparin and 3æg / ml bFGF in containers coated with 0.1% gelatin (Sigma). For the adhesion tests, cells that had not been cultured for more than Ιδ passage were used. ED-B (10 pg / ml) or plasma fibronectin (2.5 pg / ml) was immobilized overnight at 4 " C in PBS, pH 7.4, 0.9 mmol CaCl2, 5 mmol of MgCl 2 in 96 well ELISA plates and blocked with 1% RSA in PBS, pH 7.4, 0.9 mmol C & 0.5 mmol of MgCl 2 for 1 hour at 37 ° C. The cells were labeled with 0.15 pg / ml calcein for 30 minutes at 37øC and washed once in adhesion medium (MCDB 131.2 mmol glutamine, 0.11 RSA, 20 pg / ml heparin) . 1 x 105 cells were incubated for 20 minutes at 37 ° C with the antibody concentration indicated in each case, diluted in adhesion medium 31 (final volume 100 μl). The cell suspension was added to the ED-B coated plates for 2 hours at 37 ° C. After the cells were washed 2x with PBS, pH 7.4, 0.9 mmol CaCia, 0.5 mmol of the adherent cells were detected in a plate fluorimeter (excitation at 485 nm, emission at 530 nm).

As a control, (A) the binding of the cells to the ligand-coated plates was determined without the addition of specific antibodies, and (B) the adhesion of the cells to the wells without ligand coating was determined, wherein the value obtained in the last control was defined as a minimum cell adhesion in the test. 1.9 Affinity Maturation of Selected Fab Molecules by Switching CDR Cassettes in Steps

To increase the affinity and biological activity of selected antibody fragments, the CDR regions were optimized by cassette mutagenesis using trinucleotide-directed mutagenesis.

To this end, Fab fragments were cloned from the pMORPHx9 expression vector in the pMORPH-23 phagemid vector using EcoRI / XbaI restriction sites. To optimize the affinity of the selected Fab fragments, two successive maturation steps were performed for each maturation group. In the first step, an antibody-phage fragment library was produced in which the L-CDR3 region of the initial clone was varied through a repertoire of 7x108 (Group 1) and 3.8x10θ (Group 2) CDR sequences individual light chain. Then, the affinity-enhanced derivatives of the first maturation step were exposed to a second maturation round by substituting the H-CDR-2 region through a library of diverse elements. Thus, two phage libraries were produced with 1 x 108 individual clones in each case.

Affinity maturation libraries were produced by transformation into E. coli TOPIOF. Phage were produced as described above. Selection in Fab fragments with improved affinity was performed under severe conditions for three laps at the first maturation and for two laps in a second step. 1.10 Determination of Ability through Surface Plasmon Resonance

To determine the KD values, monomer fractions (at least 80% monomeric content, determined by analytical SEC; Superdex75, Amersham Pharmacia) of Fab fragments were used. Fl-Chips (Biacore, Sweden) were coated with about 200 RU ED-B (30 Âμg / ml, 10 mmol acetate buffer, pH 4.0) and reference flow cells with a corresponding amount of human serum albumin (20 Âμg / ml, 10 mmol of acetate, pH 4.5) with the use of conventional BDC-NHS-amine coupling chemistry. The density of the antigen was reduced to about 100 RU for the characterization of Fab from the second maturation. Regeneration was performed with 10 mmol HCl. All kinetic measurements were performed in PBS buffer (136 mmol of NaCl, 2.7 mmol of KCl, 10 mmol of KBKI, 1.76 mmol of pH 7.4) at a flow rate of 20 pL / min with use of a concentration range of Fab of 1.5-500 nmol. The injection period was 1 minute in every 33 case. All the sensograms were evaluated with the use of BIA evaluation software 3.1.

Abbreviations: EDC: L-Ethyl-3- (3-dimethylaminopropyl) -carbodiimide, NHS: N-Hydroxysuccinimide, RU:

Resonance 2. Results 2.1 Production of Antibodies against Human ED-B

Two different screening assays were implemented. The ED-B coating for the first assay (screen A) was performed according to the known conditions of the biological assay to present ED-B in a conformation which allows adhesion of HDMVEc cells to the immobilized antigen. With the second screen (B), the phages were further blocked with 6FN excess to avoid a selection of binding molecules that cross-react with the fibronectin domain 6.

Together, 23 different Fab-HuCAL molecules were found from 1315 primary candidates satisfying the criteria for binding to ED-B and not to 6FN. In addition, the antibodies were tested for their ability to bind recombinantly expressed fibronectin comprising domains 7, 8 and 9 with and without the ED-B domains introduced in their natural array (see Figure 3). All antibodies tested have specific recognition for construct 7-ED-B-8-9 but did not react with the corresponding construct without the ED-B domain.

2.2 Functional characterization of the ED-B Specific Binding Molecule

Antibodies as specifically identified in ELISA were purified and tested in their ability to block adhesion of HDMVEc cells to ED-B coated plates. HDMVEc cell adhesion was tested in the presence of ED-B specific Fab fragments at two concentrations, compared to a non-specific control Fab-HuCAL molecule and mouse control positive sera.

Twelve of the 23 Fab molecules described in Section 2.1 showed inhibition of cell adhesion in immobilized ED-B. A representative selection of the six most effective Fab molecules is shown in Figure 4. At a concentration of 25 pg / ml, cell adhesion was inhibited by 50% to almost 100%. At a concentration of 0.4 pg / mL, only a few Fab molecules; e.g., MOR02610, MOR02616, MOR02715 and MOR02718, exhibited reproducible inhibition of cell adhesion.

Function-blocking antibody Fab fragments were characterized by immunohistochemistry for their localization in mouse F9-teratocarcinoma cells and in human MRI-xenotransplantation-neuroblastoma cryocasts. All antibodies tested had a vascular localization in two tissue sections, but no staining in normal tissue vessels (e.g., normal and sclerotic liver and skin). In Figures 5B and 5D, there is shown a perivascular abluminal staining of vessels, proliferative endothelium and tumor stroma by MOR02616. A collection of ED-B may be detected in the vicinity of neovascular structures of exponentially growing tumors, but not in normal vessels. With a negative control antibody against lysozyme the same concentration, no staining was visible (Figures 5A and 5C).

The properties of twelve selected binding molecules were determined by BIAcore analysis (see Table 1). The affinities (Kon) were in the range of 15 to 500 nmol. The affinity of the bivalent L39 derivative AP39 (a biologically inactive comparative antibody against ED-B) was determined with 2.4 nmol. Table 1 also shows CDR sequences (L-CDR3 and H-CDR3 only) and structure combinations. At least two independent measurements were performed with different batches of Fab molecules for protein expression and protein purification. The binding rate (Kon) and the dissociation rate (K0ff) of the Fab molecule are indicated in separate columns.

Table 1

3a

Fig. loft 1® | P / * teJ míi xm AVW 33TSM-fX 3,

2.3 Affinity Maturities of ED-B Antibodies from

Function Blocking through Region Optimization L-CDR3 and H-CDR2

The affinity maturations of the Fab molecules were performed in two sections. First, the L-CDR3 sequence was diversified, and then the H-CDR2 sequence of the improved Fab molecule, obtained in the first step, was switched.

Two affinity maturation libraries were produced for each step. Optimization was performed in two separate groups. Library 1 of L-CDR3 with a degree of diversity of 7 x 108 elements contained the four initial Fab molecules MOR0261O, MOR02616, M0R02619 and MOR02622. Library 2 of

Q-CDR3 with a degree of diversity of 3.8 x 10-elements contained only derivatives of M0R02715 and MOR02718. Here, the Fab molecules were combined in clusters, in each case according to their affinity and biological activity in the adhesion test.

The two libraries were kept separate during the selection procedure. In this case, two screening strategies were performed. Screening I was performed with ED-B immobilized on maxisorb plates for three laps as previously indicated. With screening II, a selection of biotinylated ED-B in solution was performed. In this case, the phage-antigen complex was recovered through streptavidin-coated particles in the first round and in neutravidin plates on the subsequent two turns. Restriction conditions were used in the selection procedure. The selection in optimized Fab molecules was performed by determining the values of K0fj in the BIAcore system. Together, 11 derivatives of library I were characterized. The 5 derivatives with the highest affinity are shown in Table 2. In this case, all the improved clones are derived from M0R02619 with an increase in affinity up to 7x. In the MOR03075 clone, an affinity of 2.4 nmol was found. From library 2, two MOR02715 derivatives were analyzed in detail. For clone MOR03062, a 15-fold affinity increase was found so that a monomeric affinity of 2.4 nm was obtained. Changes in the amino acid sequence of the L-CDR3 region are presented in Tables 2a and 2b.

Table 2a

Screening MORO Clone LCDR3 Kon Koff KD Initial x Increase × 1 / *] [nm] Times Group 1 Relative to Parental Clone Kon Koff KD AP 39- Biotin QQTGRI-PP 6.6E + 05 1.4 ΘΕΟ 03 2,4 ± 0.6 2619 QSWDGAS-TG 7.8E + 05 1.2E-02 15.4 i 0.6 Solid 3055 2619 QAWTRAHRYP 1.8E + 06 5.1E-03 3.0 ± 2.2 0.5 2 , 6 5.4 Dissolved 3066 2619 SSYD-TQVTR 1.1E + 06 4.7E-03 4.2 ± 1.4 0.6 2.8 3.8 Solved " Ύ07Γ "261T" [QSWDP-RSFT [1, T '+ 0 6j I7IF 72 ^ 4 ™ ttj 5To "T Υ, ΤΊ | 03 | 0,3 1 1 | Dissolved 3069 1 2 3 4 5 6 7 8 6 7 8 9 10 10 10 10 10 10 20 20 25 30 30 30 30 30 30 30 30 30 30 30 40 40 40 ^ | 03 \ 0.2 | | t ..... Dissolved 3071 | 2619 fLAYIQS-KGH | 1,9E + 06J 5,7E-3,1 ± 2,3,3,3 (5,12,12) 11 | tL L .1hh..ihhí [ihh, l ........... .V ____ ___

Table 2b

Screening MORO Clone LCDR3 Kon Koff KD Increase of Parental x J The / * J [nm] \ times; Group 2 Relative to; Clone Parental | Kon Koff KD | AP "39- " | qqtgri ^ W1T75 ^ I7T9 " 2 'ftti 1 ................ τ ................ τ ... Biotin LO 0 03 1 0.6 r ............. 4 .............. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 13, 13, 1 1 1 5 1 02 1 ± 1.7 ξ 5: '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' 'Q'SW ^ ΤΓΤε- 1 10 i μ, 7 | 3.5: 5.3 æm | | 1 6 | 02 | 3., S 5 * > J Solid TòTf '" ΤΓϊεγ] " 3 ', T " i'i \ \ 6 ^ 02 | 0.8 1 | The specificity for ED-B (determined by ELISA, immunohistochemistry and cell adhesion test) of all derivatives from the first round of maturation was unchanged. rnmnffmTffrrrrrrrrrrrrnmnmmfftin »nn > wmiiiiiiiii

The Fab molecules shown in Tables 2a and 2b were selected for a subsequent H-CDR2 maturation in two groups. In group 1, five Fab molecules were subjected to a similar activity, but with L-CDR3 regions other than a H-CDR2 diversification (library size of 7 x 107 elements). For group 2 (8.5 x 107-element library size), two Fab molecules were selected. The libraries were separately selected as described above. Binding molecules with increased affinity were concentrated through two rounds of screening in solution under stringent conditions.

Three Fab molecules of group 1 were selected. For the derivatives M0R03243 and MOR03245, affinities of about 0.7 nmol were found. For the MOR03246 derivative, an affinity of 0.6 nmol was found.

The H-CDR2 sequences of the corresponding clones and the affinity data are shown in Table 3a.

Table 3a

Derivatives with improved properties could also be selected from group 2. Compared to parental clones, the affinities of the derivatives were improved by a factor of 26-40 to 250x. The affinities of clones M0R03255 and M0R03258 were determined at 30 pM or 40 pM.

In Table 3b, the H-CDR2 amino acid sequences of the clones selected from group 2 are shown, as well as the corresponding affinity data.

Table 3b

M0R03251 S 3062 IVISNMSYTIYYADSVKG 3,3E + 06 [2,0E-04A 0,07 MORÕ3252 | 3062 f VISNYSWHYYYADSVKG f 3, lE + OlTffc, lE-'0'5 | 0.03 £ M0R03253 * Í3Ò6F77ut ΤΤΓβΕ + δΤΤΤ, ΙΙ ^ ΟΜ ΤΓ, ΎΪ M0R03255 M0R03257 ί M0R03258 "f" ......................... i ·· 3062 " 3062 " 3064 S VISNRSSYIYYADSVKG IVfSNRWYIYYÃSVKG " Tvisnqsnytyyds Wg i 4.9E + 068, 6E-05; C, Ò 3 C'Ô8O; 5.3 E + 06 I 3.0E-04; 0.04 S '

0.04 �ToT 0.7Õ5 " oTToToT oToF 2.4 Characterization of High Affinity Function Blocking ED-B Antibodies

To test whether the antibodies that are obtained by affinity maturation are still always specific for ED-B, ELISA specificity tests (Figure 6), immunohistochemical studies (Figure 7) and adhesion tests (Figure 8). In all three tests, it was observed that the specificity of affinity matured Fab molecules for ED-B remained unchanged. Furthermore, it is evident from Figure 8 that both parental clones, such as MOR 02715, and clones that are produced through affinity maturation, such as MOR 03062, MOR 03255, MOR 03064 and MOR 03259, have an activity (inhibition of adhesion) than the known L19 antibody.

In addition, the thermal stability of Fab molecules in human plasma was tested. To this end, the Fab molecules were incubated with human plasma for 4 hours at 37øC and no significant loss of immune reactivity determined by ELISA was observed (Figure 9).

All selected Fab molecules are capable of blocking the interaction of a receptor with human microvascular endothelial cells in ED-B in a dose-dependent manner, a property that the known L19 ED-B antibody lacks. Since adhesion of HDMVEc to the extracellular matrix is one of the first steps in neoangiogenesis, blocking this process through the binding molecules according to the invention produces a therapeutic agent to inhibit the formation of new vessels and to inhibit tumor growth. 2.5 Live iπ action

F9-teratocarcinoma cells (106 / Matrigel mouse with / without 100æg of MOR03255 Fab) were implanted s.c. on the flanks of peeled mice. After 3 days, the animals were treated for 7 successive days with, in each case, 100æg MOR03255 / mouse. In comparison to solvent control, both treatment groups show inhibition of tumor growth in the range of 42-64%. A summary of the test results is shown in Figure 10.

Without further elaboration, it is believed that one skilled in the art can, using the foregoing description, utilize the present invention in its entirety. The foregoing preferred specific embodiments are thus to be construed as merely illustrative, and not limiting the remainder of the disclosure in any case.

In the foregoing and in the examples all temperatures are given uncorrected in degrees Celsius and all parts and percentages are by weight, unless otherwise noted.

The full disclosures of all applications, patents and publications cited herein and the corresponding German application NO. 102004050101.7, filed October 14, 2005 and U.S. Provisional Application Serial No. 60 / 6975,65 filed July 11, 2005, are hereby incorporated by reference.

The foregoing examples may be repeated with similar success by substituting the generically or specifically described reagents and / or the conditions of operation of the present invention for those used in the foregoing examples. From the foregoing description, one skilled in the art can readily ascertain the essential features of the present invention and, without departing from the spirit and scope thereof, may make various modifications and modifications of the invention to suit various uses and conditions.

Literature (1) Brown, L. F .; Guidi, A. J .; Schnitt, S. J .; Van De Water, L .; Iruela-Arispe, M. L .; Yeo, T.-K .; Tognazzi, K .; Dvorak, H. F. (1999) Clin. Cancer Res. 5: 1041-1056 (2) Folkman, J. (1995) Nature (Med.) 1: 27-31 (3) Risau, W. and Lemmon, V. (1988) Develop. Biol. 125: 441-450. (4) Van Den Hoff, A. (1988) Adv. Cancer Res. 50: 159-196 (5) Folkman, J. and Shing, Y. (1992) J. Biol. Chem. 267: 10931-10934 (6) George, E. L .; Baldwin, H. S .; Hynes, R. O. (1997) Blood 90: 3073-3081 (7) Bowersox, J.C. and Sorgente, N. (1982) Cancer Res. 42: 2547-8 (8) Madrid, J.A .; Pratt, B. M .; Tucker, A.M. (1988) J. Cell Biol. 106: 1375-1384 (9) Nicosia, R.F .; Bonnano, E .; Smith, M. (1993) J. Cell. Physiol. 154: 654-661 (10) Kornblihtt, A.R .; Vibe-Pedersen, K .; and Baralle, F.E., 1983. Isolation and Characterization of cDNA Clones for Human and Bovine Fibronectins. Proc. Natl. Acad. Know. USA, 80; 3218-22 (11) Leahy, D. J .; Hendrickson, W.A .; Aukhil, I. and Erickson, H. P., 1992. Structure of Fibronectin Type III Domain from

Tenascin Phased by MAS Analysis of the Selenomethionyl 44

Protein. Science, 258, 987-91 (12) Hynes, R.O., 1987, Cell 48, 549-550 (13) Plow, E. F. et al. 2000, J. Biol. Chem., 275, 21785-21788 (14) Castellani, P .; Viale, G .; Dorcaratto, A .; Nicolo, G .; Kaczmarek, L .; Querze, A .; Zardi, L. (1994) Int. J. Cancer 59: 612-618 (15) Hashimoto-Uoshima, M .; Yan, Y. Z .; Schneider, G .; Aukhil, I. (1997) J. Cell Science 110: 227-2280 16) Chen, W. and Culp, LA (1996) Exp. Cell Res. 223: 9-19 17) Chen, W. and Culp, LA (1998) Clin, Exp. Metastasis 16: 30

SEQUENCE PROTOCOL < 110 > Schering Aktiengesellschaft < 120 > Identification and Characterization of Anti-ED-B-Fibronectin Function Blocking Antibodies < 130 > 33042P DE (WWHC) <14; D: > < 170 > Patentln Ver. 2.1

< 210 > 1 < 211 > 354 DNA < 213 > human < 2 > 2 > < 221 > CDS < 222 > (1) .. (354) < 223 >Antibody-Region-VH; MORO2610 V ·. cag gtg caa ttg gtt cag age ggc gcg gaa gtg aaa aaa ccg ggc gcg 48 Gin Vai Gin Leu Go Gin Be Gly Ala Glu Go Lys Lys Pro Gly Ala 5 10 45 age gtg aaa gtg age tgc aaa gee tcc gga tat acc ttt act ggt ttt 96 Ser Val Lys val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Phe 20 25 30 tat att aat tgg gtc ege caa gee cct ggg cag ggt et gag tgg atg 144 Tyr Ile Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45 gg c tg g tg g tg g tg g tg g tg g tg g tg tg tg tg t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t acc cgt gat acc age att age acc gcg tat 240 Gin Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 atg gaa ctg age age ctg cgt age gaa gat acg gee gtg tat tat tgc 288 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 gcg cgt tet cct gtt tat tat aag tat gat tat tgg gg c caa ggc acc 336

Ala Arg Ser Pro Val Tyr Tyr Lys Tyr Asp Tyr Trp Gly Gin Gly Thr 100 105 ctg gtg acg gtt age tea Leu Vai Thr Va Ser Ser 115 < 210 > 2 < 211 > 118 PRT < 213 > human < 400 > 2 Gin Go Gin Go Gin Go Gly Go Glu Go Go Lys Lys Pro Gly Ala 1 5 10 15

Ser Vys Lys Will Be Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Phe 20 25 30 Tyr 11 and Asn Trp V Arg Arg Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Tyr Ser Gly Asn Thr Arg Tyr Ala Gin Lys Phe 50 55 60 Gin Gly Arg Will Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Pro Go Tyr Tyr Lys Tyr Asp Tyr Trp Gly Gin Gly Thr 100 105 110 Leu Will Thr Be Ser <210 &gt; 3 &lt; 211 &gt; 336 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) . . (336) &lt; 223 &gt;Antibody-Region-VL; MORO2610 &lt; 4 0 0 &gt; 3 gat gtg ctg acc cg ccg cctg gtg agt ggc gea cca ggt cag Asp Ile Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 1 5 10 15 cgt gtg acc ate teg tgt age ggc age age ggc aac att ggt att aat Arg Go Thr Ile Ser Cys Ser Gly Ser Ser Gly Asn Ile Gly Ile Asn 20 25 30 ttt gtg aat tgg tac cag cag ttg ccc ggg acg gcg ccg aaa ctt ctg Phe Go Asn Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 att tat aag aat aat aag cgt ccc tea ggc gtg ccg gat cgt ttt age Ile Tyr Lys Asn Asn Lys Arg Pro Ser Gly Pro Pro Asp Arg Phe Ser 50 55 60 gga tcc aaa age ggc acc age gcg age ctt gcg att acg ggc ctg caa Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gin 65 70 75 80 age gaa gac gaa gcg gat tat tat tgc cag tet tat gat aag act tet Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ser Tyr Asp Lys Thr Ser 48 96 144 192 240 288 SS 9o 95 tct act tat gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc cag 336

Ser Thr Tyr Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105 lio &lt; 211 &gt; 112 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 4

Asp Ile Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 15 10 15

Arg Will Thr Ile Ser Cys Ser Gly Ser Ser Gly Asn Ile Gly Ile Asn 20 25 30

Phe Go Asn Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45

Ile Tyr Lys Asn Asn Lys Arg Pro Ser Gly Pro Pro Asp Arg Phe Ser 50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gin 65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ser Tyr Asp Lys Thr Ser 85 90 95

Ser Thr Tyr Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105 110

&lt; 211 &gt; 351 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 22 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (351) &lt; 223 &gt;Antibody-Region-VH; M0R02611 &lt; 400 &gt; 5 cag gtg caa ttg gtt cag age ggc gcg gaa gtg aaa aaa ccg ggc gcg 48 Gin Vai Gin Leu Val Gin Be Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 age gtg aaa gtg age tgc aaa gee tcc gga tat acc ttt tet ggt tet 96 Will Go Lys Will Be Cys Lys Will Be Gly Tyr Thr Phe Will Be Gly Ser 20 25 30 tat atg cat tgg gtc ege cae gee cct ggg cag ggt gag tgg atg 144 Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45 ggc att t a cg gct tet g gc aag acg ctt gcg cag aag ttt 192 Gly ile i n Asn Pro Ala Ser Gly Lys Thr Leu Tyr Ala Gin Lys Phe 50 55 60 cag ggc cgg gtg acc atg acc cgt gat acc age att age acc gcg tat 240 Gin Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 atg gaa ctg age age ctg age gaa gat acg gee gtg tat tat tgc 288 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 gcg cgt ggt ctt tat tat cgt ttt gct tet tgg ggc caa ggc acc ctg 3 33 $.

Ala Arg Gly Leu Tyr Tyr Arg Phe Ala Ser Trp Gly Gin Gly Thr Leu 100 105 no gtg acg gtt age tea Vai Thr Will Be Ser <210 &gt; 6 &lt; 211 &gt; 117 &lt; 212 &gt; PRT &lt; 213 &gt; human

Gin Go Gin Gin Go Gin Gin

Being Going Lys Going To Be Cys Lys Ala 20

Tyr Met His Trp Go Arg Arg Ala 35 40

Gly Ile Ile Asn Pro Ala Ser Gly 50 55

Gin Gly Arg Will Thr Met Thr Arg 65 70

Met Glu Leu Ser Ser Leu Arg Ser 85

Ala Arg Gly Leu Tyr Tyr Arg Phe 100

Ala Glu Vai Lys Lys Pro Gly Ala V,

Ser Gly Tyr Thr Phe Ser Gly Ser 25 30

Pro Gly Gin Gly Leu Glu Trp Met 45

Lys Thr Leu Tyr Ala Gin Lys Phe 60

Asp Thr Ser Ile Ser Thr Ala Tyr 75 80

Glu Asp Thr Ala Val Tyr Tyr Cys 90 95

Ala Ser Trp Gly Gin Gly Thr Leu 105 110

Go Thr Will Be Ser t 'Τ' ϋ £ < 210 &gt; 7 &lt; 211 &gt; 327 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 2 2 0 &gt; cds &lt; 222 &gt; (1) .. (327) &lt; 223 &gt;Antibody-Region-VL; MOR02611 &lt; 4 0 0 &gt; 7 gat ate gea ctg acc cag cca gct tea gtg age ggc tea cca ggt cag 48 Asp Ile Ala Leu Thr Gin Pro Ala Ser Goa Ser Gly Ser Pro Gly Gin 1 5 10 15 age att acc ate teg tgt acg ggt act age age gat att ggt ggt tat 96 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Gly Tyr 20 25 30 cat tet gtg tet tgg tac cag cag cat ccc ggg aag gcg ccg aaa ctt 144 His Being Will Be Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45 atg att cgt tet aat cgt ccc tea ggc gtg age aac cgt ttt age 192 Met Ile Tyr Arg Ser Asn Arg Pro Ser Gly Will Be Asn Arg Phe Ser 50 55 60 gga tcc aaa age ggc aac acc gcg age ctg acc att age ggc ctg caa 240 Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gin 65 70 75 80 gcg gaa gac gaa gc gat tat tat tgc gct gct gct act ggt ggt tgg 288 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Ala Thr Gly Gly Trp gtg ttt ggc ggc ggc acg aat tta acc gtt ctt ggc cag Go Phe Gly Gly Gl and Thr Asn Leu Thr Vai Leu Gly Gin 100 105 &lt; 210 &gt; 8 &lt; 2ll &gt; &Lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 8

Asp Ile Ala Leu Thr Gin Pro Ala Will Be Gly Ser Pro Gly Gin 15 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Gly Tyr 20 25 30

His Being Will Be Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45

Met Ile Tyr Arg Ser Asn Arg Pro Ser Gly Will Be Asn Arg Phe Ser 50 55 50

Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gin 65 70 75 80

Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Ala Thr Gly Gly Trp 85 90 95

Go Phe Gly Gly Gly Thr Asn Leu Thr Go Leu Gly Gin 100 105 &lt; 211 &gt; 348 &lt; 212 * DNA &lt; 213 &gt; human &lt; 220 &gt;

&lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (348) &lt; 223 &gt;Antibody-Region-VH; M0R02613 cg gtg caa ttg gtg gaa age ggc ggc ggc ctg gtc caa ccg ggc ggc Gin Vai Gin Leu Go Glu Be Gly Gly Gly Kj Leu Go Gin Pro Gly 1 ç Gly age ctg cgt ctg age tgc gcg gee tcc gga ttt acc ttt tet aat tat Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 act atg act tgg gtg ege caa gee cct ggg aag ggt etc gag tgg gtg Thr Met Thr Trp Go Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Go 35 40 45 48 96 144 age ttt att att ggt tet ggt age aat acc tet tat gcg gat age gtg Ser Phe Ile Ile Gly Ser Gly Ser Asn Thr Ser Tyr Ala Asp Ser is 50 55 60 aaa ggc cgt ttt acc att tea cgt gat aat teg aaa aac acc ctg tat Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 ctg caa atg aac age ctg cgt gcg gaa gat acg gee gtg tat tat tgc Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala will Tyr Tyr Cys 85 90 95 gcg cgt tat gtt aat ggt ttt gat att tgg ggc caa ggc acc ctg gtg 192 240 288 336

Ala Arg Tyr Go Asn Gly Phe Asp Ile Trp Gly Gin Gly Thr Leu Go 100 105 110 acg g 11 age tea &gt; Thr Will Be &lt; 210 &gt; 10 &lt; 211 &gt; 116 &lt; £ I: 2 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 10

Gin Go Go Gin Go Go Glu Be Gly Go Gly Go Go Go Gin Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30

Thr Met Thr Trp Go Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Go 35 40 45

Ser Phe Ile Ile Gly Ser Gly Ser Asn Thr Ser Tyr Ala Asp Ser Go 50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95

Ala Arg Tyr Go Asn Gly Phe Asp Ile Trp Gly Gin Gly Thr Leu Go 100 105 lio

Thr Will Be Ser 115 &lt; 210 &gt; 11 &lt; 211 &gt; 339 The DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (339) &lt; 223 &gt;Antibody-Region-VL; M0R02613 &lt; 400 &gt; 11 gat ate gea ctg acc cag cca gct tea gtg age ggc tea cca ggt cag 48 Asp Ile Ala Leu Thr Gin Pro Ala Be Gonna Be Gly Ser Pro Gly Gin 1 5 10 15 age att att gt gt gt gt gt act gtt ggt gtt tat 96 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Go Gly Vai Tyr 20 25 30 tat tat gtg tet tgg tac cag cag cat ccc ggg aag gcg ccg aaa ctt 144 Tyr Tyr Will Be Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45 atg att tat tat gat tet aag cgt ccc tea ggc gtg age aac cgt ttt 192 Met Ile Tyr Tyr Asp Ser Lys Arg Pro Ser Gly Will Be Asn Arg Phe 50 55 60 age gga tcc aaa age ggc aac acc gcg age ctg acc att age ggc ctg 240 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 caa gcg gaa gac gaa gcg gat tat tat tgc cag act tat gct aag aag 288

Gin Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Thr Tyr Ala Lys Lys 85 90 95 gat tat tct ctt gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc 336

Asp Tyr Ser Leu Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly 100 105 110

Gin &lt; 210 &gt; 12 &lt; 211 &gt; 113

&lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 4 0 0 &gt; 12

Asp Ile Ala Leu Thr Gin Pro Ala Will Be Gly Ser Pro Gly Gin 15 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Val Tyr 20 25 30

Tyr Tyr Will Be Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45

Met Ile Tyr Tyr Asp Ser Lys Arg Pro Ser Gly Will Be Asn Arg Phe 50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80

Gin Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Thr Tyr Ala Lys Lys 85 90 95

Asp Tyr Ser Leu Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly 100 105 110

Gin

&lt; 210 &gt; 13 &lt; 211 &gt; 339 DNA A ΓΟ I-1 OJ V human &lt; 220 &gt; THE'?' CDS CM2 &gt; (1) .. (339) &lt; 223 &gt;Antibody-Region-VH; M0R02614 &lt; 4 0 0 &gt; 13 cag gtg caa ttg gtg gaa age ggc ggc ggc ctg gtc caa ccg ggc ggc 48 Gin Vai Gin Leu Go Glu Be Gly Gly Gly Leu Go Gin Pro Gly Gly 1 5 10 15 age ctg cgt ctg age tgc gcg gee tcc gga ttt acc ttt aat aat aat 96 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Asn 20 25 30 tgg atg cat tgg gtg ege caa gee cct ggg aag ggt gag tgg gtg 144 Trp Met His Trp Go Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Go 35 40 45 ttt tet gt tet gt gt gt gat age gtg 192 Ser Phe Ile Ser Gly Ser Gly Ser His Thr Tyr Tyr Ala Asp Ser Go 50 55 60 aaa ggc cgt ttt acc att tea cgt gat aat teg aaa aac acc ctg tat 240

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 ctg caa atg aac age ctg cgt gcg gaa gat acg gee gtg tat tat tgc 288

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95 gcg cgt gct tat gat gtt tgg ggc caa ggc acc ctg gtg acg gtt age 336

Ala Arg Ala Tyr Asp Go Trp Gly Gin Gly Thr Leu Go Thr Will Be 100 105 110 tea

&Lt; 210 &gt; 14 &lt; 211 &gt; 113 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 14

Gin Go Go Gin Go Go Glu Be Gly Go Gly Go Go Go Gin Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Asn 20 25 30

Trp Met His Trp Go Arg Arg Pro Gly Lys Gly Leu Glu Trp Go 35 40 45

Ser Phe Ile Ser Gly Ser Gly Ser His Thr Tyr Tyr Ala Asp Ser Go 50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95

Ala Arg Ala Tyr Asp Go Trp Gly Gin Gly Thr Leu Vai Thr Will Be 100 105 110

Ser &lt; 21Q &gt; 15 &lt; 211 &gt; 327 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 22Q &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (327) &lt; 223 &gt;Antibody-Region-VL; M0R02614 &lt; 400 &gt; 15 gat gtg ctg acc cg ccg cct gtg agt ggc gea cca ggt cag 48 Asp Ile Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 1 5 10 15 cgt gtg acc tgt gt gg gt ggc age a att ggt ttt aat 96 Arg Go Thr ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Phe Asn 20 25 30 tat gtg aat tgg tac cag ctg ccc ggg acg gcg ccg aaa ctt ctg 144 Tyr Go Asn Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 att tat ggt aat tet aag cgt ccc tea ggc gtg ccg gat cgt ttt age 192 Ile Tyr Gly Asn Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 gga tcc Gly Ser aaa

Lys age ggc acc a9c gcg aCfc ctt gcg Ser Gly Thr Ser Ala Ser Leu Ala att acg ggc ctg caa 11 and Thr Gly Leu Gin 240 65 70 75 80 age gaa gac gaa gc gat tattat tgc gct atg ttt tct cet gag ggt 288 Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Met Phe Ser Pro Glu Gly 85 90 95 gtg ttt ggc ggc ggc acg aag 11 a gtt ctt ggc cag Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105

&lt; 210 &gt; 16 &lt; 211 &gt; 109 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 4 0 0 &gt; 16

Asp Ile Vai Leu Thr Gin Pro Pro 1 5

Arg Will Thr Ile Ser Cys Ser Gly 20

Tyr Go Asn Trp Tyr Gin Gin Leu 35 40

Ile Tyr Gly Asn Ser Lys Arg Pro 50 55

Gly Ser Lys Ser Gly Thr Ser Ala 65 70

Ser Glu Asp Glu Ala Asp Tyr Tyr

To Be Gonna Be Gly Ala Pro Gly Gin 10 15

Being Ser Being Asn Ile Gly Phe Asn 25 30

Pro Gly Thr Ala Pro Lys Leu Leu 45

Ser Gly Go Pro Asp Arg Phe Ser 60

Ser Leu Ala Ile Thr Gly Leu Gin 75 80

Cys Ala Met Phe Ser Pro Glu Gly 1¾ §0

Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105 &lt; 210 &gt; 17 &lt; 211 &gt; 348 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (348) &lt; 223 &gt;Antibody-Region-VH; M0R02616 &lt; 400 &gt; 17 cag gtg caa ttg gtg gaa age ggc ggc ggc ctg gtc caa ccg ggc ggc 48 Gin Vai Gin Leu Go Glu Be Gly Gly Gly Leu Go Gin Pro Gly Gly 1 5 10 15 age ctg cgt ctg age tgc gcg gee tcc gga ttt acc ttt cgt aat aat 96 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Asn 20 25 30 gct atg cat tgg gtg ege caa gee cct ggg aag ggt gag tgg gtg 144 Ala Met His Trp Go Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Go 35 40 45 gct gt tet tet gt gt gt gt gt gt gt gt gt gt gt gt gt gt gt gt gt gt gt gt gt gtg acc att tea cgt gat aat teg aaa aac acc ctg tat 240 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr ctg caa atg aac age ctg cgt gcg gaa gat acg gee gtg tat tat tgc 288 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 gcg cgt gtt att gtt ctt ttt gat tat tgg ggc caa ggc acc ctg gtg 336 Ala Arg v to Ile val Leu Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val 100 105 110 acg gtt age tea M8 Thr Be Ser Ser 115 &lt; 210 &gt; 18 &lt; 211 &gt; 116 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 40Q &gt; 18

Gin Go Go Gin Go Go Glu Be Gly Go Gly Go Go Go Gin Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Asn 20 25 30

Ala Met His Trp Go Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Go 35 40 45

Ser is Ile Ser Ser Ser Gly Ser Gly Thr Tyr Tyr Ala Asp Ser Go 50 55 60 75 80

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95

Ala Arg Go Ile Goa Leu Phe Asp Tyr Trp Gly Gin Gly Thr Leu Go 100 105 110

Thr Will Be Ser 115 &lt; 210 &gt; 19 &lt; 211 &gt; 327 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 2 &gt; 2 &gt;

CDS &lt; 222 &gt; (1) .. (327) &lt; 223 &gt;Antibody-Region-VL; M0R02616 &lt; 400 &gt; 19 gat ate gtg ctg acc cag age ccg gcg acc ctg age ctg tet ccg ggc 48 Asp Ile Vai Leu Thr Gin Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 gaa cgt gcg acc ctg age tgc aga gcg age cag aat gtt cgt tet aat 96 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Asn Va Arg Ser Asn 20 25 30 ctg gct tgg cag cag cl cg cca gg cca cg cca ct tta att 144 Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu Ile 35 40 45 tat ggt gct tct aat cgt gca act ggg gtc ccg gcg cgt ttt age ggc 192 Tyr Gly Ala Ser Asn Arg Ala Thr Gly Pro Pro Ala Arg Phe Ser Gly 50 55 60 tct gga tg ggc acg gat ttt acc ctg acc att age age ctg gaa cct 240 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 gaa gac ttt gcg gtt tat tat tgc ctt cag aag tac tct att cct ttt 288 Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gin Lys Tyr Ser Ile Pro Phe 85 90 95 acc ttt ggc cag ggt acg ddd gtt gaa att ddd cgt acg Thr Phe Gly Gin Gly Thr Lys Go Glu Ile Lys Arg Thr 100 105 &lt; 210 &gt; 20 &lt; 211 &gt; 109 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 20

Asp Ile Vai Leu Thr Gin Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Asn Vai Arg Ser Asn 20 25 30

Leu Wing Trp Tyr Gin Gin Lys Pro Gly Gin Wing Pro Arg Leu Leu Ile 35 40 45

Tyr Gly Ala Ser Asn Arg Ala Thr Gly Pro Pro Ala Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gin Lys Tyr Ser Ile Pro Phe 85 90 95

Thr Phe Gly Gin Gly Thr Lys Go Glu Ile Lys Arg Thr 100 105 < 210 &gt; 21 &lt; 211 &gt; 348 &lt; 2: 12; * DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 2 2 2 &gt; (1) .. (348) &lt; 223 &gt;Antibody-Region-VH; M0R02618 &lt; 400 &gt; 21 cag gtg caa ttg gtg gaa age ggc ggc ggc ctg gtc caa ccg ggc ggc 48 Gin Go Go Gin Go Go Glu Be Gly Gly Gly Leu Go Gin Pro Gly Gly 1 5 10 15 age ctg cgt ctg age tgc gcg gee tcc gga ttt acc ttt aat tat 96 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Tyr 20 25 30 ggt atg act tgg gtg gtg gg gt cg gg gt gt gt gt gt gt gtg Gt Met Thr Trp Go Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Go 35 40 45 tet tat tat g gt tat tat g gt g gt gt gtg 192 Be Ser Ile Tyr Gly Tyr Gly Ser Asn Thr Tyr Tyr Ala Asp Ser go so aaa ggC cgt ttt acc a 11 tc a cgt gat aat teg aaa aac acc ctg tat 240 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 ctg caa atg aac age ctg cgt cro CTQ gaa gat acg gee gtg tattat tgc 288 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95 gcg cgt a at tat tgg gtt ttt gct tat tgg ggc caa ggc a cc ctg gtg 336 Ala Arg Asn Tyr Trp Go Phe Ala Tyr Trp Gly Gin Gly Thr Leu Go 100 105 110 acg gtt age tc a MH Thr Will Be Ser &lt; 210 &gt; 22 <m &gt; ii6 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 22

Gin Go Go Gin Go Go Glu Be Gly Go Gly Go Go Go Gin Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Tyr 20 25 30

Gly Met Thr Trp Go Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Go 35 40 45

Ser Ser Ile Tyr Gly Tyr Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Vai

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95

Ala Arg Asn Tyr Trp Val Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val 100 105 110

Thr Will Be Ser &lt; 210 &gt; 23 &lt; 2: 11; &gt; 330 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (330) &lt; 223 &gt;Antibody-Region-VL; M0R02618 &lt; 400 &gt; 23 gat ate gaa ctg acc cag ccg cct tea gtg age gtt gea cca ggt cag 48 Asp Ile Glu Leu Thr Gin Pro Pro Will Be Going Ala Pro Gly Gin 1 5 10 15 acc gcg cgt gt gt g gt g gat aat att cct ggt aag ttt gtt 96 Thr Ala Arg ile Ser Cys Ser Gly Asp Asn ile Pro Gly Lys Ser Vai 20 25 30 cat tgg tac cag cag gcc cag gcg cca gtt ctt gtg att tat His Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Glu Lys Met Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 aac gg c aac acc gcg acc ctg acc att age ggc act cag gcg gaa Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gin Ala Glu 65 70 75 80 gac gaa gcg gat tat tat tgc cag tet tat gat aat ttt aat gat tet Asp Glu Ala Asp Tyr Tyr Cys Gin Ser Tyr Asp Asn Phe Asn Asp Ser 85 90 95 gtt gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc cag Go Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105 110 144 &lt; 210 &gt; 24 &lt; 211 &gt; 110 PRT &lt; 213 &gt; human Asp Ile Glu Leu Thr Gin Pro Pro Ser. V Ser Go Pro Wing Gly Gin Thr Ala Arg Ile Ser Cys Ser Gly Asp Asn Ile Pro Gly Lys Ser Vai 20 25 30 His Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Vai Leu Vai Ile Tyr 35 40 45

Gly Lys Met Asn Arg Pro Ser Gly 50 55

Asn Ser Gly Asn Thr Ala Thr Leu 65 70

Asp Glu Ala Asp Tyr Tyr Cys Gin 85

Go Go Phe Gly Gly Gly Thr Lys 100

Ile Pro Glu Arg Phe Ser Gly Ser 60

Thr Ile Ser Gly Thr Gin Ala Glu 75 80

Ser Tyr Asp Asn Phe Asn Asp Ser 90 95

Leu Thr Vai Leu Gly Gin 105 110 &lt; 210 &gt; 25 &lt; 211 &gt; 333 < 212 &gt; DNA &lt; 213 &gt; human &lt; 2 &gt; 2 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (333) &lt; 223 &gt;Antibody-Region-VH; M0R02619 &lt; 400 &gt; 25 cag gtg caa ttg caa gaa agt ggt ccg ggc ctg gtg aaa ccg ggc gaa 48 Gin Vai Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Gly Glu 1 5 10 15 acc ctg age ctg acc tgc acc gtt tcc gga ggc age att tet tet tat 96 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 tat tgg tet tgg att ege cag gee cct ggg aag ggt ctc gag tgg att 144 Tyr Trp Ser Trp Ile Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45

• V CTQ CTQ O ggt c at tgg ggc Gly Ile Gly H is Trp Gly 50 cgg gtg acc a 11 age gtt Arg Vai Thr Ile Ser Vai 65 70 ctg age age gtg acg gcg Leu S er Ser Vai Thr Ala 85 ttt ttt gat gtt tgg ggc Phe Phe Asp Go Trp Gly 100 &lt; 210 &gt; 2U &gt; 111 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 26 Gin Vai Gin Leu Gin Glu 1 5 Thr Leu Ser Leu Thr Cys 20 Tyr Trp Ser Trp Ile Arg 35 Gly 11 and Gly H is Trp Gly acc tct acc cag tat aat ccg Ser Thr Gin Tyr Asn Pro 55 60 gat ac t teg aaa aac cag Asp Thr Ser Lys Asn Gin 75 gaa gat acg gee gt g tat Glu Asp Thr Ala Vai Tyr 90 caa ggc acc ctg gtg acg Gin Gly Thr Leu Vai Thr 105

Ser Gly Pro Gly Leu Go 10 Thr Will Be Gly Gly Ser 25 Gin Ala Pro Gly Lys Gly 40 Ser Thr Gin Tyr Asn Pro 55 60 ctg aaa ggc 192 Ser Leu Lys Gly ttt age ctg aaa 240 Phe Ser Leu Lys 80 tat tgc gcg cgt 288 Tyr Cys Ala Arg 95 gtt age tc a Will be Ser 110

Lys Pro Gly Glu 15 Ile Ser Ser Tyr 30 Leu Glu Trp Ile 45 Ser Leu Lys Gly 50

Arg Go Thr Ile Ser Go Asp Thr 65 70

Leu Ser Ser Go Thr Ala Glu Asp 85

Phe Phe Asp Go Trp Gly Gin Gly 100

Ser Lys Asn Gin Phe Ser Leu Lys 75 80

Thr Ala Val Tyr Tyr Cys Ala Arg 90 95

Thr Leu Go Thr Will Be Ser 105 &lt; 210 &gt; 27 &lt; 211 &gt; 333 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (333) &lt; 223 &gt;Antibody-Region-VL; MOR02619 &lt; 400 &gt; 27 gat gtg ctg acc cag ccg cct tca gtg agt ggc geca cca ggt cag 48 Asp Ile Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 1 5 10 15 cgt gtg acc tgt gt ggc age ggc age aac aac att ggt tct aat 96 Arg Go Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 act gtg cgt tgg tac cag cag ttg ccc ggg acg gcg ccg aaa ctt ctg 144 Thr Vai Arg Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 att tat tct aat aag cgt ccc tca ggc gtg ccg gat cgt ttt age 192 240 240 I1e Tyr Ser 50 gga tcc aaa Gly Ser Lys 65 age gaa gac Ser Glu Asp act ggt gtg Thr Gly goes

Asn Asn Lys Arg Pro Ser Gly 55 age ggc acc age gcg age ctt

Be Gly Thr Be Ala Ser Leu 70 gaa gcg gat tat tat tgc cag

Glu Ala Asp Tyr Tyr Cys Gin 85 90 ttt ggc ggc ggc acg aag tta

Phe Gly Gly Gly Thr Lys Leu 100 105

Go Pro Asp Arg Phe Ser 60 gcg to 11 mg ggc ctg caa Ala Ile Thr Gly Leu Gin 75 80 tct ggg gt gt tct Ser Trp Asp Gly Ala Ser 95 gt ctt ggc cag Thr Vai Leu Gly Gin 288 333 110 < 210 &gt; 28 &lt; 211 &gt; 111 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 28

Asp Ile Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 15 10 15

Arg Will Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30

Thr Vai Arg Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45

Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Pro Pro Asp Arg Phe Ser 50 55 60

Ile Thr Gly Leu Gin

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala 65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ser Trp Asp Gly Ala Ser 85 90 95

Thr Gly Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105 110 &lt; 210 &gt; 29 &lt; 211 &gt; 348 &lt; 212 &gt; DNA &lt; 213 &lt; 220 &gt; &lt;: m &gt; CDS &lt; 222 &gt; (1) .. (348) &lt; 223 &gt;Antibody-Region-VH; M0R02622 &lt; 400 &gt; 29 cag gtg caa ttg gtg gaa age ggc ggc ggc ctg gtc caa ccg ggc ggc 48 Gin Val Gin Leu Val Glu Be Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 age ctg cgt ctg age tgc gcg gee tcc gga ttt acc ttt tet aat tat 96 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 gct atg act tgg gtg gtg gt cg gag aag ggt ctc gag tgg gtg 144 Ala Met Thr Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 age ggt till tet tac aag tet age tet acc tat tat gg gat age gtg 192 Ser Gly ile Ser Tyr Lys Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 UHmmmmwwiinniHHHHHHHinmn! aaa ggc cgt ttt acc att tca cgt gat Lys Gly Arg Phe Thr Ile Ser Arg Asp 65 70 aat tcg aaa aac acc ctg tat 240

Asn Ser Lys Asn Thr Leu Tyr 75 80 ctg caa atg aac age ctg cgt gcg gaa Leu Gin Met Asn Ser Leu Arg Ala Glu 85 gcg cgt ggt ctt gtt act ttt gat aat Ala Arg Gly Leu Vai Thr Phe Asp Asn 100 105 acg gtt age tca Thr Will Be Ser 115 gat acg gcc gtg tat tat tgc 288

Asp Thr Ala Vai Tyr Tyr Cys 90 95 tgg ggc caa ggc acc ctg gtg 336 Trp Gly Gin Gly Thr Leu Vai 110 &lt; 210 &gt; 30 &lt; 212 &gt; PRT &lt; 213 &gt; human

Gly Leu Go Pro Gly Gly Gly Gly Phe Thr Phe Ser Asn Tyr Gly Lys Gly Leu Glu Trp Go 45 Thr Tyr Tyr Ala Asp Ser Vai 60

Gin Go Go Gin Go Go Glu Be Gly Gly

Ser Leu Arg Leu Ser Cys Ala Ala Ser 20 25

Ala Met Thr Trp Go Arg Arg Ala Pro 35 40

Ser Gly Ile Ser Tyr Lys Ser Ser Ser 555!

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95

Ala Arg Gly Leu Go Thr Phe Asp Asn Trp Gly Gin Gly Thr Leu Go 100 105 110

Thr Will Be Ser 115 &lt; 210 31 &lt; 211 &gt; 339 &lt; 112 &gt; DNA &lt; 213 &gt; human <220

&lt; 221 &gt; CDS &lt; 222 &gt; (1) . . (339) &lt; 223 &gt;Antibody-Region-VL; &Lt; 400 &gt;

Asp Ile Ala Leu Thr Gin Pro Ala Be Gonna Be Gly Ser Pro Gly Gin 15 10 15 act att att att gt gt gt act

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Gly Gly Thr Tyr 20 25 30 aat ttt gtg tet tgg tac cag cag cat ccc ggg aag gcg ccg aaa ctt

Asn Phe Will Be Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 48 96 45 144 atg to 11 tat cgt gtt tet aat cgt ccc tc g gc gt g age a c ct ttt 192 Met Ile Tyr Arg Will Be Asn Arg Pro Ser Gly Will Be Asn Arg Phe 50 55 6 0 age gga tcc aaa age ggc aac acc gcg age ctg acc a 11 age ggc ctg 240 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 caa gcg gaa gac gaa gcg gat tattat tgc tet tet tgg ac tcat tet 288 Gin Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Trp Thr His Ser 85 90 95 111 act gat tat gtg 111 ggc ggc ggc acg aag 11 aacc 'gt t (and 11 g gc 336 Phe Thr Asp Tyr Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly 100 105 110 cag 3! f

Gin &lt; ::: - 0: - 32 &lt; 211 &gt; 113 frt &lt; 213 &gt; human &lt; 400 &gt; 32

Asp Ile Ala Leu Thr Gin Pro Ala Will Be Gly Ser Pro Gly Gin 15 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Gly Gly Thr Tyr 20 25 30

Asn Phe Go 35

Ser Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 45 40

MM

Met Ile Tyr Arg Will Be Asn Arg Pro Ser Gly Will Be Asn Arg Phe 50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80

Gin Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Trp Thr His Ser 85 90 95

Phe Thr Asp Tyr Go Phe Gly Gly Gly Thr Lys Leu Thr goes Leu Gly 100 105 110

Gin &lt; 210 &gt; 33 &lt; 211 &gt; &Lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (348) &lt; 223 &gt;Antibody-Region-VH; M0R02715 &lt; 400 &gt; 33 cg gtg caa ttg gtg gaa age ggc ggc ggc ctg gtc caa ccg ggc ggc 48 Gin Vai Gin Leu Go Glu Be Gly Gly Gly Leu Go Gin Pro Gly Gly 1 5 10 15 age ctg cgt ctg age tgc gcg gee tcc gga ttt acc ttt tet tet tat 96 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 ggt atg cat tgg gtg ege cae gee cct ggg aag ggt ctc gag tgg gtg 144

Gly Met His Trp Go Arg Arg Pro Gly Lys Gly Leu Glu Trp Go 35 40 45 gtt gt tet tet tet gt gt gt gt gt gt gt gt gt gt gt gt gt gt gtg Ser is 50 55 60 aaa ggc cgt ttt acc att cgt gat aat teg aaa aac acc ctg tat 240 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 ctg caa atg aac age ctg cgt gcg gaa gat acg gee gtg tat tat tgc 288 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95 gcg cgt aag gtt gt gt gat gtt tgg ggc caa ggc acc ctg gtg 336 Ala Arg Asn Lys Go Gly Phe Asp Go Trp Gly Gin Gly Thr Leu Go 100 105 110 acg gtt age tea <4!

Thr Will Be Ser 115 &lt; 210 &gt; &Lt; tb &gt; 116 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 34

Gin Go Go Gin Go Go Glu Be Gly Go Gly Go Go Go Gin Gly Gly is 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Gly Met His Trp Go Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Go 35 40 45

To Be Ile To Be To Be Gly Ser Tyr Ile Tyr Tyr Ala Asp Ser Go 50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95

Ala Arg Asn Lys Go Gly Phe Asp Go Trp Gly Gin Gly Thr Leu Go 100 105 110

Thr Will Be Ser 115 &lt; 210 &gt; &Lt; tb &gt; 339 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 2 20 &gt; &lt; 2 &gt; 21 &gt; CDS &lt; 222 &gt; (1) .. (339) &lt; 223 &gt;Antibody-Region-VL; M0R02715 gat ate gea ctg acc cag cca gct tea gtg age ggc tea cca ggt cag 48

Asp Ile Ala Leu Thr Gin Pro Ala Will Be Gly Ser Pro Gly Gin age att att gt gt gt act gt gt gt gt gt gt gt gt gt

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Gly Gly Gly Tyr. aat act gtg tct tgg tac cag cag cat ccc ggg aag gcg ccg aaa ctt 144 Asn Thr Will Be Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45 atg att tat tat gtt cat aag cgt ccc tca ggc gtg age aac cgt ttt 192 Met Ile Tyr Tyr Will His Lys Arg Pro Be Gly Will Be Asn Arg Phe 50 55 60 age gga tcc aaa age ggc aac acc gcg age ctg acc att age ggc ctg 240 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 caa gcg gaa gac gaa gcg gat tat tat tgc cag gct tgg gat aat cag 288 Gin Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ala Trp Asp Asn Gin 85 90 95 ggt atg aag tat gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc 336 Gly Met Lys Tyr Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly 100 105 cio Gin &lt; 210 &gt; 36 &lt; 211 &gt; 113 PRT Λ ΓΟ 1-1 (human N V &lt; 400 &gt; 36

Asp Ile Ala Leu Thr Gin Pro Ala Will Be Gly Ser Pro Gly Gin 15 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Gly Gly Gly Tyr 20 25 30

Asn Thr Will Be Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45

Met Ile Tyr Tyr Go His Lys Arg Pro Ser Gly Will Be Asn Arg Phe 50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80

Gin Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ala Trp Asp Asn Gin 85 90 95

Gly Met Lys Tyr Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly 100 105 110

Gin &lt; 210 &gt; 37 &lt; 211 &gt; 345 2: 1 DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (345) &lt; 223 &gt;Antibody-Region-VH; M0R02718 &lt; 400 &gt; 37 cag gtg caa ttg gtg gaa age ggc ggc ggc ctg gtg caa ccg ggc ggc 48

Gin Go Leu Go Glu Be Gly Gly Gly Leu Go Gin Pro Gly Gly age ctg cgt ctg age tgc gcg gee tcc gga ttt acc ttt aat tet aat 96 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ser Asn 20 25 30 gct atg cat tgg gtg ege caa gee cct ggg aag ggt et gag tgg gtg 144 Ala Met Hys Trp Go Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Go 35 40 45 age ttt till tet ggt tet ggt age tet acc tat tat gcg gat age gtg 192 Ser Phe Ile Ser Gly Ser Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Go 50 55 60 aaa ggc cgt ttt acc att tea cgt gat aat teg aaa aac acc ctg tat 240 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 ctg caa atg aac age ctg cgt gcg gaa gat acg gee gtg tat tat tgc 288 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 gcg cgt ggt tgg ttt gtc tg ggc cat ggc acc ctg gtg acg 336 Ala Arg Gly Trp Phe Phe Ala His Trp Gly Gin Gly Thr Leu Vai Thr 100 10 5 110 gtt age tea 345 will be Ser 115 &lt; 210 &gt; 38 &lt; 211 &gt; 115 &lt; 5 / &gt; PRT &lt; 213 &gt; human

Gin Go Go Gin Go Go Glu Be Gly Gly Gly Leu Go Gin Pro Gly Gly i: S l

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ser Asn 20 25 30

Ala Met His Trp Go Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Go 35 40 45

Ser Phe Ile Ser Gly Ser Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Go 50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95

Ala Arg Gly Trp Phe Phe Ala His Trp Gly Gin Gly Thr Leu Vai Thr 100 105 110

Vai Ser Ser 115 &lt; 210 &gt; 39 &lt; 211 &gt; 327 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt;

CDS &lt; 222 &gt; (1) .. (327) &lt; 223 &gt;Antibody-Region-VL; M0R02718 &lt; 400 &gt; 39 gat ate gtg ctg acc cag age ccg gcg acc ctg age ctg tct ccg ggc 48 Asp Ile Val Leu Thr Gin Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 gaa cgt gcg acc ctg age tgc aga gcg age cag tct ggt cgt ggt aat 96 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Gly Arg Gly Asn 20 25 30 ctg gct tgg cag cag cca ggt caa gea ccg cta tta att 144 Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu ile 35 40 45 tat gat gct tct aat cgt gea act ggg gtc ccg gcg cgt ttt ggc 192 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 tct gga tcc ggc acg gat ttt acc ctg acc att age age ctg gaa cct 240 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 gaa gac ttt gcg gtt tat tat tgc ttt cag tat tct tct gtt cct ctt 288 Glu Asp Phe Ala Val Tyr Tyr Cys Phe Gin Tyr Ser Ser Val Pro Leu 85 90 95 acc ttt ggc cag ggt acg aaa gtt gaa att aaa cg t acg 327 Thr Phe Gly Gin Gly Thr Lys Val Glu ile Lys Arg Thr 100 105 &lt; 210 &gt; 40 &lt; 211 &gt; 109 &lt; 212 &gt; PRT &lt; 213 &gt; human <&gt; ΐ.

Asp Ile Vai Leu Thr Gin Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Gly Arg Gly Asn 20 25 30

Leu Wing Trp Tyr Gin Gin Lys Pro Gly Gin Wing Pro Arg Leu Leu Ile 35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Pro Pro Ala Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80

Glu Asp Phe Ala Go Tyr Tyr Cys Phe Gin Tyr Ser Ser Go Pro Leu 85 90 95

Thr Phe Gly Gin Gly Thr Lys Go Glu Ile Lys Arg Thr 100 105 &lt; 210 &gt; 41 &lt; 211 &gt; 342 &lt; 211 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (342) &lt; 223 &gt;Antibody-Region-VH; M0R02721 &lt; 4 0 0 &gt; 41 cag gtg caa ttg gtt cag age ggc gcg gaa gtg aaa aaa ccg ggc gaa 48

Gin Go Leu Go Go Gin Be Gly Ala Glu Go Lys Lys Pro Gly Glu 1 $ age ctg aaa att age tgc aaa ggt tcc gga tat tcc ttt act tet tat 96 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 tat att aat tgg gtg ege cag atg cct ggg aag ggt ctc gag tgg atg 144 Tyr Ile Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 ggc att till tat ccg tet act age cgt acc att tat tet ccg age ttt 192 Gly ile Ile Tyr Pro Ser Thr Ser Arg Thr Ile Tyr Ser Pro Ser Ser Phe 50 55 60 cag ggc cg gtg acc att age gcg gat aaa age att age acc gcg tat 240 Gin Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 ctt caa tgg age age ctg aaa gcg age gat acg gee atg tat tat tgc 288 Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 gcg cgt tat cat ggt gct ttt tgg ggc caa ggc acc ctg gtg acg gtt 336 Ala Arg Tyr His Gly Ala Phe Trp Gly Gin Gly Thr Leu Val Thr Val 100 105 110 age tea M3.

Ser Ser &lt; 210 &gt; 42 &lt; 211 &gt; 114 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt;4C; -o &gt; 42

Gin Go Go Gin Go Go Gin Go Glu Go Go Go Lys Lys Go Glu Glu 15 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30

Tyr Ile Asn Trp Go Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45

Gly Ile Ile Tyr Pro Ser Thr Ser Arg Thr Ile Tyr Ser Pro Ser Phe 50 55 60

Gin Gly Gin Go Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80

Leu Gin Trp Ser Ser Leu Lys Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95

Ala Arg Tyr His Gly Ala Phe Trp Gly Gin Gly Thr Leu Vai Thr Go 100 105 110

Ser Ser &lt; 210 &gt; 43 &lt; 211 &gt; 342 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt;

&lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (342) &lt; 223 &gt;Antibody-Region-VL; M0R02721 &lt; 4 Ο Ο &gt; 43 cag gtg caa 11 g gtt cag age ggc gcg gaa gtg aaa aaa ccg ggc gaa 48 Gin Vai Gin Leu Go Gin Be Gly Ala Glu Go Lys Lys Pro Gly Glu 1 5 10 15 age ctg aaa a 11 age tgc aaa ggt tcc gga tat tcc ttt act tet tat 96 Ser Leu Lys 11 and Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 tata 11 aat tgg gtg ege cag atg cct ggg aag ggt ctc gag tgg atg 144 Tyr 11 and Asn Trp Go Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 ggc at 11 to tb cctv t tc tg tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb tb Pro Ser Phe 50 55 60 cag ggc cag gtg acc a 11 age gcg gat aaa age a 11 age acc gcg tat 240 Gin Gly Gin Go Thr 11 and Ser Ala Asp Lys Ser 11 and Ser Thr Ala Tyr 65 70 75 80 c 11 caa tgg age age ctg aaa gcg age gat acg gee atg tattat tgc 288 Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 gcg cgt t a tg at ggt gct ttt tgg ggc caa ggc acc ctg gtg acg gtt 336 Ala Arg Tyr HIS Gly Ala Phe Trp Gly Gin Gly Thr Leu Vai Thr Go 100 105 110 age tea Ser Ser

&lt; 210 &gt; 44 &lt; 211 &gt; 114 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 44

Gin Go Gin Go Gin Gin Go 1 5

Ser Leu Lys Ile Ser Cys Lys Gly 20

Tyr Ile Asn Trp Go Arg Gin Met 35 40

Gly Ile Ile Tyr Pro Ser Thr Ser 50 55

Gin Gly Gin Go Thr Ile Be Ala 65 70

Leu Gin Trp Ser Ser Leu Lys Wing 85

Ala Arg Tyr His Gly Ala Phe Trp 100

Ala Glu Vai Lys Lys Pro Gly Glu 10 15

Ser Gly Tyr Ser Phe Thr Ser Tyr 25 30

Pro Gly Lys Gly Leu Glu Trp Met 45

Arg Thr II and Tyr Ser Pro Ser Phe 60

Asp Lys Ser Ile Ser Thr Ala Tyr 75 80

Ser Asp Thr Ala Met Tyr Tyr Cys 90 95

Gly Gin Gly Thr Leu Vai Thr Go 105 105

Ser Ser &lt; 210 &gt; 45 &lt; 211 &gt; 339 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; CDS &lt; 222 &gt; (1) .. (339), wherein: (1) and (2) and (3) gi g g g g g g c g gc g gc g gc g gc g gc g gc g gc g gc g gc g gc g gc g gc g gc g gc g gc g gc gga ttt acc ttt tet tet aat 96 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Asn 20 25 30 gct att cat tgg gt g ca g g c c g g g a g g t g g t g g t g g tg Gin Ala Pro Gly Lys Gly Leu Glu Trp Go 35 40 45 tet tet gt tet gt gt gt gt gt gt gt gt gt gt gt gt gt gt gt gt gtg ggc cgt ttt acc att tca cgt gat aat teg aaa aac acc ctg tat 240 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 ctg caa atg aac age ctg cgt gcg gaa gat acg gee gt tat tat tgc 288 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95 gcg cgt ttt att gct tet tgg ggc caa ggc acc ctg gtg acg gtt age 336 Ala Arg Phe Ile Ala Ser Trp Gly Gin Gly Thr Leu Go Thr Will Be 100 105 110 tca Ser

&lt; 211 &gt; 113 &lt; 212 &gt; PRT &lt; 213 &gt; human '400 &gt; 4

Gin Goes Gin Leu Goes Glu Ser Gly

Ser Leu Arg Leu Ser Cys Ala Ala 20

Ala Ile His Trp Go Arg Arg Ala 35 40

Ser Ser Gly Ser Gly Ser Gly Ser 50 55

Lys Gly Arg Phe Thr Ile Ser Arg 65 70

Leu Gin Met Asn Ser Leu Arg Ala 85

Ala Arg Phe Ile Ala Ser Trp Gly 100

Gly Gly &amp; W Leu Go Pro Gin Gly Gly Ser Gly Phe Thr Phe Ser Ser Asn 25 30 Pro Gly Lys Gly Leu Glu Trp Go 45 Asn Thr Tyr Tyr Ala Asp Ser Vai 60 Asp Asn Ser Lys Asn Thr Leu Tyr 75 80 Glu Asp Thr Ala Go Tyr Tyr Cys 90 95 Gin Gly Thr Leu Will Thr Will Be 105 110

&Lt; 210 &gt; 47 &lt; 211 &gt; 342 human DNA &lt; 213 &gt; ''> c '2 V ·' '<221> CDS &lt; 222 &gt; (1) . . (342) &lt; 223 &gt;Antibody-Region-VL; M0R02722 &lt; 400 &gt; 47 gat ate gtg atg acc cag age cca ctg age ctg cca gtg act ccg ggc 48 Asp Ile Vai Met Thr Gin Ser Pro Leu Ser Leu Pro Go Thr Pro Gly 1 5 10 15 gag cct gcg age att age tgc aga age age caa age ctg gtt cat tet 96 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gin Ser Leu Vai His Ser 20 25 30 aat ggc tat act gat ctg aat tgg tac ctt caa aaa cca ggt caa age 144 Asn Gly Tyr Thr Asp Leu Asn Trp Tyr Leu Gin Lys Pro Gly Gin Ser 35 40 45 ccg cta tta att tat ctt gttt tet tat cgt gee agt ggg gtc ccg 192 Pro Gin Leu Leu ile Tyr Leu Gly Ser Tyr Arg Ala Ser Gly Pro Pro 50 55 60 gat cgt ttt age ggc tet gga tcc ggc acc gat ttt acc ctg aaa att 240 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 age cgt gtg gaa gct gaa gac gtg ggc gtg tat tat tgc cag cag tat 288 Ser Arg Go Glu Ala Glu Asp Go Gly Go Tyr Tyr Cys Gin Gin Tyr 85 90 95 tet aat ttt ctt ttt acc ttt ggc cag ggt acg aaa gtt gaa att aaa 336 Ser Asn Phe Pro Phe Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys 100 105 110 cgt ac Arg Arg Thr &lt; 210 &gt; 48 &lt; 211 &gt; 114 &lt; 212 &gt; PRT &lt; 213 &gt; human

Asp Ile Vai Met Thr Gin Ser Pro Leu Ser Leu Pro Go Thr Pro Gly

Glu Pro Ala Ser Ile Ser Cys Arg 20

Asn Gly Tyr Thr Asp Leu Asn Trp 35 40

Pro Gin Leu Leu Ile Tyr Leu Gly 50 55

Asp Arg Phe Ser Gly Ser Gly Ser 65 70

Ser Arg Go Glu Ala Glu Asp Go 85

Ser Asn Phe Pro Phe Thr Phe Gly 100

Being A Gin Being A Leu Goes His Being 25 30

Tyr Leu Gin Lys Pro Gly Gin Ser 45

Ser Tyr Arg Ala Ser Gly Go Pro 60

Gly Thr Asp Phe Thr Leu Lys Ile 75 80

Gly Vai Tyr Tyr Cys Gin Gin Tyr 90 95

Gin Gly Thr Lys Go Glu Ile Lys 105 110

Arg Thr &lt; 210 &gt; 49 &lt; 211 &gt; 336 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (336) &lt; 223 &gt;Antibody-Region-VL; MORO3055 &lt; 400 &gt; 49 gat gtg ctg acc cag ccg cct gtg agt ggc geca cca ggt cag 48 Asp Ile Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 1 5 10 15 cgt gtg acc tgt gt ggc age ggc age aac aac att ggt tet aat 96 Arg Go Thr He Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 act gtg cgt tgg tac cag cag ttg ccc ggg acg gcg ccg aaa ctt ctg 144 Thr Vai Arg Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 att tat tat aat aag cgt ccc tea ggc gtg ccg gat cgt ttt age 192 Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Pro Pro Asp Arg Phe Ser 50 55 60 gga tcc aaa age ggc acc age gcg age ctt gcg att acg ggc ctg caa 240 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gin 65 70 75 80 age gaa gac gaa gcg gat tat tat tgc cag gct tgg act cgt gct cat 288 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ala Trp Thr Arg Ala His 85 90 95 cgt tat cct gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc cag 336 Arg Tyr Pro Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105 110 &lt; 210 &gt; 50 &lt; 211 &gt; 112 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 50

Asp Ile Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 15 10 15

Arg Will Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30

Thr Vai Arg Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45

Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Pro Pro Asp Arg Phe Ser 50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gin 65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ala Trp Thr Arg Ala His 85 90 95

Arg Tyr Pro Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105 110 &lt; 210 &gt; 51 &lt; 211 &gt; 333 < 212 &gt; DNA &lt; 213 &gt; human

&lt; 220 &gt; &lt; 221 &gt; CDS € 2 &gt; UK. | 333 &gt; &lt; 223 &gt; MO &amp; 03DS3 &lt; 4 Ο Ο &gt; 51 gat gtg ctg acc cg ccg cct tc gtg agt ggc geca cca ggt cag 48 Asp Ile Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 1 5 10 15 cgt gtg acc tgt gt ggc age g age aac at 11 gg tet aat 96 Arg Go Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 act gtg cgt tgg tac cag cag tg ccc ggg acg gcg ccg aaa c 11 ctg 144 Thr Go Arg Arg Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 to 11 tattct aat aag cgt ccc tc a ggc gtg ccg gat cgt ttt age 192 Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Pro Pro Asp Arg Phe Ser 50 55 60 gga tcc aaa age ggc acc age gcg age c 11 gcg a 11 acg ggc ctg caa 240 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gin 65 70 75 80 age gaa gac gaa gc gat tattat tgc tet tcttat gat act cag gtt 288 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Asp Thr Gin Go 85 90 95 act cgt gtg ttt ggc ggc ggc acg aag 11 a acc gtt ctt ggc cag 333 Thr Arg Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105 110

&lt; 210 &gt; 52 &lt; 211 &gt; 111 &lt; 212 &gt; FRT &lt; 213 &gt; human &lt; 400 &gt; 52

Asp Ile Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 15 10 15

Arg Will Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30

Thr Vai Arg Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45

Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Pro Pro Asp Arg Phe Ser 50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gin 65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Asp Thr Gin Go 85 90 95

Thr Arg Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105 110 <21Q> 53 < 211 &gt; 333 &lt; 212 &gt; DNA &lt; 213 &gt; human

&lt; 220 &gt; &lt; 221 &gt; CDS · β% ΪΊ & Η.}. . ; $ 323

<223> MOB23STS &lt; 400 &gt; 53 gat gtg ctg acc cag ccg cct gtg agt ggc gea cca ggt cag 48 Asp Ile Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 1 5 10 15 cgt gtg acc tgt gt ggc age ggc age age aac att ggt tet aat 96 Arg Go Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 act gtg cgt tgg tac cag cag ttg ccc ggg acg gcg ccg aaa ctt ctg 144 Thr Vai Arg Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 att tat tat aat aag cgt ccc tea ggc gtg ccg gat cgt ttt age 192 Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Pro Pro Asp Arg Phe Ser 50 55 60 gga tcc aaa age ggc acc age gcg age ctt gcg att acg ggc ctg caa 240 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gin 65 70 75 80 age gaa gac gaa gc gat tat tat tgc cag tet tgg gat cct cgt tet 288 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ser Trp Asp Pro Arg Ser 85 90 95 ttt act gtg ttt ggc ggc ggc acg aag tta acc gt t ctt ggc cag 333 Phe Thr Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105 110 &lt; 211 &gt; 111 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 4 0 0 &gt; 54 Asp Ile Vai Leu Thr Gin Pro Pro 1 5

Arg Will Thr Ile Ser Cys Ser Gly 20

Thr Vai Arg Trp Tyr Gin Gin Leu 35 40

Ile Tyr Ser Asn Asn Lys Arg Pro 50 55

Gly Ser Lys Ser Gly Thr Ser Ala 65 70

To Be Gonna Be Gly Ala Pro Gly Gin 10 15

Being Ser Being Asn Ile Gly Ser Asn 25 30

Pro Gly Thr Ala Pro Lys Leu Leu 45

Ser Gly Go Pro Asp Arg Phe Ser 6 0

Ser Leu Ala Ile Thr Gly Leu Gin 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ser Trp Asp Pro Arg Ser 85 90 95

Phe Thr Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105 110 &lt; 210 &gt; 55 &lt; 211 &gt; 330 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; cds &lt; 222 &gt; (1) .. (330) &lt; 223 &gt;Antibody-Region-VL; MORO3069 &lt; 4CKV-55 gat gtg ctg acc cag ccg cct tc gtg agt ggc geca cca ggt cag 48 Asp 11 e Go Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 1 5 10 15 cgt gtg acc ate teg tgt age ggc age age age aac 11 ggt tct aat 96 Arg Will Thr 11 and Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 ac t gtg cgt tgg t ac cag cag ttg ccc ggg acg gcg ccg aaa c 11 ctg 144 Thr Go Arg Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 a 11 tattct aat aag cgt ccc tc a ggc gtg ccg gat cgt ttt age 192 11 and Tyr Ser Asn Asn Lys Arg Pro Ser Gly Go Pro Pro Asp Arg Phe Ser 50 55 60 gga tc c age ggc acc age gcg age 11 gcg a 11 ac g gc c ca g 240 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gin 65 70 75 80 age gaa gac gaa gcg gat tattat tgc tgg ac t ggt atg tcttatc at 288 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Trp Thr Gly Met Ser Tyr His 85 9 0 95 ttt gtg ttt ggc ggc ggc acg aag 11 a gt cg 11 ggc cag; · Phe Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105 110

&lt; 210 &gt; 56 &lt; 211 &gt; 110 PRT &lt; 213 &gt; human &lt; 400 &gt; 56

Asp Ile Vai Leu Thr Gin Pro Pro 1 5

Arg Will Thr Ile Ser Cys Ser Gly 20

Thr Vai Arg Trp Tyr Gin Gin Leu 35 40

Ile Tyr Ser Asn Asn Lys Arg Pro 50 55

Gly Ser Lys Ser Gly Thr Ser Ala 65 70

Ser Glu Asp Glu Ala Asp Tyr Tyr 85

Phe Go Phe Gly Gly Gly Thr Lys 100

To Be Gonna Be Gly Ala Pro Gly Gin 10 15

Being Ser Being Asn Ile Gly Ser Asn 25 30

Pro Gly Thr Ala Pro Lys Leu Leu 45

Ser Gly Go Pro Asp Arg Phe Ser 60

Ser Leu Ala Ile Thr Gly Leu Gin 75 80

Cys Trp Thr Gly Met Ser Tyr His 90 95

Leu Thr Vai Leu Gly Gin 105 110 &lt; 210 &gt; 57 &lt; 211 &gt; 333 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) . . (333) &lt; 223 &gt;Antibody-Region-VL; MORO3071 &lt; 4Q0 &gt; 57 gat ate gtg ctg acc cag ccg cct tea gtg agt ggc geca cca ggt cag 48

Asp Ile Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 1 5 10 15 cgt gtg acc ate teg tgt age ggc age age age aac att ggt tet aat 96 Arg Will Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 act gtg cgt tgg tac cag cag ttg ccc ggg acg gcg ccg aaa ctt ctg 144 Thr Go Arg Arg Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 att tat tat aat aag cgt ccc gg gt cg gt cgt ttt age 192 Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Pro Pro Asp Arg Phe Ser 50 55 60 gga tcc aaa age ggc acc age gcg age ctt gcg att acg ggc ctg caa 240 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gin 65 70 75 80 age gaa gac gaa gc gat tat tat tgc ctt gct tat att cag tet aag 288 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Leu Ala Tyr Ile Gin Ser Lys 85 90 95 ggt cat gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc cag jS Gly His Go Phe Gly Gly Gly Thr Lys Leu Thr Go L I Gly Gin 100 105 110 &lt; 210 &gt; 58 &lt; 211 &gt; 111 &lt; 2 VI &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 58

Asp Ile Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 5 10 15 1 iMpttiiinnnmimniiTi

Arg Will Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30

Thr Vai Arg Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45

Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Pro Pro Asp Arg Phe Ser 50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gin 65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Leu Ala Tyr Ile Gin Ser Lys 85 90 95

Gly His Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105 lio &lt; 210 &gt; 59 &lt; 211 &gt; 339 &lt; 212 &gt; DNA &lt; 21: -i &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (339) &lt; 223 &gt;Antibody-Region-VL; MORO3064

&lt; 40Q &gt; 59 gat cg g cg gct tea gtg age ggc tea cca ggt cag 48 Asp Ile Ala Leu Thr Gin Pro Ala Ser Vai Ser Gly Ser Pro Gly Gin 1 5 10 15 age att att att gt gt gt gt gt act ggt ggt ggt tat 96

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Gly Gly Gly Tyr 20 25 30 aat act gtg tet tgg tac cag cag cat ccc ggg aag gcg ccg aaa ctt 144 Asn Thr Will Be Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45 atg att tat tat gtt cat aag cgt ccc tea ggc gtg age aac cgt ttt 192 Met Ile Tyr Tyr Go His Lys Arg Pro Be Gly Will Be Asn Arg Phe 50 55 60 age gga tcc aaa age ggc aac acc gcg age ctg acc att age ggc ctg 240 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 caa gcg gaa gac gaa gcg gat tat tat tgc cag tet tgg gat ctt ctt 288 Gin Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ser Trp Asp Leu Leu 85 90 95 gct cct tet gtt gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc 336 Ala Pro Be Will Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly 100 105 110 cag 33 #

Gin &lt; 210 &gt; 60 &lt; 211 &gt; 113 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 4 0 0 &gt; 6 0

Asp Ile Ala Leu Thr Gin Pro Ala Will Be Gly Ser Pro Gly Gin 5 10 15 1

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Gly Gly Gly Tyr 20 25 30

Asn Thr Will Be Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45

Met Ile Tyr Tyr Go His Lys Arg Pro Ser Gly Will Be Asn Arg Phe 50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80

Gin Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ser Trp Asp Leu Leu 85 90 95

Ala Pro Ser Go Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly 100 105 110

Gin &lt; 210 &gt; 61 &lt; 211 &gt; 339 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (339) &lt; 223 &gt;Antibody-Region-VL; MORO3062 &lt; 400 &gt; 61 gat ate gea ctg acc cag cca gct tea gtg age ggc tea cca ggt cag 48

Asp Ile Ala Leu Thr Gin Pro Ala Will Be Gly Ser Pro Gly Gin 1 5 10 15 96 age att acc tgt acg ggt act age age gat ggt gt gt gt gt gt gt gt gt gt gt gt gt gt gt gt gt gt gt gt gt gt Gly Gly Tyr 20 25 30 aat act gtg tet tgg tac cag cag cat ccc ggg aag gcg ccg aaa ctt Asn Thr Will Be Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45 atg att tat tat gtt cat aag cgt ccc ggc gtg age aac cgt ttt Met Ile Tyr Tyr Go His Lys Arg Pro Ser Gly Will Be Asn Arg Phe 50 55 60 age gga tcc aaa age ggc aac acc gcg age ctg acc att age ggc ctg Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 caa gcg gaa gac gaa gc gat tat tat tgc cag tet tgg gat ctt tet Gin Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ser Trp Asp Leu Ser 85 90 95 gtt cat cag gtt gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc Go His Gin Go Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly 100 105 110 144 192 240 288 336 cag

Gin &lt; 210 &gt; 62 &lt; 211 &gt; 113 &lt; 215 &gt; PRT &lt; 213 &gt; human &lt; 400 62

Asp Ile Ala Leu Thr Gin Pro Ala Will Be Gly Ser Pro Gly Gin

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Gly Gly Gly Tyr 20 25 30

Asn Thr Will Be Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45

Met Ile Tyr Tyr Go His Lys Arg Pro Ser Gly Will Be Asn Arg Phe 50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80

Gin Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ser Trp Asp Leu Ser 85 90 95

Go His Gin Go Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly 100 105 110

Gin &lt; 210 &gt; 63 «ms 336 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (336) &lt; 223 &gt; Derived from MOR03055: Antibody-Region-VH; M0R03243: x. *

It **** t **** iil <l ** l <lt; <li> <li> Gin Gin Gin Leu Gin Gin Gin Gin Leu Gin Glu Ser Gly Pro Gly Leu Go Lys Pro Gly Glu 1 5 10 15 acc ctg age ctg acc tgc acc gtt cg gg gc age tct tct tat 96 Thr Leu Ser Leu Thr Cys Thr Will Be Gly Gly Ser Ile Ser Ser Tyr 20 25 30 tat tgg tct tgg att ege cag gee cct ggg aag ggt ctc gag tgg att 144 Tyr Trp Ser Trp Ile Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 ggc gag att cat cgt ggt ggt tat act cag tat aat cct tct ctt aag 192 Gly Glu Ile His Arg Gly Gly Tyr Thr Gin Tyr Asn Pro Ser Leu Lys 50 55 60 tct cgg gtc acc att age gtt gat act teg aaa aac cag ttt age ctg 240 Ser Arg Go Thr Ile Ser Go Asp Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80 aaa ctg age age gtg acg gcg gcg gat acg gcg gtg tat tat tgc gcg 288 Lys Leu Ser Ser Go Thr Ala Ala Asp Thr Ala Go Tyr Tyr Cys Ala 85 90 95 cgt ttt ttt gat gtt tgg ggc caa ggc acc ctg gtg acg gtt age tea 336 Arg Phe Phe Asp Go Trp Gly Gin Gly Thr Leu Go Thr Will Be Ser 100 105 110 &lt; 210 &gt; 64 &lt; 211 &gt; 112 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 64

Gin Go Gin Gin Gin Glu Be Gly Pro Gly Leu Go Lys Pro Gly Glu

Thr Leu Ser Leu Thr Cys Thr Will Be Gly Gly Ser Ile Ser Ser Tyr 20 25 30

Tyr Trp Ser Trp Ile Arg Gin Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45

Gly Glu Ile His Arg Gly Gly Tyr Thr Gin Tyr Asn Pro Ser Leu Lys 50 55 60

Ser Arg Go Thr Ile Ser Go Asp Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80

Lys Leu Ser Ser Go Thr Ala Ala Asp Thr Ala Go Tyr Tyr Cys Ala 85 90 95

Arg Phe Phe Asp Go Trp Gly Gin Gly Thr Leu Go Thr Go Ser Ser 100 105 HO <2I8> 65: 2: 1.1: 5-33 C: i2 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (336) &lt; 223 &gt; Derived from MOR03055: Antibody-Region-VL; M0R03243 gat ate gtg ctg acc cag ccg cct tea gtg agt ggc geca cca ggt cag 48

Asp Ile Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin

96 cgt gtg acc ate teg tgt age ggc age Arg Val Thr Ile Ser Cys Ser Gly Ser 20 25 act gtg cgt tgg tac cag cag ttg ccc Thr Val Arg Trp Tyr Gin Gin Leu Pro 35 40 att tat tet aat aag cgt ccc tea Ile Tyr Ser Asn Asn Lys Arg Pro Ser 55 55 gga tcc aaa age ggc acc age gcg age Gly Ser Lys Ser Gly Thr Ser Ala Ser 65 70 age gaa gac gaa gc gat tat tat tgc Ser Glu Asp Glu Ala Asp Tyr Tyr Cys 85 cgt tat cct gtg ttt ggc ggc ggc acg Arg Tyr Pro Val Phe Gly Gly Gly Thr 100 105 age aac att ggt tet aat Ser Ser Asn ile Gly Ser Asn 30 ggg acg gcg ccg aaa ctt ctg 144 Gly Thr Ala Pro Lys Leu Leu 45 ggc gtg ccg gat cgt ttt age 192 Gly Val Pro Asp Arg Phe Ser 60 ctt gcg att acg ggc ctg caa 240 Leu Ala ile Thr Gly Leu Gin 75 80 cag gct tgg act cgt gct cat 288 Gin Ala Trp Thr Arg Ala His 90 95 aag tta acc gtt ctt ggc cag 336 Lys Leu Thr Val Leu Gly Gin 110 &lt; 210 &gt; 66 &lt; 211 &gt; 112 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 66

Asp Ile Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 15 10 15

Being Ser Asn Ile Gly Ser Asn

Arg Is Thr Ile Is Cys Ser Gly Ser 11

Thr Vai Arg Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45

Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Pro Pro Asp Arg Phe Ser 50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gin 65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ala Trp Thr Arg Ala His 85 90 95

Arg Tyr Pro Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105 110

&lt; 210 &gt; 67 &lt; 11 &gt; 336 DNA &lt; 213 &gt; human &lt; 220 &gt;

&lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (336) &lt; 223 &gt; Derived from MOR03069; Antibody-Region-VH; M0R03245 6 7 cag gtg caa ttg caa gaa agt ggt ccg ggc ctg gtg aaa ccg ggc gaa 48

Gin Vai Gin Leu Gin Glu Be Gly Pro Gly Leu Go Lys Pro Gly Glu 15 10 15 acc ctg age ctg acc tgc acc gtt tcc gga ggc age att tet tat 96

Thr Leu Ser Thu Cys Thr Will Be Gly Gly Ser Ile Ser Ser Tyr 20 25 30 tat tgg tct tgg a 11 ege cag gee cct ggg aag ggt ctc gag tgg att 144 Tyr Trp Ser Trp Ile Arg Gin Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 ggc gtt a 11 c at a g tg g t g t t t t t t t t t t t t t t aag 192 Gly Vai 11 and His Lys Trp Gly Phe Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 tct cgg gtc acc a 11 age gtt gat act teg aaa aac cag ttt age ctg 240 Ser Arg Vai Thr Ile Ser Vai Asp Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80 aaa ctg age age gtg acg gcg gcg gat acg gee gtg tattat tgc gcg 288 Lys Leu Ser Ser Go Thr Ala Ala Asp Thr Ala Go Tyr Tyr Cys Ala 85 90 95 cgt ttt ttt gat gtt tgg ggc caa ggc acc ctg gtg acg gtt age tc a 336 Arg Phe Phe Asp Go Trp Gly Gin Gly Thr Leu Go Thr Will Be Ser 100 105 110 &lt; 210 &gt; 68 &lt; 211 &gt; 112 &lt; 212 &gt; FRT &lt; 213 &gt; human &lt; 400 &gt; 68

Gin Go Gin Gin Glu Be Gly Pro Gly Leu Go Lys Pro Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Will Be Gly Gly Ser 11 and Ser Ser 20 25 30 113

Tyr Trp Ser Trp Ile Arg Gin Ala 35 40

Gly Ile Ile His Lys Trp Gly Phe 50 55

Ser Arg Go to Thr Ile Ser Go to Asp 65 70

Lys Leu Ser Ser Go Thr Ala Ala 85

Arg Phe Phe Asp Go Trp Gly Gin 100

Pro Gly Lys Gly Leu Glu Trp Ile 45

Thr Asn Tyr Asn Pro Ser Leu Lys 60

Thr Ser Lys Asn Gin Phe Ser Leu 75 80

Asp Thr Ala Val Tyr Tyr Cys Ala 90 95

Gly Thr Leu Go Thr Will Be Ser 105 110 <210> 69 &lt; 211 &gt; 330 • ΐ; •; •: • &gt; adn &lt; 213 &gt; human &lt; 22 &gt; cds &lt; 222 &gt; (1) .. (330) &lt; 223 &gt; Derived from MOR03069; Antibody-Region-VL; MOR03245 · - ·. ··· (5 0> gat gtg ctg acc cag ccg cct tea

Asp Ile Vai Leu Thr Gin Pro Pro Ser 15 gg gtg acc gtg ggc age

Arg will be Ile Ser Cys Ser Gly Ser 20 gtg agt ggc geca gca cag 48 Will Be Gly Ala Pro Gly Gin 'x. 1a v 2a age age aac att ggt tet aat 96

Ser Ser Asn Ile Gly Ser Asn 30 25

act gtg cgt tgg t ac cag cag ttg ccc ggg acg gcg ccg aaa c 11 ctg 144 Thr Go Arg Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 a 11 tattct aat aat aag cgt ccc tc a ggc gtg ccg gat cgt ttt age 192 Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly V Pro Pro Asp Arg Phe Ser 50 55 60 gga tcc aaa age ggc acc age gcg age 11 gcg a 11 acg ggc ctg caa 240 Gly Ser Lys Ser Gly Thr Be Ala Ser Leu Ala Ile Thr Gly Leu Gin 65 70 75 80 age gaa gac gaa gcg gat tattat tgc tgg act ggt atg tcttat cat 288 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Trp Thr Gly Met Ser Tyr His 85 90 95 ttt gtg ttt ggC ggc ggc acg aag 11 a acc gtt c 11 ggc cag Phe Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105 110 &lt; 210 &gt; 70 &lt; 211 &gt; 110 &lt; 212 &gt; FRT &lt; 213 &gt; human &lt; 400 &gt; 70

Asp 11 and Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 1 5 10 15 Arg Will Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Thr Vai Arg Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45

He Tyr Ser Asn Asn Lys Arg Pro Ser Gly Pro Pro Asp Arg Phe Ser 50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gin 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Trp Thr Gly Met Ser Tyr HIS 85 90 95 Phe Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly Gin 100 105 110 &lt; 210 &gt; 71 &lt; 211 &gt; 354 adn &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (354) &lt; 223 &gt; Derived from MOR03075; Antibody-Region-VH; MOR03246 &lt; 400 &gt; 71 cag gtg caa ttg gtt cag age ggc gcg gaa gtg aaa aaa ccg ggc gcg 48 Gin Vai Gin Leu Go Gin Be Gly Ala Glu Go Lys Lys Pro Gly Ala 1 5 10 15 age gtg aaa gtg age tgc aaa gee tcc gga tat acc ttt act ggt ttt 96 Will Be Lys Will Be Cys Lys Will Be Gly Tyr Thr Phe Thr Gly Phe 20 25 30 tat att aat tgg gtc gt c g g g g ct c g g t g gt gt gt gt gt tg Gly Gin Gly Leu Glu Trp Met ggc tgg gt ct gt cgt gt gt cgt gg cg aag ttt 192 Gly Trp Ile Asn Pro Tyr Ser Gly Asn Thr Arg Tyr Ala Gin Lys Phe 50 55 60 cag ggc cgg gtg acc atg acc cgt gat acc age att age acc gcg tat 240 Gin Gly Arg Go Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 atg gaa ctg age age ctg cgt age gaa gat acg gee gtg tat tat tgc 288 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 gcg cgt tet cct gtt tat tat aag tat gat tat tgg ggc caa ggc acc 336 Ala Arg Ser Pro Val Tyr Tyr Lys Tyr Asp Tyr Trp Gly Gin Gly Thr 100 105 ctg gtg acg gtt age tea 1-3: 4 Leu Vai Thr Will Be Ser 115

&lt; 21Q &gt; 72 < 211 &gt; 118 PRT &lt; 213 &gt; human &lt; 400 &gt; 72

Gin Go Gin Gin Go Gin Go Gly Go Go Lys Lys Pro Gly Ala 15 10 15

Ser Goes Lys Goes Ser Cys Lys Ser Ser Gly Tyr Thr Phe Thr Gly Phe 20 25 30

Tyr Ile Asn Trp Go Arg Arg Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Trp Ile Asn Pro Tyr Ser Gly Asn Thr Arg Tyr Ala Gin Lys Phe 50 55 60

Gin Gly Arg Will Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Ser Pro Val Tyr Tyr Lys Tyr Asp Tyr Trp Gly Gin Gly Thr 100 105 110

Leu Vai Thr Will Be Ser 115 &lt; 210 &gt; 73 &lt; 211 &gt; 333 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt;

&lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (333) &lt; 223 &gt; Derived from MOR03075; Antibody-Region-VL; M0R03246 &lt; 400 &gt; 73 gat ate gtg ctg acc cag ccg cct tea gtg agt ggc geca cca ggt cag 48

Asp Ile Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 15 10 15 cgt gtg acc ate teg tgt age ggc age age age aac att ggt tet aat 96 118 ΗΒΒΒ! ΜΒΒΒ ||| ΒΒΒΒΒΒΒΒΒΗΜΜΜΙ11111 «» Ι «ΙΙΙΙΙΒΐηΐΙΙΙ1111Ι111Ί1ΊΏ

Arg Will Thr 11 and Ser Cys Ser Gly Ser Ser Ser Asn 11 and Gly Ser Asn 20 25 30 ac t gtg cgt tgg t ac cag cag ttg ccc ggg acg gcg ccg aaa c 11 ctg 144 Thr V a Arg Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 to 11 tattct aat aag cgt ccc tc a ggc gtg ccg gat cgt ttt age 192 11 and Tyr Ser Asn Asn Lys Arg Pro Ser Gly Pro Pro Asp Arg Phe Ser 50 55 60 gga tc c aaa age ggc acc age gcg age c 11 gcg a 11 acg ggc ctg caa 240 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala 11 and Thr Gly Leu Gin 65 70 75 80 age gaa gac gaa gc gat tattat tgc cag tct tgg gat cct cgt tct 288 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ser Trp Asp Pro Arg Ser 85 90 95 ttt ac tgtg ttt ggc ggc ggc acg aag 11 a gt cg 11 ggc cag 313 Phe Thr Go Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin 100 105 110 &lt; 210 &gt; 74 &lt; 211 &gt; 111 &gt; 2: 12 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 74

Asp 11 and Vai Leu Thr Gin Pro Pro Will Be Gly Ala Pro Gly Gin 1 5 10 15 Arg Will Thr 11 and Ser Cys Ser Gly Ser Ser Ser Asn 11 and Gly Ser Asn 11

Thr Vai Arg Trp Tyr Gin Gin Leu 35 40

Ile Tyr Ser Asn Asn Lys Arg Pro 50 55

Gly Ser Lys Ser Gly Thr Ser Ala 65 70

Ser Glu Asp Glu Ala Asp Tyr Tyr 85

Phe Thr Go Phe Gly Gly Gly Thr 100

Pro Gly Thr Ala Pro Lys Leu Leu 45

Ser Gly Go Pro Asp Arg Phe Ser 60

Ser Leu Ala Ile Thr Gly Leu Gin 75 80

Cys Gin Ser Trp Asp Pro Arg Ser 90 95

Lys Leu Thr Go Leu Gly Gin 105 110 &lt; 210 &gt; 75 &lt; 211 &gt; 348 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; zn &gt; CDS &lt; 222 &gt; (1) .. (348) &lt; 223 &gt; Derived from MOR03062; Antibody-Region-VH; M0R03251 &lt; 400 &gt; 75 cag gtg caa ttg gtg gaa age ggc ggc ggc ctg gtg caa ccg ggc ggc 48

Gin Go Go Gin Go Glu Be Gly Gly Gly Leu Go Gin Pro Gly Gly 15 10 15 age ctg cgt ctg age tgc gcg gee tcc gga ttt acc ttt tet tat 96

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Glycine Gly Met His Trp Arg Arg 35 age gtt att tet aat atg Ser Ile Ile Ser Asn Met 50 aag ggt cgt ttt acc att Lys Gly Arg Phe Thr Ile 65 70 g g cct g g g a g gt G A Gly Lys Gly 40 tet tat act att tat tat Ser Tyr Thr Ile Tyr Tyr 55 60 cgt gat aat te g aaa Ser Arg Asp Asn Ser Lys 75 etc. gag tgg gtg 144

Leu Glu Trp Go 45 gct gat tet gtt 192

Wing Asp Ser Go to ac acc ctg tat 240

Asn Thr Leu Tyr 80 ctg caa atg aac age ctg cgt gcg gaa gat acg gee gtg tat tat tgc 288

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Tyr Tyr Cys 85 90 95 gcg cgt aat aag gtt gt gt gt gtt tg ggc caa ggc acc ctg gtg 336

Ala Arg Asn Lys Go Gly Phe Asp Go Trp Gly Gin Gly Thr Leu Go 100 105 110 acg gtt age tea 141

Thr Will Be Ser 115 &lt; 210 &gt; 76 &lt; 211 &gt; 116 &lt; 2L2 &gt; PRT &lt; 213 &gt; human &lt; 4m &gt; 76

Gin Go Gin Gin Go Glu Be Gly Gly Gly Leu Go Gin Pro Gly Gly 15 5 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Gly Met His Trp Go Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Go 35 40 45

Ser Ile Ile Ser Asn Met Ser Tyr Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95

Ala Arg Asn Lys Go Gly Phe Asp Go Trp Gly Gin Gly Thr Leu Vai, 100 105 110

Thr Will Be Ser 115 &lt; 210 &gt; 77 &lt; 211 &gt; 339 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (339) &lt; 223 &gt; Derived from MOR03062; Antibody-Region-VL; M0R03251 &lt; 400 &gt; 77 gat ate gea ctg acc cag cca gct tea gtg age ggc tea cca ggt cag 48

Asp Ile Ala Leu Thr Gin Pro Ala Will Be Gly Ser Pro Gly Gin 1 5 10 15 age att acc tgt acg ggt act age age gat ggt ggt gt gt tat 96 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Gly Gly Gly Tyr 20 25 30 aat act gtg tet tgg tac cag cag cat ccc ggg aag gcg ccg aaa ctt 144 Asn Thr Will Be Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45 atg att tat tat gtt cat aag cgt ccc tea ggc gtg age aac cgt ttt 192 Met Ile Tyr Tyr Will His Lys Arg Pro Be Gly Will Be Asn Arg Phe 50 55 60 age gga tcc aaa age ggc aac acc gcg age ctg acc att age ggc ctg 240 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 caa gcg gaa gac gaa gc gat tat tat tgc cag tet tgg gat ctt tet 288 Gin Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ser Trp Asp Leu Ser 85 90 95 gtt cat cag gtt gtt gtt ggc ggc ggc acg aag tta gtt ctt ggc 336 Go Your Gin Will Go Phe Gly Gly Gly Thr Lys Leu Thr Go Leu Gly 100 105 110 cag

Gin

&lt; 210 &gt; 78 &lt; 211 &gt; &Lt; 21 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 78

Asp Ile Ala Leu Thr Gin Pro Ala 15

Ser Ile Thr Ile Ser Cys Thr Gly 20

Asn Thr Will Be Trp Tyr Gin Gin 35 40

Met Ile Tyr Tyr Go His Lys Arg 50 55

Ser Gly Ser Lys Ser Gly Asn Thr 65 70

Gin Ala Glu Asp Glu Ala Asp Tyr 85

Go His Gin Goes Phe Gly Gly 100

Being Gly Ser Pro Gly Gin 10 15

Thr Ser Ser Asp Gly Gly Gly Tyr 25 30

His Pro Gly Lys Ala Pro Lys Leu 45

Pro Ser Gly Will Be Asn Arg Phe 60

Ala Ser Leu Thr Ile Ser Gly Leu 75 80

Tyr Cys Gin Ser Trp Asp Leu Ser 90 95

Gly Thr Lys Leu Thr Go Leu Gly 105 110

Gin

&lt; 210 &gt; 79 &lt; 211 &gt; 348 &lt; 213 &gt; human &lt; 22 &gt;

&lt; 221 * CDS &lt; 222 &gt; (1) .. (348) &lt; 4 Ο Ο &gt; 79 cg gtg caa ttg Gin Vai Gin Leu 1 age ctg cgt ctg Ser Leu Arg Leu 20 ggt atg cat tgg Gly Met His Trp 35 age gtt att tet Ser Val Ile Ser 50 aag ggt ct ttt Lys Gly Arg Phe 65 ctg caa atg aac Leu Gin Met Asn gcg cgt aat aag Ala Arg Asn Lys 100: 10-¾ Osi; Gtg gaa age ggc ggc Val Glu Gly Gly 5 age tgc gcg gt tgc Ser Cys Ala Ala Ser 25 gtg cae gee cct Val Arg Gin Proa 40 aat tat tet tgg cat Asn Tyr Ser Trp His 55 acc att gt gat Thr Ile Ser Arg Asp 70 age ctg cgt gcg Gaa Ser Leu Arg Ala Glu 85 gt gt gt gt gt Gt Gt Phe Asp Val 105 ggc gtg caa Gly Leu val Gt 10 gga ttt acc ttt Gly Phe Thr Phe ggg aag ggt etc. Gly Lys Gly Leu 45 att tat tat gct Ile Tyr Tyr Ala 60 aat teg aaa aac Asn Ser Lys Asn 75 gat ac g gt g Asp Thr Ala Val 90 tgg ggc caa ggc Trp Gly Gin Gly ccg ggc ggc 48 Pro Gly Gly 15 tet tet tat 96 Ser Ser Tyr 30 gag tgg gtg 144 Glu Trp Val gat tet gtt 192 Asp Ser Val acc ctg tat 240 Thr Leu Tyr 80 tat tat tgc 288 Tyr Tyr Cys 95 acc ctg gtg 336 Thr Leu Val 110 acg gtt age tea Thr Will Be Ser 115

&lt; 211 &gt; 116 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 80

Gin Go Go Gin Go Go Glu Be Gly Go Gly Go Go Go Gin Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Gly Met His Trp Go Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Go 35 40 45

Ser Ile Ile Ser Asn Tyr Ser Trp His Ile Tyr Tyr Ala Asp Ser Go 50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95

Ala Arg Asn Lys Go Gly Phe Asp Go Trp Gly Gin Gly Thr Leu Go 100 105 110

Thr Will Be Ser 115 &lt; 210 &gt; 81 &lt; 211 &gt; 348 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 2 &gt; 2 &gt;

&lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (348) &lt; 223 &gt;Antibody-Region-VH; M0R03253

&lt; 10δ &gt; SI Gin gtg caa ttg gtg gaa age ggc ggc ggc ctg gtg caa ccg ggc ggc 48 Gin Vai Gin Leu Vai £ ·. Glu Ser Gly Gly Gly: Leu Val Gin Pro Gly X; Γ 'Gly age cgt ctg age tgc gcg gee tcc gga ttt acc ttt tet tet tat 96 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 ggt atg cat tgg gtg ca gee cct ggg aag ggt ctc gag tgg gtg 144 Gly Met His Trp Go Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 age gtt att tet aat atg gt ttt gat att tat tat gct gat tet gtt 192 Be Ile Ile Be Asn Met Gly Phe Glu Ile Tyr Tyr Ala Asp Ser Val 50 55 60 aag ggt cgt ttt acc att tea cgt gat aat teg aaa aac acc ctg tat 240 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 ctg caa atg aac age ctg cgt gcg gaa gat acg gee gtg tat tat tgc 288 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 gcg cgt aat aag gtt gt gt gt gtt tgg ggc caa ggc acc ctg gtg 336 Ala Arg Asn Lys Go Gly Phe Asp val Trp Gly Gin Gly Thr Leu val 100 105 110 acg gtt age tea Thr Will Be Ser < 210 &gt; 82 &lt; 211 &gt; € 116 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 82

Gin Go Go Gin Go Go Glu Be Gly Go Gly Go Go Go Gin Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Gly Met His Trp Go Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Go 35 40 45

Ser Ile Ile Ser Asn Met Gly Phe Glu Ile Tyr Tyr Ala Asp Ser Go 50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95

Ala Arg Asn Lys Go Gly Phe Asp Go Trp Gly Gin Gly Thr Leu Go 100 105 110

Thr Will Be Ser 115

&lt; 211 &gt; 348 &lt; 212 &gt; DNA &gt; human &lt; 2 &gt; 2 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (348) &lt; 223 &gt;Antibody-Region-VH; M0R03255 &lt; 400 &gt; 83 cag gtg caa ttg gtg gaa age ggc ggc ggc ctg gtc caa ccg ggc ggc 48 Gin Vai Gin Leu Go Glu Be Gly Gly Gly Leu Go Gin Pro Gly Gly 1 5 10 15 age ctg cgt ctg age tgc gcg gee tcc gga ttt acc ttt tet tet tat 96 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 ggt atg cat tgg gtg ege caa gee cct ggg aag ggt gag tgg gtg 144 Gly Met His Trp Go Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Vai 35 40 45 age gtt att tet aat cgt tet tet tat att tat tat gct gat tet gtt 192 Ser Val Ile Ser Asn Arg Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 aag ggt cgt ttt acc att tea cgt gat aat teg aaa aac acc ctg tat 240 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 ctg caa atg aac age ctg cgt gcg gaa gat acg gee gtg tat tat tgc 288 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 336 gcg cgt aat aag gtt gttt ttt gat gtt tgg ggc caa ggc acc ctg g tg

Ala Arg Asn Lys Go Gly Phe Asp Go Trp Gly Gin Gly Thr Leu Go 100 105 110 acg gtt age tea Thr Go Ser Ser 115 &lt; 210 &gt; 84 &lt; 211 &gt; 116 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 84

Gin Go Go Gin Go Go Glu Be Gly Go Gly Go Go Go Gin Gly Gly 1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Gly Met His Trp Go Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Go 35 40 45

Ser Ile Ile Ser Arg Arg Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Go 50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95

Ala Arg Asn Lys Go Gly Phe Asp Go Trp Gly Gin Gly Thr Leu Go 100 105 110

Thr Will Be Ser 115 &lt; 210 &gt; 85 &lt; 211 &gt; 348 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (348) &lt; 223 &gt;Antibody-Region-VH; M0R03257 &lt; 400 &gt; 85 cag gtg caa ttg gtg gaa age ggc ggc ggc ctg gtc caa ccg ggc ggc 48 Gin Vai Gin Leu Go Glu Be Gly Gly Gly Leu Go Gin Pro Gly Gly 1 5 10 15 age ctg cgt ctg age tgc gcg gee tcc gga ttt acc ttt tet tet tat 96 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 ggt atg cat tgg gtg ege caa gee cct ggg aag ggt gag tgg gtg 144 Gly Met His Trp Go Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Vai 35 40 45 age gtt att tet aat cgt ggt aat tat att tat tat gct gat tet gtt 192 Ser Vai Ile Ser Asn Arg Gly Asn Tyr Ile Tyr Tyr Ala Asp Ser Vai 50 55 6 0 aag ggt cgt ttt acc att tea cgt gat aat teg aaa aac acc ctg tat 240 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 ctg caa atg aac age ctg cgt gcg gaa gat acg gee gtg tat tat tgc 288

13X

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Tyr Tyr Cys 85 90 95 gcg cgt aat aag gtt gt gt gt gtt tg ggc caa ggc acc ctg gtg 336

Ala Arg Asn Lys Go Gly Phe Asp Go Trp Gly Gin Gly Thr Leu Go

100 105 HO acg gtt age tea

Thr Will Be Ser &lt; 210 &gt; 86 &lt; 211 &gt; 116 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 4 0 0 &gt; 86

Gin Go Go Gin Go Go Glu Be Gly Go Gly Go Go Go Gin Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Gly Met His Trp Go Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Go 35 40 45

Ser Ile Ile Ser Asn Arg Gly Asn Tyr Ile Tyr Tyr Ala Asp Ser Go 50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95

Ala Arg Asn LyS Go Gly Phe Asp Go Trp Gly Gin Gly Thr Leu Go 100 105 110

Thr Will Be Ser 115 &lt; 210 &gt; 87 &lt; 211 &gt; 348 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt; &lt; 221 &gt; CDS &lt; 222 &gt; (1) .. (348) &lt; 223 &gt; Derived from MOR03075; Antibody-Region-VH; M0R03258 &lt; 400 &gt; 87 cag gtg caa ttg gtg gaa age ggc ggc ggc ctg gtc caa ccg ggc ggc 48 Gin Vai Gin Leu Go Glu Be Gly Gly Gly Leu Go Gin Pro Gly Gly 1 5 10 15 age ctg cgt ctg age tgc gcg gee tcc gga ttt acc ttt tet tet tat 96 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 ggt atg cat tgg gtg ege caa gee cct ggg aag ggt gag tgg gtg 144 Gly Met His Trp Go Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Vai 35 40 45 age gtt att tet aat cag tet aat tat att tat tat gct gat tet gtt 192 Be Ile Ile Be Asn Gin Be Asn Tyr Ile Tyr Tyr Ala Asp Be Go 50 55 60 aag ggt cgt ttt acc att tea cgt gat aat teg aaa aac acc ctg tat 240

Lys Gly Arg Phe Thr Ile Ser Arg 65 70 ctg caa atg aac age ctg cgt gcg Leu Gin Met Asn Ser Leu Arg Ala 85 gcg cgt aat aag gtt gt ttt gat Ala Arg Asn Lys Go Gly Phe Asp 100 g gtt age tea Thr Go Ser Ser 115 &lt; 210 &gt; 85 <211> 116 PRT?: 'J1: human &lt; 400 &gt; 85 3 Gin Go Leu Gin Go Glu Ser Gly 1 5 Ser Leu Arg Leu Ser Cys Ala Ala 20 Gly Met His Trp Go Arg Arg Ala 35 40 Ser Vai Ile Ser Asn Gin Ser Asn 50 55 Lys Gly Arg Phe Thr Ile Ser Arg 65 70 80

Asn Ser Lys Asn Thr Leu Tyr 75 80 gat acg gcc gtg tat tat tgc 288

Asp Thr Ala Ty Tyr Ty Cys 90 95 tgg ggc caa ggc acc ctg gtg 336

Trp Gly Gin Gly Thr Leu Vai 110

Gly Leu Go Gin Pro Gly Gly 10 15

Gly Phe Thr Phe Ser Ser Tyr 30

Gly Lys Gly Leu Glu Trp Go 45

Ile Tyr Tyr Ala Asp Ser Vai 60

Asn Ser Lys Asn Thr Leu Tyr 75

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Go Tyr Tyr Cys 85 90 95

Ala Arg Asn Lys Go Gly Phe Asp Go Trp Gly Gin Gly Thr Leu Go 100 105 110

Thr Will Be Ser &lt; 210 &gt; 89 &lt; 211 &gt; 354 &lt; 212 &gt; DNA &lt; 213 &gt; human &lt; 220 &gt;

&lt; 221 &gt; CDS &lt; 222 &gt; (1) (354) <223> Derived from MOR03075; Antibody-Region-VL; MOR03258 cag gtg caa ttg gtt cag age ggc gcg gaa gtg aaa aaa ccg ggc gcg 48

Gin Go Leu Go Go Gin Be Gly Ala Glu Go Lys Lys Pro Gly Ala age gtg aaa gtg age tgc aaa gee tcc gga tat acc ttt act ggt ttt 96 Be Go Lys Go Be Cys Lys Ala Be Gly Tyr Thr Phe Thr Gly Phe 20 25 30 tat att aat tgg gtc ege caa gee cct ggg cag ggt gag tgg atg 144 Tyr He Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45 ggc tgg till aat ceg tat tct ggc aat Gly Trp Ile Asn Pro Tyr Ser Gly Asn 50 55 cg ggc cgg gtg acc atg acc cgt gat Gin Gly Arg Go Thr Met Thr Arg Asp 65 70 atg gaa ctg age age ctg cgt age gaa Met Glu Leu Ser Ser Leu Arg Ser Glu 85 gcg cgt tct cct gtt tat tat aag tat Ala Arg Ser Pro Go Tyr Tyr Lys Tyr 100 105 ctg gtg acg gtt age tc a Leu Vai Thr Will Be 115 ttt 192 acg cgt cgt cgt gag cag aag Thr Arg Tyr Ala Gin Lys Phe 60 acc age att age acc gcg tat 240

Thr Ser Ile Ser Thr Ala Tyr 75 80 gat acg gee gtg tat tat tgc 288

Asp Thr Ala Vai Tyr Tyr Cys 90 95 gat tat tgg ggc caa ggc acc 336

Asp Tyr Trp Gly Gin Gly Thr 110 354 &lt; 21G &gt; 90 &lt; 211 &gt; 118 &lt; 212 &gt; PRT &lt; 213 &gt; human &lt; 400 &gt; 90

Gin Go Gin Gin Go Gin Go Gly Go Go Lys Lys Pro Gly Ala 15 10 15

Ser Goes Lys Goes Ser Cys Lys Ser Ser Gly Tyr Thr Phe Thr Gly Phe 20 25 30

Tyr Ile Asn Trp Go Arg Arg Ala Pro Gly Gin Gly Leu Glu Trp Met 35 45 40

Gly Trp Ile Asn Pro Tyr Ser Gly Asn Thr Arg Tyr Ala Gin Lys Phe 50 55 60

Gin Gly Arg Will Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80

Met Glu Len Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Ser Pro Val Tyr Tyr Lys Tyr Asp Tyr Trp Gly Gin Gly Thr 100 105 110

Leu Vai Thr Will Be Ser 115

Lisbon, July 3, 2006

Claims (58)

A polypeptide, characterized by (i) binding specifically to the ED-B domain of fibronectin and (ii) inhibiting the interaction between the ED-B domain and its receptor, characterized in that it is selected from the antibodies or antibody fragments comprising: a) A useful VH region encoded by a nucleic acid sequence SEQ ID NO. 1 (MOR 02610), NO. of SEQ ID. 5 (MOR 02611), SEQ ID NO. 9 (MOR 02613), SEQ ID NO. 13 (MOR 02614), SEQ ID NO. 17 (MOR 02616), SEQ ID NO. 21 (MOR 02618), SEQ ID NO. 25 (MOR 02619), SEQ ID NO. 29 (MOR 02622), SEQ ID NO. 33 (MOR 02715), SEQ ID NO. 37 (MOR 02718), SEQ ID NO. 41 (MOR 02721), SEQ ID NO. 45 (MOR 02722) or at least one H-CDR1-, H-CDR-2 and / or H-CDR3-region of one of the abovementioned VH regions, or (ii) Derived from a VH region of (i) through a change in at least one H-CDR region and / or (b) a VL (i) region encoded by a nucleic acid sequence SEQ ID NO. 3 (MOR 02610), SEQ ID NO. 7 (MOR 02611), SEQ ID NO. 11 (MOR 02613), SEQ ID NO. 15 (MOR 02614), SEQ ID NO. 19 (MOR 02616), SEQ ID NO. 23 (MOR 02618), SEQ ID NO. 27 (MOR 02619), SEQ ID NO. 31 (MOR 02622), SEQ ID NO. 35 (MOR 02715), SEQ ID NO. 39 (MOR 02718), SEQ ID NO. 43 (MOR 02721), SEQ ID NO. 47 (MOR 02722) or at least one L-CDR 1, L-CDR 2 - and / or L-CDR 3 - region of one of the aforementioned VL regions or (ii) Derived from a VL region according to ( i) by a change in at least one L-CDR region. A polypeptide according to claim 1, characterized in that it has a VL region which is derived from a VL region according to (b) (i) by a change in the L-CDR3 region. A polypeptide according to claim 2, characterized in that it has a VL region which is derived from a VL region which is encoded by the nucleic acid sequence SEQ ID NO. 27 (MOR 02619) or SEQ ID NO. 35 (MOR 02715). A polypeptide according to one of claims 1 to 3, characterized in that it comprises (a) a VH (i) region encoded by the nucleic acid sequence SEQ ID NO. 25 (MOR 02619) or SEQ ID NO. 33 (MOR 02715) or at least one H-CDR 1, H-CDR-2 and / or H-CDR 3 region of one of the abovementioned VH regions, or (ii) Derived from a VH region according to (i) through a change in at least one H-CDR region, and / or (b) a VL region (i) encoded by the nucleic acid sequence SEQ ID NO. 49 (MOR 03055), SEQ ID NO. 51 (MOR 03066), SEQ ID NO. 53 (MOR03075), SEQ ID NO. 55 (MOR 03069), SEQ ID NO. 57 (MOR 03071), SEQ ID NO. 59 (MOR 03064), SEQ ID NO. (MOR 03062), or at least the L-CDR3 region of one of the aforementioned VL regions or (ii) Derived from a VL region according to (i) through a change in at least one L-CDR region. A polypeptide according to any one of claims 1 to 4, characterized in that it has a VH region which is derived from a VH region according to (a) (i), through a change in the H-CDR2 region. A polypeptide according to claim 5, characterized in that it has a V H region which is derived from the V H region, encoded by the nucleic acid sequence SEQ ID NO. 25 (MOR 02619) or SEQ ID NO. 33 (MOR 02715). A polypeptide according to any one of claims 1 to 6, characterized in that it comprises (a) a VH (i) region encoded by the nucleic acid sequence SEQ ID NO. 63 (MOR 03243), SEQ ID NO. 67 (MOR 03245), SEQ ID NO. 71 (MOR 03246), SEQ ID NO. 75 (MOR 03251), SEQ ID NO. 79 (MOR 03252), SEQ ID NO. 81 (MOR 03253), SEQ ID NO. 83 (MOR 03255), SEQ ID NO. 85 (MOR 03257), SEQ ID NO. 87 region (MOR 03258) or at least its H-CDR2 region, or (ii) Derived from a VH region according to (i) through a change in at least one H-CDR region and / or (c) A VL region (i) encoded through the nucleic acid sequence SEQ ID NO. 65 (MOR 03243), SEQ ID NO. 69 (MOR 03245), SEQ ID NO. 73 (MOR 03246), region SEQ ID NO. 77 (MOR 03251), SEQ ID NO. 89 (MOR 03258) or at least the L-CDR1-, L-CDR2- or L-CDR3-region of one of the abovementioned VL regions, or (ii) Derived from a VL region according to (i) ) by a change in at least one L-CDR region. A polypeptide according to one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 1 and the VL region which is encoded by SEQ ID NO. 3 (MOR 02610) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 5 and the VL region which is encoded by SEQ ID NO. 7 (MOR 02611) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 9 and the VL region which is encoded by SEQ ID NO. 11 (MOR 02613) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to any one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 13 and the VL region which is encoded by SEQ ID NO. 15 (MOR 02614) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to any one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 17 and the VL region which is encoded by SEQ ID NO. 19 (MOR 02616) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 21 and the VL region which is encoded by SEQ ID NO. 23 (MOR 02618) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to any one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 25 and the VL region which is encoded by SEQ ID NO. 27 (MOR 02619) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 29 and the VL region which is encoded by SEQ ID NO. 31 (MOR 02622) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 33 and the VL region which is encoded by SEQ ID NO. 35 (MOR 02715) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. Polypeptide according to one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 37 and the VL region which is encoded by SEQ ID NO. 39 (MOR 02718) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to any one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 41 and the VL region which is encoded by SEQ ID NO. 43 (MOR 02721) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. Polypeptide according to one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 45 and the VL region which is encoded by SEQ ID NO. 47 (MOR 02722) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to any one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 25 and the VL region which is encoded by SEQ ID NO. 49 (MOR 03055) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to any one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 25 and the VL region which is encoded by SEQ ID NO. 51 (MOR 03066) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to any one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 25 and the VL region which is encoded by SEQ ID NO. 53 (MOR 03075) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to any one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 25 and the VL region which is encoded by SEQ ID NO. 55 (MOR 03069) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to any one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 25 and the VL region which is encoded by SEQ ID NO. 57 (MOR 03071) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 33 and the VL region which is encoded by SEQ ID NO. 59 (MOR 03064) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to any one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 33 and the VL region which is encoded by SEQ ID NO. 61 (MOR 03062) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 63 and the VR region which is encoded by SEQ ID NO. 65 (MOR 03243) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. Polypeptide according to one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 67 and the VR region which is encoded by SEQ ID NO. 69 (MOR 03245) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. Polypeptide according to one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 71 and the VL region which is encoded by SEQ ID NO. 73 (MOR 03246) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to any one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 75 and the VL region which is encoded by SEQ ID NO. 77 (MOR 03251) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to any one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 79 and the VL region which is encoded by SEQ ID NO. 77 (MOR 03252) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to any one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 81 and the VL region which is encoded by SEQ ID NO. 77 (MOR 03253) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to any one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 83 and the VL region which is encoded by SEQ ID NO. 77 (MOR 03255) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 85 and the VL region which is encoded by SEQ ID NO. 77 (MOR 03257) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to any one of claims 1 to 6, characterized in that it comprises the VH region which is encoded by SEQ ID NO. 87 and the VL region which is encoded by SEQ ID NO. 89 (MOR 03258) or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region thereof. A polypeptide according to any one of claims 1 to 35, characterized in that it is in the form of a conjugate with a therapeutic active ingredient. The polypeptide of claim 36, wherein the therapeutic active ingredient is selected from radiotherapeutic and chemotherapeutic agents. A polypeptide according to any one of claims 1 to 35, characterized in that it is in the form of a fusion protein. A polypeptide according to claim 38, characterized in that it is a fusion protein with a cytokine or as a bispecific antibody. A polypeptide according to any one of claims 1 to 35, characterized in that it is in the form of a conjugate with a diagnostic marker group. Polypeptide according to claim 38, characterized in that it is selected from radioactive, NMR, coloring, enzymatic and fluorescent labeling groups. Pharmaceutical composition, characterized in that it comprises as active ingredient a polypeptide according to one of claims 1 to 39, as well as pharmaceutically acceptable carriers, adjuvants and / or diluents. The composition of claim 42, for use in the prevention or treatment of hyperproliferative diseases. A composition according to claim 42 or 43, characterized in that it is used in the prevention or treatment of cancer. Diagnostic composition, comprising as diagnostic reagent a polypeptide according to one of claims 1 to 35, 40 or 41. A composition according to claim 45, characterized in that it is used in the diagnosis of hyperproliferative diseases or a pre-disposition thereof. The composition of claim 45 or 46, for use in the diagnosis of cancer or a pre-disposition thereof. Composition according to one of Claims 42 to 47, characterized in that it is used for use in human medicine. A nucleic acid characterized by encoding a polypeptide according to one of claims 1 to 35 or 38 to 47. A nucleic acid according to claim 49, characterized in that it is in operative connection with an expression control sequence. A vector, characterized in that it contains a nucleic acid according to one of claims 49 to 50. A cell, characterized in that it is transformed with a nucleic acid according to one of claims 49 to 50 or a vector according to claim 51. A non-human organism which is transformed with a nucleic acid according to any one of claims 49 to 50 or a vector according to claim 51. A process for the production of a polypeptide according to any of claims 1 to 35, characterized in that a cell is cultured according to claim 52 or a non-human organism according to claim 53, the culture is grown under conditions in that an expression of the polypeptide is performed and the expressed polypeptide is obtained. Use of a polypeptide according to any one of claims 1 to 39 for the production of a pharmaceutical agent for the prevention or treatment of diseases associated with ED-B. The use according to claim 54 for the production of a pharmaceutical agent, for the purpose of preventing or treating cancer. Use of a polypeptide according to one of claims 1 to 35, 40 or 41 for the production of a detection reagent, characterized in that it is intended for the diagnosis of diseases associated with ED-B or a pre-disposition thereof . Use according to claim 57 for the production of a detection reagent characterized in that it is intended for the diagnosis of the cancer or a pre-disposition thereof. Lisbon, July 3, 2006